Fused thiophone derivatives and drugs containing the same as the active ingredient
The present invention relates to a fused thiophene derivative of the formula (I) (wherein all the symbols are defined as described in the specification) and an inhibitor of producing interleukin-6 and/or interleukin-12 comprising the said derivative as an active ingredient.
[0001] The present invention relates to fused thiophene derivatives and inhibitors of producing Interleukin-6 (abbreviated as IL-6 hereafter) and/or Interleukin-12 (abbreviated as IL-12 hereafter) containing fused thiophene derivatives as an active ingredient.
[0002] More particularly, the present invention relates to inhibitors of producing IL-6 and/or IL-12 comprising, as an active ingredient, fused thiophene derivatives of the formula (I) 2
[0003] (wherein all the symbols are as defined hereafter.) and non-toxic salts thereof, novel fused thiophene derivatives of the said formula (IA) or non-toxic salts thereof and methods for preparation thereof.
[0004] Moreover, the present invention relates to a method for preparation of a compound of the formula (XI) which is an intermediate for the compounds of the formula (I).
BACKGROUND[0005] Cytokine is a multifunctional factor which plays an important role in the host defence system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or by overresponse thereto.
[0006] IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts etc., and its various physiological effects are known e.g. induction of B cell differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells etc. But, an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations. In the experiment using an animal model in which IL-6 was forcibly expressed, various types of diseases could be observed and such results strongly suggest the existence of relationship between the abnormal production of IL-6 and the cause of certain diseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62, S60 (1992)).
[0007] IL-12 is a cytokine produced from macrophages and dendritic cells etc. and its effects are known; e.g. activation of natural killer (abbreviated as NK hereafter) cells, induction of Interferon-&ggr; (abbreviated as IFN-&ggr; hereafter) production from NK cells and T cells, and regulation of Th1 and Th2 balance etc. Helper T cells are classified into Th1 which stimulates cellular-mediated immunity and Th2 which assists humoral immunity. IL-12 functions to induce Th1 from helper T cell precursors. It is thought that succeedingly, IL-12 induces production of IFN-&ggr; from Th1 cells (which are further differentiated) and accelerates killer activity, so that IL-12 plays a role as a main cytokine causing inflammatory immune reaction which leads to organ disorders (Blood, 84, 4008 (1994)).
[0008] Therefore, inhibition of IL-6 and/or IL-12 production(s) is expected to improve various kinds of diseases such as inflammatory diseases as a representative The present invention is targeted for these cytokines and provides novel medicines through inhibiting the production thereof.
[0009] Clinical application of the compounds of the present invention involves those diseases which may be caused and be changed to worse by abnormal production of IL-6 and/or IL-12 or by overresponse to them. Inhibitors of producing IL-6 may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, gammopathy, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmune diseases (J. Immunol., 145, 4185 (1990), J. Exp. Med., 172: 1505 (1990), J. Clin. Invest., 87,739 (1991), J. Clin. Invest., 89 1681 (1992), EMBO J., 1, 1189 (1994), Hematol. Oncol. Clin. North Am., 11 159 (1997)). Inhibitors of producing IL-12 may be used for the prevention and/or treatment of various inflammatory diseases, diabetes mellitus, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, rheumatoid arthritis, infectious diseases, autoimmune diseases (J. Exp. Med., 181, 817 (1995), J. Exp. Med., 181, 381 (1995), J. Exp. Med., 182 128, (1995), Ann, NY Acad. Sci., 795, 371 (1996), Int. Immunol., 8, 569 (1996), Proc. Natl. Acad. Sci. USA, 92, 4823 (1996)).
[0010] Further, a compound of the formula (Xl) is an important intermediate of pharmaceutical agents and an efficient method for preparation thereof has been desired.
[0011] For example,
[0012] (1) In the specifications of U.S. Pat. No. 3,629,438 and U.S. Pat. No. 3,686,216, it is disclosed that a benzothiophene-1,1-dioxide derivative of the formula (X) 3
[0013] (wherein Xx is halogen, nitro, alkyl, alkoxy, haloalkyl, carboxy or sulfonylhalide,
[0014] Yx is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
[0015] Zx is alkyl, alkoxy, halogen, carboxy, haloalkyl or nitro,
[0016] aX is 0 or an integer of 2,
[0017] bX is an integer of 2,
[0018] cX is 0 or an integer of 1˜5 or
[0019] dX is 0 or an integer of 1˜4.)
[0020] has an anti-fungal and anti-vital activities.
[0021] (2) In the specification of FR1585930, a compound of the formula (Y) 4
[0022] (wherein R1Y is hydrogen, halogen or C1˜3 alkyl; R2Y and R3Y are hydrogen or C1˜3 alkyl) is described as an intermediate of diuretic agent, but there is no description about its biological activity.
[0023] (3) In the specification of SU591474, it is described that a compound of the formula (Z) 5
[0024] (wherein RZ, R1Z, R2Z and R3Z are hydrogen or methyl.) has an anti-spasm activity.
[0025] (4) In the specification of EP50326, it is described that a compound of the formula (U) 6
[0026] (wherein R1U and R2U are each hydrogen or C1˜6 alkyl, C3˜6 cycloalkyl or phenyl which may be substituted with 1-2 of halogen, hydroxy, C1˜6 alkyl or alkoxy, R3U is hydrogen or ZU, ZU is C1˜6 alkyl or CR4UR5UR6U, R4U and R5U are hydrogen or C1˜6 alkyl, R6U is COOH, CH2—OH, C1˜6 alkoxycarbonyl or hydroxyaminocarbonyl, XU is hydrogen, halogen or C1˜6 alkyl, nU is 1 or 2, mU is 0˜2) has a diuretic activity (In the explanation of groups, essential parts are extracted).
[0027] (5) In the specification of WO9527710, it is described that a compound of the formula (V) 7
[0028] (wherein R1V is t-butyl, R1V is hydrogen, lower alkyl or acyl, a broken line is arbitrary bond, R2V and R3V are hydrogen, alkyl which may be substituted or alkenyl which may be substituted, R4V does not represent anything when arbitrary bond exists and represents the same meaning as R1V when arbitrary bond does not exist and nV is 0˜2.) has an activity as antioxidant of low-density lipoprotein (LDL) (In the explanation of groups, essential parts are extracted).
[0029] (6) In the specification of Japanese Patent Application Kokai Hei 10-298180, it is described that a compound of the formula (W) 8
[0030] (wherein ZW is oxygen atom or sulfur atom; R1W, R2W, R3W and R4W are the same or different, are hydrogen etc.); EW and FW are the same or different, are nitrogen atom or CH which may be substituted with XW or YW; XW is straight or branched C1-6 alkyloxy, C3-8 cycloalkyloxy or straight or branched C1-3 alkyloxy substituted with C3˜8 cycloalkyl; Y is 9
[0031] (wherein GW is —CONH—, O(O)O—, —NHCO— or —OC(O)—; R5W is (a) straight or branched C1-6 alkyl, (b) C3-8 cycloalkyl, (c) C7-12 spiroalkyl, (d) C7-12 bicycloalkyl, (e) aryl, (f) aralkyl, (g) heteroarylalkyl, (h) non-aromatic heterocyclic ring which may be substituted with phenyl or (i) C3-8 cycloalkyl-C1˜3 alkyl. Each of them may be substituted with one or more of substituent selected from a group consisting of i) straight or branched C1-6 alkyl, ii) straight or branched C1-8 alkyloxy, iii) C1-3 haloalkyl, iv) halogen, v) C3-8 cycloalkyl, vi) carboxy, vii) alkyloxycarbonyl, viii) acyl, ix) formyl and x) nitro; nW is an integer of 1-3, pW is an integer of 1-3, (CH2)w and (CH2)pW may be substituted with a straight or branched C1-6 alkyl or C1-3 haloalkyl) has an antagonistic activity against dopamine receptor.
[0032] (7) In the specification of Japanese Patent Application Kokai Hei 10-513470, it is described that a compound of the formula (T) 10
[0033] [wherein R1T and R3T are independently hydrogen, —CH3, —C(O)—(C1˜6 alkyl), or —C(O)—ArT (ArT is phenyl which may optionally be substituted); R2T is selected from a group consisting of pyrrolidino, hexamethyleneimino and piperidino], a pharmaceutically acceptable salt thereof or a solvent additive has an activity of inhibiting the effect of IL-6.
[0034] (8) In the specification of Japanese Patent Application Kokai Hei 11-49765, it is described that a compound of the formula (S) 11
[0035] [wherein each R1S and R2S is hydrogen or hydrocarbon group which may contain substituent(s) or R1S and R2S taken together with the neighboring carbon atom represents 3- to 8-membered homo or heterocyclic ring which may contain substituent(s), R3S is hydrogen or lower alkyl which may contain subtstituent(s) or aromatic group which may contain substituent(s), R4S is (1) aromatic group which may contain substituent(s), (2) aliphatic hydrocarbon which contains aromatic group (this group is unsubstituted or substituted.) and which may contain additional substituent(s) or (3) acyl, XS and YS are each oxygen atom or sulfur atom which may be oxidized, is single bond or double bond, ring AS is benzene ring which contains a group of the formula —XSR4S (wherein each symbols represent the same meaning as defined hereinbefore) and which may contain additional substituent(s), with the proviso that when is single bond and both XS and YS are oxygen atom, then R45 is not acyl.] or a salt thereof have an excellent inhibitory effect of neurodegeneration.
[0036] (9) Further, the following compounds are known.
[0037] Compound (1): 3-(Thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156),
[0038] Compound (2): 6-Nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, catalog No. KM 08165),
[0039] Compound (3): 3-(Thiophen-2-yl)thio-2,3-dihydro-11-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138),
[0040] Compound (4): 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140),
[0041] Compound (5): 4,5-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-04-4),
[0042] Compound (6): 4,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-05-5),
[0043] Compound (7): 4,7-Dimethyl-11-dioxidebenzo[b]thiophene (CAS Registry No. 102036-06-6),
[0044] Compound (8): 5,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-07-7),
[0045] Compound (9): 5,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-08-8),
[0046] Compound (10) 6,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-09-9),
[0047] Compound (11) 4-Carboxymethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102539-83-3),
[0048] Compound (12): 6-(2,2-Bis(ethoxycarbonyl)ethenyl)amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 118675-43-7),
[0049] Compound (13): 4-Methylaminocarbonyloxy-1,1 -dioxidebenzo[b]thiophene (CAS Registry No. 13687-26-8),
[0050] Compound (14): 5-(2-(N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188110-86-3),
[0051] Compound (15): 5-(2-Hydroxyethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188111-49-1),
[0052] Compound (16): 5-Bromo-7-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-24-5),
[0053] Compound (17): 7-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-25-6),
[0054] Compound (18): 5-Bromo-6-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-26-7),
[0055] Compound (19): 5-Bromo-4-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-27-8),
[0056] Compound (20): 6-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-28-9),
[0057] Compound (21): 4-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-29-0),
[0058] Compound (22): 6-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-40-6),
[0059] Compound (23): 6-Acetyamino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-41-7),
[0060] Compound (24): 6-(4-Diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 33431-95-7),
[0061] Compound (25): 1,1-Dioxidethieno[2,3-b]pyridine (CAS Registry No. 37049-39-1),
[0062] Compound (26): 1,1-Dioxidethieno[3,2-b]pyridine (CAS Registry No. 37049-40-4),
[0063] Compound (27): 1,1-Dioxidethieno([2,3-c]pyridine (CAS Registry No. 37049-41-5),
[0064] Compound (28): 5-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 51956-01-5),
[0065] Compound (29): 5-(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene (GAS Registry No. 51956-06-0),
[0066] Compound (30): 4-(2-(1,1-Dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 57011-92-4),
[0067] Compound (31): 7-Methyl-1,1-dioxidethieno[2,3-c]pyridine (CAS Registry No. 76905-90-3),
[0068] Compound (32): 1,1-Dioxidebenzo[b]thiophene (CAS Registry No. 825-44-5),
[0069] Compound (33): 4-(4-Methoxyphenyl)-1,1 -dioxidethieno[3,2-c]pyridine (CAS Registry No. 97104-25-1).
[0070] (10) In addition, as to a method for preparation of a compound of the formula (XI), for example, the method of the following Reaction Scheme 2 is known.
[0071] These are described in detail in Nihonkagakuzasshi 1966, 87(2), 186-189, J. Org. Chem., 1953, Vol. 18, 1511 and J. Org. Chem. 1973, Vol. 38, 146. 12
[0072] In Reaction Scheme 2, Me is methyl, Ac is acetyl and NBS is N-bromosuccinimide.
[0073] The above method of Reaction Scheme 2 requires 5 or 6 steps in total and Ag2O, which is an expensive reagent, in oxidation reaction from the compound of the formula (XI-A-6) to the compound of the formula (XI).
[0074] Further, in the specification of Japanese Patent Application Kokai Hei 6-49058, the following Reaction Scheme 3 is disclosed as a method for preparation of the compound of the formula (XI). 13
[0075] In Reaction Scheme 3, Et is ethyl.
[0076] The above method of Reaction Scheme 3 requires 5 steps in total and the total yield is around 2˜3%.
[0077] In Tetrahedron Letters, 1996, Vol. 37, No. 19, 3243 and Tetrahedron Letters 1990, Vol.31, No.28, 4011, a reaction wherein ketone is converted into nitrile, followed by dehydrogenation to give aromatic ring is disclosed (Reaction Scheme 4). 14
[0078] In Reaction Scheme 4, TMS is trimethylsilyl, DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
[0079] This reaction is a method for preparation of aromatic nitrile of the formula (XI-C-2) which comprises that cyclic ketone of the formula (XI-C-1) is converted into cyanohydrin, followed by dehydration to give nitrile of the formula (XI-C-2), and then followed by dehydrogenation by an oxidizer.
DISCLOSURE OF THE INVENTION[0080] The present inventors have investigated to find new compounds possessing an inhibitory activity of producing IL-6 and/or IL-12, so that the present inventors have found that the purpose has been achieved by fused thiophene derivatives of the formula (I).
[0081] Fused heterocyclic compounds of the formula (I) of the present invention has not been known as inhibitors of producing IL-6 and/or IL-12 at all. Further, a fused thiophene derivative of the formula (IA) is a novel compound which is not known at all.
[0082] In addition, the present inventors have investigated to find an efficient method for preparation at a low cost, so that the present inventor have found a method of the following Reaction Scheme 5. 15
[0083] The old methods require 5-6 steps, whereas the method of the present invention diminishes to 3 steps in total, so it become possible to produce efficiently. In addition, it is also confirmed that in mass-production of it, the cost for the production is reduced, so that the present inventors have completed the present invention.
[0084] The present invention relates to
[0085] (1) an inhibitor of producing Interleukin-6 and/or Interleukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I) 16
[0086] [wherein is a single or double bond, Y is (i) 17
[0087] or
[0088] (ii) hydrogen
[0089] (with a proviso that when is a double bond, Y is hydrogen, and when is a single bond, Y is 18
[0090] m and n are each independently 0 or an integer of 1-2,
[0091] p is 0 or an integer of 1-4,
[0092] q is 0 or an integer of 1-5,
[0093] Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, 19
[0094] is
[0095] (i) benzene ring or
[0096] (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), 20
[0097] is
[0098] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0099] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, each R1 of (R1)p is independently,
[0100] (i) C1-8 alkyl,
[0101] (ii) C2-8 alkenyl,
[0102] (iii) C2-8 alkynyl,
[0103] (iv) nitro,
[0104] (v) cyano,
[0105] (vi) halogen,
[0106] (vii) Cyc1,
[0107] (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1or
[0108] (ix) —A1—A2—A3,
[0109] A1 is
[0110] (i) single bond,
[0111] (ii) C1-8 alkylene,
[0112] (iii) C2-8 alkenylene or
[0113] (iv) C2-8 alkynylene,
[0114] A2 is
[0115] (i) —O—,
[0116] (ii) —NR3—
[0117] (iii) —C(O)—,
[0118] (iv) —CH(OH)—,
[0119] (v) —C(O)NR4—,
[0120] (vi) —NR11C(O)—,
[0121] (vii) —C(O)O—,
[0122] (viii) —OC(O)—,
[0123] (ix) —SO2NR6—,
[0124] (x) —NR7SO2—,
[0125] (xi) —C(O)NR9O—,
[0126] (xii) —OC(O)NR10—,
[0127] (xiii) —NR11C(O)NR12—,
[0128] (xiv) —NR13C(O)O— or
[0129] (xv) —OC(O)O—
[0130] (wherein R3, R4, R5, R6 R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
[0131] A3 is
[0132] (i) hydrogen,
[0133] (ii) C1-8 alkyl,
[0134] (iii) C2-8 alkenyl,
[0135] (iv) C2-8 alkynyl,
[0136] (v) Cyc1 or
[0137] (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
[0138] (a) halogen,
[0139] (b) cyano,
[0140] (c) —P(O)(R15)2,
[0141] (d) —Si(R16)3,
[0142] (e) Cyc1,
[0143] (f) —C(O)R17,
[0144] (g) —OR18,
[0145] (h) —NR19R20,
[0146] (i) —SR21;
[0147] plural R15s are each independently, hydroxy or C1-8 alkoxy,
[0148] plural R16s are each independently C1-8 alkyl,
[0149] R17 is
[0150] (i) hydrogen,
[0151] (ii) C1-8 alkyl,
[0152] (iii) hydroxy,
[0153] (iv) C1-8 alkoxy,
[0154] (v) Cyc1 or
[0155] (vi) —NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
[0156] R18 is
[0157] (i) hydrogen,
[0158] (ii) C1 -8 alkyl,
[0159] (iii) C2-8 alkenyl,
[0160] (iv) Cyc1 or
[0161] (v) C1-8 alkyl substituted with Cyc′, Si(R26)3 (wherein plural R27 are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
[0162] R19 is
[0163] (i) hydrogen,
[0164] (ii) C1-8 alkyl,
[0165] (iii) phenyl or
[0166] (iv) C1-8 alkyl substituted with phenyl,
[0167] R20 is
[0168] (i) hydrogen,
[0169] (ii) C1-8 alkyl or
[0170] (iii) —C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
[0171] (iv) Cyc1 or
[0172] (v) C1-8 alkyl substituted with Cyc1 or cyano,
[0173] R21 is
[0174] (i) hydrogen,
[0175] (ii) C1-8 alkyl or
[0176] (iii) Cyc1,
[0177] Cyc1 is
[0178] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0179] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) —OR3, (xiv) —SR32, (xv) —NR33R34, (xvi) —SO2NR35 R36 (xvii) —C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or —C(O)—Cyc2,
[0180] R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
[0181] R33 is hydrogen or C1-8 alkyl,
[0182] R34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
[0183] R37 is hydrogen or C1-8 alkyl, R36 is hydrogen, C1-8 alkyl or Cyc2,
[0184] R37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)-Cyc2,
[0185] R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
[0186] Cyc2 is
[0187] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0188] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0189] the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) —OR41, (xi) —SR42, (xii) —NR43R44, (xiii) —SO2NR45R46, (xiv) —C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
[0190] R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
[0191] R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
[0192] each R2 of (R2)q is independently,
[0193] (i) C1-8 alkyl,
[0194] (ii) C2-8 alkenyl,
[0195] (iii) C2-8 alkynyl,
[0196] (iv) —OR48
[0197] (v) —NR49R50,
[0198] (vi) —C(O)R51,
[0199] (vii) nitro,
[0200] (viii) cyano,
[0201] (ix) halogen or
[0202] (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR48, —NR49R50, —C(O)R51, halogen or Cyc3,
[0203] R48 is
[0204] (i) hydrogen,
[0205] (ii) C1-8 alkyl,
[0206] (iii) C2-8 alkenyl,
[0207] (iv) C2-8 alkynyl,
[0208] (v) Cyc3 or
[0209] (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR52, —NR53R54, —C(O)R55 or Cyc3,
[0210] R49 and R50 are each independently, hydrogen, C1-8 alkyl or —COR59,
[0211] R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR50R61,
[0212] R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
[0213] —R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3),
[0214] R55 is hydroxy, C1-8 alkoxy, or —NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3),
[0215] R59 is C1-8 alkyl or C1-8 alkoxy,
[0216] R60 and R61 are each independently, hydrogen or C1-8 alkyl,
[0217] Cyc3 is
[0218] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0219] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0220] the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) —NR62R63, (ix) —COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR62R63 or —COOR64,
[0221] R62 and R63 are each independently, hydrogen or C1-8 alkyl,
[0222] R64 is hydrogen or C1-8 alkyl,
[0223] with the proviso that when A2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—, then A3 is not hydrogen.],
[0224] an N-oxide derivative thereof or a non-toxic salt thereof,
[0225] (2) a fused thiophene derivative of the formula (IA) 21
[0226] [wherein is a single or double bond,
[0227] Y is (i) 22
[0228] or
[0229] (ii) hydrogen
[0230] (with a proviso that when is a double bond, Y is hydrogen, and when is a single bond, Y is 23
[0231] m and n are each independently 0 or an integer of 1-2,
[0232] p is 0 or an integer of 1-4,
[0233] q is 0 or an integer of 1-5,
[0234] Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, 24
[0235] is
[0236] (i) benzene ring or
[0237] (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), 25
[0238] is
[0239] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0240] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0241] each R1 of (R1)p is independently,
[0242] (i) C1-8 alkyl,
[0243] (ii) C2-8 alkenyl,
[0244] (iii) C2-8 alkynyl,
[0245] (iv) nitro,
[0246] (v) cyano,
[0247] (vi) halogen,
[0248] (vii) Cyc1,
[0249] (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or
[0250] (ix) —A1—A2—A3,
[0251] A1 is
[0252] (i) single bond,
[0253] (ii) C1-8 alkylene,
[0254] (iii) C2-8 alkenylene or
[0255] (iv) C2-8 alkynylene,
[0256] A 2 is
[0257] (i) —O—,
[0258] (ii) —NR3—
[0259] (iii) —C(O)—,
[0260] (iv) —CH(OH)—,
[0261] (v) —C(O)NR4—,
[0262] (vi) —NR5C(O)—,
[0263] (vii) —C(O)O—,
[0264] (viii) —OC(O)—,
[0265] (ix) —SO2NR6,
[0266] (x) —NR7SO2—,
[0267] (xi) —C(O)NR9O—,
[0268] (xii) —OC(O)NR10—,
[0269] (xiii) —NR11C(O)NR12—,
[0270] (xiv) —NR13C(O)O— or
[0271] (xv) —OC(O)O—
[0272] (wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
[0273] A3 is
[0274] (i) hydrogen,
[0275] (ii) C1-8 alkyl,
[0276] (iii) C2-8 alkenyl,
[0277] (iv) C2-8 alkynyl,
[0278] (v) Cyc1 or
[0279] (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
[0280] (a) halogen,
[0281] (b) cyano,
[0282] (c) —P(O)(R15)2,
[0283] (d) —Si(R16)3,
[0284] (e) Cyc1,
[0285] (f) —C(O)R17,
[0286] (g) —OR18,
[0287] (h) —NR19R20,
[0288] (i) —SR21;
[0289] plural R15s are each independently, hydroxy or C1-8 alkoxy,
[0290] plural R16s are each independently C1-8 alkyl,
[0291] R17 is
[0292] (i) hydrogen,
[0293] (ii) C1-8 alkyl,
[0294] (iii) hydroxy,
[0295] (iv) C1-8 alkoxy,
[0296] (v) Cyc1 or
[0297] (vi) —NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
[0298] R18 is
[0299] (i) hydrogen,
[0300] (ii) C1-8 alkyl,
[0301] (iii) C2-8 alkenyl,
[0302] (iv) Cyc1 or
[0303] (v) C1-8 alkyl substituted with Cyc1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
[0304] R19 is
[0305] (i) hydrogen,
[0306] (ii) C1-8 alkyl,
[0307] (iii) phenyl or
[0308] (iv) C1-8 alkyl substituted with phenyl,
[0309] R20 is
[0310] (i) hydrogen,
[0311] (ii) C1-8 alkyl or
[0312] (iii) —C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
[0313] (iv) Cyc1 or
[0314] (v) C1-8 alkyl substituted with Cyc1 or cyano,
[0315] R21 is
[0316] (i) hydrogen,
[0317] (ii) C1-8 alkyl or
[0318] (iii) Cyc1,
[0319] Cyc1 is
[0320] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0321] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0322] the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) —OR31, (xiv) —SR2, (xv) —NR33R34, (xvi) —SO2NR35R36, (xvii) —C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or —C(O)-Cyc2,
[0323] R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
[0324] R33 is hydrogen or C1-8 alkyl,
[0325] R34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
[0326] R36 is hydrogen or C1-8 alkyl,
[0327] R36 is hydrogen, C1-8 alkyl or Cyc2,
[0328] R37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)—Cyc2,
[0329] R36, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
[0330] Cyc2 is
[0331] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0332] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0333] the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) —OR41, (xi) —SR42, (xii) —NR43R44, (xiii) —SO2NR45R46, (xiv) —C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
[0334] R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl, R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
[0335] each R2 of (R2q is independently,
[0336] (i) C1-8 alkyl,
[0337] (ii) C2-8 alkenyl,
[0338] (iii) C2-8 alkynyl,
[0339] (iv) —OR48,
[0340] (v) —NR49R50,
[0341] (vi) —C(O)R51,
[0342] (vii) nitro,
[0343] (viii) cyano,
[0344] (ix) halogen or
[0345] (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR48, -NR49R50, —C(O)R51, halogen or Cyc3,
[0346] R48 is
[0347] (i) hydrogen,
[0348] (ii) C1-8 alkyl,
[0349] (iii) C2-8 alkenyl,
[0350] (iv) C2-8 alkynyl,
[0351] (v) Cyc3 or
[0352] (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR52, —
[0353] NR53R54, —C(O)R55 or Cyc3,
[0354] R49 and R51 are each independently, hydrogen, C1-8 alkyl or —COR59,
[0355] R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR6“R6,
[0356] R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
[0357] R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3),
[0358] R55 is hydroxy, C1-8 alkoxy, or —NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3),
[0359] R59 is C1-8 alkyl or C1-8 alkoxy,
[0360] R60 and R61 are each independently, hydrogen or C1-8 alkyl,
[0361] Cyc3 is
[0362] (i) C3-15 mono-, bi- or tricyclic carbo ring or
[0363] (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
[0364] the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) —NR62R63, (ix) —COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR62R63 or —COOR64,
[0365] R62 and R63 are each independently, hydrogen or C1-8 alkyl,
[0366] R64 is hydrogen or C1-8 alkyl,
[0367] with the proviso that when
[0368] (1) when A2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—,
[0369] then A3 is not hydrogen,
[0370] (2) when is a double bond and Y is hydrogen, then n is 1 or 2,
[0371] (3) when is a single bond, Y is 26
[0372] n is 2,
[0373] m is 0 or 2, p is O or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
[0374] (4) when is a single bond, Y is 27
[0375] n is 2,
[0376] m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, and q is an integer of 1-5, then R2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen,
[0377] (5) when is a double bond, Y is hydrogen, n is 2, p is 1 and ring A is benzene ring, then R1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
[0378] (6) when is a double bond, Y is hydrogen, n is 2, p is 2 and ring A is benzene ring and one R1 is phenylsulfonylamino, 2-methylphenyisulfonylamino, 3-methylphenylsulfonylamino or 4-methylphenylsulfonylamino, then the other R1 is not C1-8 alkyl,
[0379] (7) when is a double bond, Y is hydrogen, n is 2, p is 2-3, ring A is benzene ring, one R1 is hydroxy, C1-8 alkoxy, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl, then the other R1 is neither halogen nor C1-8 alkyl,
[0380] (8) when is a double bond, Y is hydrogen, n is 2, p is 3-4 and ring A is benzene ring, then two or three R1 are not t-butyl at the same time, and
[0381] (9) the following compounds (1)-(32) are excluded:
[0382] (1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
[0383] (2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
[0384] (3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[blthiophene,
[0385] (4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
[0386] (5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
[0387] (6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
[0388] (7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
[0389] (8) 5,7-dimethyl-1,1-dioxidebenzo[b[thiophene,
[0390] (9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
[0391] (10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
[0392] (11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-ioxidebenzo[b]thiophene,
[0393] (12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
[0394] (13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene,
[0395] (14) 5-(2-hydroxyethyl)-1,1-dioxidebenzo[b]thiophene,
[0396] (15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
[0397] (16) 7-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
[0398] (17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
[0399] (18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
[0400] (19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
[0401] (20) 4-bromo-5-methyl-1, -dioxidebenzo[b]thiophene,
[0402] (21) 6-amino-1,1-dioxidebenzo[b]thiophene,
[0403] (22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
[0404] (23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
[0405] (24) 1,1-dioxidethieno[2,3-b]pyridine,
[0406] (25) 1,1 -dioxidethieno[3,2-b]pyridine,
[0407] (26) 1,1-dioxidethieno[2,3-c]pyridine,
[0408] (27) 5-amino-1,1-dioxidebenzo[b]thiophene,
[0409] (28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
[0410] (29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene,
[0411] (30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
[0412] (31) 1,1-dioxidebenzo[b]thiophene or
[0413] (32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine.],
[0414] an N-oxide derivative thereof or a non-toxic salt thereof,
[0415] (3) a method for preparation of a fused thiophene derivative of the formula (IA), an N-oxide derivative thereof or a non-toxic salt thereof and
[0416] (4) a method for preparation of a compound of the formula (XI) 28
[0417] which is characterized by cyanization of a compound of the formula (XII) 29
[0418] to obtain a compound of the formula (XIII) 30
[0419] then by subjecting to dehydration of the said compound of the formula (XII) to obtain a compound of the formula (XIV) 31
[0420] and then by subjecting to hydrolysis of the said compound of the formula (XIV).
DETAILED EXPLANATION OF THE INVENTION[0421] Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene group include straight or branched ones. In addition, isomers on double bond, ring, fused ring (E—, Z—, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R—, S—, &agr;—, &bgr;-isomer, enantiomer, diastereomer), optically active isomers (D—, L—, d-, I-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
[0422] In the present invention, an N-oxide derivative of a compound of the formula (I) and (IA) means a compound wherein nitrogen atom(s) in a compound containing nitrogen atom(s) of the formula (I) and (IA) is (are) oxidized.
[0423] In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof.
[0424] C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomers thereof.
[0425] C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the isomers thereof.
[0426] C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof.
[0427] C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof.
[0428] C2-8 alkynylene means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof.
[0429] Halogen means chloride, bromide, fluoride and iodide.
[0430] C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers thereof.
[0431] Trihalomethyl means methyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
[0432] Trihalomethoxyl means methoxyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
[0433] C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
[0434] 6Membered monocyclic hetero aryl containing 1-2 nitrogen atom(s) includes, for example, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide ring etc.
[0435] C3-15 Mono-, bi- or tricyclic carbo ring includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopenten, cyclohexen, cyclopentadien, cyclohexadien, benzene, penthalene, indene, naphthalene, azulene, florene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene ring etc.
[0436] 4-18 Membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom or corresponding hetero ring in which ring is saturated partially or fully.
[0437] The said 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes, for example, pyrrole, pyrrole-N-oxide, imidazole, triazole, tetrazole, pyrazole, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, quinoline-N-oxide, isoquinoline, isoquinoline-N-oxide, phthalazine, naphthyridine, naphthyridine-N-monoxide, naphthyridine-N-dioxide, quinoxaline, quinoxaline-N-monoxide, quinoxaline-N-dioxide, quinazoline, quinazoline-N-monoxide, quinazoline-N-dioxide, cinnoline, benzoxazole, benzothiazole, benzoimidazole, carbazole, acridine ring etc.
[0438] The said 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom in which ring is saturated partially or fully includes, for example, pyrroline, pyrrolidine, pyrrolidine-N-oxide, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyridine-N-oxide, dihydropyrazine, dihydropyrazine-N-monoxide, dihydropyrazine-N-dioxide, dihydropyrimizine, dihydropyrimizine-N-monoxide, dihydropyrimizine-N-dioxide, dihydropyridazine, dihydropyridazine-N-monoxide, dihydropyridazine-N-dioxide, piperidine, piperidine-N-oxide, piperazine, piperazine-N-monoxide, piperazine-N-dioxide, tetrahydropyrimizine, tetrahydropyrimizine-N-monoxide, tetrahydropyrimizine-N-dioxide, tetrahydropyridazine, tetrahydropyridazine-N-monoxide, tetrahydropyridazine-N-dioxide, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydroxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, morpholine-N-oxide, thiomorpholine, thiomorpholine-N-oxide, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, dihydroquinoline-N-oxide, tetrahydroquinoline, tetrahydroquinoline-N-oxide, perhydroquinoline, perhydroquinoline-N-oxide, dihydroisoquinoline, dihydroisoquinoline-N-oxide, tetrahydroisoquinoline, tetrahydroisoquinoline-N-oxide, perhydroisoquinoline, perhydroisoquinoline-N-oxide, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, dihydronaphthyridine-N-monoxide, dihydronaphthyridine-N-dioxide, tetrahydronaphthyridine, tetrahydronaphthyridine-N-monoxi de, tetrahydronaphthyridine-N-dioxide, perhydronaphthyridine, perhydronaphthyridine-N-monoxide, perhydronaphthyridine-N-dioxide, dihydroquinoxaline, dihydroquinoxaline-N-monoxide, dihydroquinoxaline-N-dioxide, tetrahydroquinoxaline, tetrahydroquinoxaline-N-monoxide, tetrahydroquinoxaline-N-dioxide, perhydroquinoxaline, perhydroquinoxaline-N-monoxide, perhydroquinoxaline-N-dioxide, dihydroquinazoline, dihydroquinazoline-N-monoxide, dihydroquinazoline-N-dioxide, tetrahydroquinazoline, tetrahydroquinazoline-N-monoxide, tetrahydroquinazoline-N-dioxide, perhydroquinazoline, perhydroquinazoline-N-monoxide, perhydroquinazoline-N-dioxide, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, indroxoazepine, indrotetrahydroxazepine, indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine, indrotetrahydrothiazepine, indrothiadiazepine, indrotetrahydrothiadiazepine, indroazepine, indrotetrahydroazepine, indrodiazepine, indrotetrahydrodiazepine, benzofurazane, benzothiadiazole, benzotriazole, camphar, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, 1,3-dioxaindan, 1,4-dioxoindan ring etc.
[0439] In the present invention, m is, preferably, 0 or 2 and most preferably, 2.
[0440] n is, preferably, 0 or 2 and most preferably, 2.
[0441] p is, preferably, 1 or 2 and most preferably, 2.
[0442] q is, preferably, 0 or 1.
[0443] Z is, preferably, single bond or C1-8 alkylene, and most preferably, single bond. 32
[0444] is, preferably, pyridine or benzene ring, and most preferably, benzene ring. 33
[0445] is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, more preferably, benzene, cyclohexane, thiophene, furan, pyridine, pyrimizine, imidazole ring, and most preferably, benzene or thiophene ring.
[0446] R1 is, preferably, C1-8 alkyl, nitro, cyano, halogen, Cyc1 or C1-8 alkyl substituted with halogen or Cyc1, or A1—A2—A3, and most preferably, C1-8 alkyl substituted with Cyc1 or A1—A2—A3.
[0447] A1 is, preferably, single bond, C1-8 alkylene, C2-8 alkenylene, and most preferably, single bond or C1-8 alkylene.
[0448] A2 is, preferably, —O—, —NR3—, —C(O)—, —C(O)NR4—, —NR5C(O)—, —C(O)O—, —NR13C(O)O—, and most preferably, O—, —NR3—, —C(O)—, —C(O)NR4—, —NR5C(O)—.
[0449] A3 is, preferably, C1-8 alkyl, Cyc1, or C1-8 alkyl or C2-8 alkenyl substituted with Cyc1, —C(O)R 7, —NR19R20 or —OR18, and most preferably, C1-8 alkyl substituted with Cyc1 or NR19R20.
[0450] Cyc1 is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, and more preferably, C5-10 monocyclic carbo ring or 5-10 membered monocyclic hetero ring containing 1-2 nitrogen atom(s) and/or one oxygen atom, and most preferably, benzene, piperidine, piperazine, pyrrolidine, pyridine or morpholine ring.
[0451] R19, R20 is, preferably, hydrogen or C1-8 alkyl, and most preferably, methyl, ethyl, propyl or isopropyl.
[0452] [Salts]
[0453] In the present invention, non-toxic salts include all such salts, for example, ordinal salts, acid-addition salts and hydrate salts.
[0454] The compounds of the present invention of the formula (I) may be converted into the corresponding salts by known method. Non toxic and water-soluble salts are preferable. Suitable salts include the salts of alkalimetal (sodium, potassium etc.), alkaline-earth metal (calcium, magnesium etc.), ammonium salts, salts of organic amine which is pharmaceutically permitted (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenetylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-gulcamine etc.).
[0455] The compounds of the present invention of the formula (I) may be converted into the corresponding acid-addition salts by known method. Non toxic and water-soluble acid-addition are preferable. Suitable acid-addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfonic acid, phosphonic acid, nitric acid and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
[0456] The compounds of the present invention of the formula (I) or salts thereof may be converted into a corresponding hydrate by known methods.
[0457] In the compounds of the formula (I), preferred compounds are as follows: the compound of the formula (I-A) 34
[0458] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-B) 35
[0459] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-C) 36
[0460] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-D) 37
[0461] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-E) 38
[0462] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-F) 39
[0463] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-G) 40
[0464] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-H) 41
[0465] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-J) 42
[0466] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-K) 43
[0467] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-L) 44
[0468] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-M) 45
[0469] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-N) 46
[0470] (wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-O) 47
[0471] (wherein all the symbols are the same meanings as hereinbefore described.), or the compound of the formula (I-P) 48
[0472] (wherein all the symbols are the same meanings as hereinbefore described.).
[0473] In the compounds of the formula (I-A), the compound of the formula (I-A′) 49
[0474] (wherein, R1′ is C1-8 alkyl substituted with Cyc1, or 50
[0475] (wherein, A1′ is single bond or C1-8 alkylene, A2′ is —O—, —NR3—, —C(O)—, —C(O)NR4— or NR5C(O)— and the other symbols are the same meanings as hereinbefore described.) and the other symbols are the same meanings as hereinbefore described.) is most preferable.
[0476] In the compound of the formula (I-N), the compound of the formula (I-N′) 51
[0477] (wherein all the symbols are the same meanings as hereinbefore described.) is most preferable.
[0478] The following compounds (1)-(4) are known and marketed ones, but their activities as inhibitor of producing IL-6 and/or IL-12 have not been known at all. The compounds (1)-(4) and non-toxic salts thereof are also preferable ones used in the present invention.
[0479] For example,
[0480] Compound (1): 3-(thiophene-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156): 52
[0481] Compound (2): 6-nitro-3-(thiophene-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08165): 53
[0482] Compound (3): 3-(thiophene-2-yl)thio-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138): 54
[0483] Compound (4): 3-phenylsulfonyl-2,3-dihydro-11-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140): 55
[0484] More preferable compounds are the following known compounds and the compounds shown in the Tables 1 to 78 and described in Examples and non-toxic salts thereof.
[0485] In the following tables, 3-Py is pyridin-3-yl, Me is methyl, Et is ethyl, n-Pr is normalpropyl, i-Pr is isopropyl, t-Bu is t-butyl and the other symbols are the same meanings as hereinbefore described. 1 TABLE 1 (I-A) 56 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 1 7 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 1 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 1 4′ —O—(CH2)2-(3-Py) 12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 1 4′ —O—(CH2)2—N(CH3)2 16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 20 1 7 —O—(CH2)2-(3-Py) 2 3′, 5′ —O—(CH2)2-(3-Py)
[0486] 2 TABLE 2 (I-B) 57 No. p position R1 q position R2 1 1 5 —O—(CH2)2-(3-Py) 0 — — 2 1 6 —O—(CH2)2-(3-Py) 0 — — 3 1 7 —O—(CH2)2-(3-Py) 0 — — 4 2 6, 7 —O—(CH2)2-(3-Py) 0 — — 5 1 5 —O—(CH2)2—N(CH3)2 0 — — 6 1 6 —O—(CH2)2—N(CH3)2 0 — — 7 1 7 —O—(CH2)2—N(CH3)2 0 — — 8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 1 4′ —O—(CH2)2-(3-Py) 12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 1 4′ —O—(CH2)2—N(CH3)2 16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2 17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 6 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 7 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 20 2 6, 7 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
[0487] 3 TABLE 3 (I-C) 58 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 2 4, 5 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 1 4′ —O—(CH2)2-(3-Py) 12 0 — — 2 3′, 5′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 1 4′ —O—(CH2)2—N(CH3)2 16 0 — — 2 3′, 5′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 20 2 4, 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
[0488] 4 TABLE 4 (I-D) 59 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 1 7 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 1 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 3′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 3′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 1 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0489] 5 TABLE 5 (I-E) 60 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 1 7 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 1 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 1 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0490] 6 TABLE 6 (I-F) 61 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 1 7 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 1 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py) 12 0 — — 2 2′, 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2 16 0 — — 2 2′, 6′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 20 1 7 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py)
[0491] 7 TABLE 7 (I-G) 62 No. p position R1 q position R2 1 1 5 —O—(CH2)2-(3-Py) 0 — — 2 1 6 —O—(CH2)2-(3-Py) 0 — — 3 1 7 —O—(CH2)2-(3-Py) 0 — — 4 2 6, 7 —O—(CH2)2-(3-Py) 0 — — 5 1 5 —O—(CH2)2—N(CH3)2 0 — — 6 1 6 —O—(CH2)2—N(CH3)2 0 — — 7 1 7 —O—(CH2)2—N(CH3)2 0 — — 8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 3′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 3′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 18 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 7 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 2 6, 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0492] 8 TABLE 8 (I-H) 63 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 2 4, 5 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 3′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 3′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 2 4, 5 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0493] 9 TABLE 9 (I-J) 64 No. p position R1 q position R2 1 1 5 —O—(CH2)2-(3-Py) 0 — — 2 1 6 —O—(CH2)2-(3-Py) 0 — — 3 1 7 —O—(CH2)2-(3-Py) 0 — — 4 2 6, 7 —O—(CH2)2-(3-Py) 0 — — 5 1 5 —O—(CH2)2—N(CH3)2 0 — — 6 1 6 —O—(CH2)2—N(CH3)2 0 — — 7 1 7 —O—(CH2)2—N(CH3)2 0 — — 8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 6 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 7 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 2 6, 7 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0494] 10 TABLE 10 (I-K) 65 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 2 4, 5 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 4′ —O—(CH2)2-(3-Py) 11 0 — — 1 5′ —O—(CH2)2-(3-Py) 12 0 — — 1 6′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 4′ —O—(CH2)2—N(CH3)2 15 0 — — 1 5′ —O—(CH2)2—N(CH3)2 16 0 — — 1 6′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 4′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 1 5′ —O—(CH2)2-(3-Py) 20 2 4, 5 —O—(CH2)2-(3-Py) 1 6′ —O—(CH2)2-(3-Py)
[0495] 11 TABLE 11 (I-L) 66 No. p position R1 q position R2 1 1 5 —O—(CH2)2-(3-Py) 0 — — 2 1 6 —O—(CH2)2-(3-Py) 0 — — 3 1 7 —O—(CH2)2-(3-Py) 0 — — 4 2 6, 7 —O—(CH2)2-(3-Py) 0 — — 5 1 5 —O—(CH2)2—N(CH3)2 0 — — 6 1 6 —O—(CH2)2—N(CH3)2 0 — — 7 1 7 —O—(CH2)2—N(CH3)2 0 — — 8 2 6, 7 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 2 2′, 3′ —O—(CH2)2-(3-Py) 12 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 2 2′, 3′ —O—(CH2)2—N(CH3)2 16 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2 17 1 5 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 6 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 7 —O—(CH2)2-(3-Py) 2 2′, 3′ —O—(CH2)2-(3-Py) 20 2 6, 7 —O—(CH2)2-(3-Py) 2 2′, 5′ —O—(CH2)2-(3-Py)
[0496] 12 TABLE 12 (I-M) 67 No. p position R1 q position R2 1 1 4 —O—(CH2)2-(3-Py) 0 — — 2 1 5 —O—(CH2)2-(3-Py) 0 — — 3 1 6 —O—(CH2)2-(3-Py) 0 — — 4 2 4, 5 —O—(CH2)2-(3-Py) 0 — — 5 1 4 —O—(CH2)2—N(CH3)2 0 — — 6 1 5 —O—(CH2)2—N(CH3)2 0 — — 7 1 6 —O—(CH2)2—N(CH3)2 0 — — 8 2 4, 5 —O—(CH2)2—N(CH3)2 0 — — 9 0 — — 1 2′ —O—(CH2)2-(3-Py) 10 0 — — 1 3′ —O—(CH2)2-(3-Py) 11 0 — — 2 2′, 3′ —O—(CH2)2-(3-Py) 12 0 — — 2 2′, 5′ —O—(CH2)2-(3-Py) 13 0 — — 1 2′ —O—(CH2)2—N(CH3)2 14 0 — — 1 3′ —O—(CH2)2—N(CH3)2 15 0 — — 2 2′, 3′ —O—(CH2)2—N(CH3)2 16 0 — — 2 2′, 5′ —O—(CH2)2—N(CH3)2 17 1 4 —O—(CH2)2-(3-Py) 1 2′ —O—(CH2)2-(3-Py) 18 1 5 —O—(CH2)2-(3-Py) 1 3′ —O—(CH2)2-(3-Py) 19 1 6 —O—(CH2)2-(3-Py) 2 2′, 3′ —O—(CH2)2-(3-Py) 20 2 4, 5 —O—(CH2)2-(3-Py) 2 2′, 5′ —O—(CH2)2-(3-Py)
[0497] 13 TABLE 13 (I-A-1) 68 No. R1 No. R1 1 69 11 70 2 71 12 72 3 73 13 74 4 75 14 76 5 77 15 78 6 79 16 80 7 81 17 82 8 83 18 84 9 85 19 86 10 87 20 88
[0498] 14 TABLE 14 (I-A-2) 89 No. R1 No. R1 1 90 11 91 2 92 12 93 3 94 13 95 4 96 14 97 5 98 15 99 6 100 16 101 7 102 17 103 8 104 18 105 9 106 19 107 10 108 20 109
[0499] 15 TABLE 15 (I-A-3) 110 No. R1 No. R1 1 111 11 112 2 113 12 114 3 115 13 116 4 117 14 118 5 119 15 120 6 121 16 122 7 123 17 124 8 125 18 126 9 127 19 128 10 129 20 130
[0500] 16 TABLE 16 (I-A-4) 131 No. R1 No. R1 1 132 11 133 2 134 12 135 3 136 13 137 4 138 14 139 5 140 15 141 6 142 16 143 7 144 17 145 8 146 18 147 9 148 19 149 10 150 20 151
[0501] 17 TABLE 17 (I-B-1) 152 No. R1 No. R1 1 153 11 154 2 155 12 156 3 157 13 158 4 159 14 160 5 161 15 162 6 163 16 164 7 165 17 166 8 167 18 168 9 169 19 170 10 171 20 172
[0502] 18 TABLE 18 (I-B-2) 173 No. R1 No. R1 1 174 11 175 2 176 12 177 3 178 13 179 4 180 14 181 5 182 15 183 6 184 16 185 7 186 17 187 8 188 18 189 9 190 19 191 10 192 20 193
[0503] 19 TABLE 19 (I-B-3) 194 No. R1 No. R1 1 195 11 196 2 197 12 198 3 199 13 200 4 201 14 202 5 203 15 204 6 205 16 206 7 207 17 208 8 209 18 210 9 211 19 212 10 213 20 214
[0504] 20 TABLE 20 (I-C-1) 215 No. R1 No. R1 1 216 11 217 2 218 12 219 3 220 13 221 4 222 14 223 5 224 15 225 6 226 16 227 7 228 17 229 8 230 18 231 9 232 19 233 10 234 20 235
[0505] 21 TABLE 21 (I-C-2) 236 No. R1 1 237 2 238 3 239 4 240 5 241 6 242 7 243 8 244 9 245 10 246 11 247 12 248 13 249 14 250 15 251 16 252 17 253 18 254 19 255 20 256
[0506] 22 TABLE 22 (I-C-3) 257 No. R1 1 258 2 259 3 260 4 261 5 262 6 263 7 264 8 265 9 266 10 267 11 268 12 269 13 270 14 271 15 272 16 273 17 274 18 275 19 276 20 277
[0507] 23 TABLE 23 (I-D-1) 278 No. R1 1 279 2 280 3 281 4 282 5 283 6 284 7 285 8 286 9 287 10 288 11 289 12 290 13 291 14 292 15 293 16 294 17 295 18 296 19 297 20 298
[0508] 24 TABLE 24 (I-D-2) 299 No. R1 1 300 2 301 3 302 4 303 5 304 6 305 7 306 8 307 9 308 10 309 11 310 12 311 13 312 14 313 15 314 16 315 17 316 18 317 19 318 20 319
[0509] 25 TABLE 25 (I-D-3) 320 No. R1 1 321 2 322 3 323 4 324 5 325 6 326 7 327 8 328 9 329 10 330 11 331 12 332 13 333 14 334 15 335 16 336 17 337 18 338 19 339 20 340
[0510] 26 TABLE 26 (I-D-4) 341 No. R1 1 342 2 343 3 344 4 345 5 346 6 347 7 348 8 349 9 350 10 351 11 352 12 353 13 354 14 355 15 356 16 357 17 358 18 359 19 360 20 361
[0511] 27 TABLE 27 (I-E-1) 362 No. R1 1 363 2 364 3 365 4 366 5 367 6 368 7 369 8 370 9 371 10 372 11 373 12 374 13 375 14 376 15 377 16 378 17 379 18 380 19 381 20 382
[0512] 28 TABLE 28 (I-E-2) 383 No. R1 1 384 2 385 3 386 4 387 5 388 6 389 7 390 8 391 9 392 10 393 11 394 12 395 13 396 14 397 15 398 16 399 17 400 18 401 19 402 20 403
[0513] 29 TABLE 29 (I-E-3) 404 No. R1 1 405 2 406 3 407 4 408 5 409 6 410 7 411 8 412 9 413 10 414 11 415 12 416 13 417 14 418 15 419 16 420 17 421 18 422 19 423 20 424
[0514] 30 TABLE 30 (I-E-4) 425 No. R1 1 426 2 427 3 428 4 429 5 430 6 431 7 432 8 433 9 434 10 435 11 436 12 437 13 438 14 439 15 440 16 441 17 442 18 443 19 444 20 445
[0515] 31 TABLE 31 446 No. R1 1 447 2 448 3 449 4 450 5 451 6 452 7 453 8 454 9 455 10 456 11 457 12 458 13 459 14 460 15 461 16 462 17 463 18 464 19 465 20 466
[0516] 32 TABLE 32 467 No. R1 1 468 2 469 3 470 4 471 5 472 6 473 7 474 8 475 9 476 10 477 11 478 12 479 13 480 14 481 15 482 16 483 17 484 18 485 19 486 20 487
[0517] 33 TABLE 33 488 No. R1 1 489 2 490 3 491 4 492 5 493 6 494 7 495 8 496 9 497 10 498 11 499 12 500 13 501 14 502 15 503 16 504 17 505 18 506 19 507 20 508
[0518] 34 TABLE 34 509 No. R1 1 510 2 511 3 512 4 513 5 514 6 515 7 516 8 517 9 518 10 519 11 520 12 521 13 522 14 523 15 524 16 525 17 526 18 527 19 528 20 529
[0519] 35 TABLE 35 530 No. R1 1 531 2 532 3 533 4 534 5 535 6 536 7 537 8 538 9 539 10 540 11 541 12 542 13 543 14 544 15 545 16 546 17 547 18 548 19 549 20 550
[0520] 36 TABLE 36 551 No. R1 1 552 2 553 3 554 4 555 5 556 6 557 7 558 8 559 9 560 10 561 11 562 12 563 13 564 14 565 15 566 16 567 17 568 18 569 19 570 20 571
[0521] 37 TABLE 37 572 No. R1 1 573 2 574 3 575 4 576 5 577 6 578 7 579 8 580 9 581 10 582 11 583 12 584 13 585 14 586 15 587 16 588 17 589 18 590 19 591 20 592
[0522] 38 TABLE 38 593 No. R1 1 594 2 595 3 596 4 597 5 598 6 599 7 600 8 601 9 602 10 603 11 604 12 605 13 606 14 607 15 608 16 609 17 610 18 611 19 612 20 613
[0523] 39 TABLE 39 614 No. R1 1 615 2 616 3 617 4 618 5 619 6 620 7 621 8 622 9 623 10 624 11 625 12 626 13 627 14 628 15 629 16 630 17 631 18 632 19 633 20 634
[0524] 40 TABLE 40 635 No. R1 1 636 2 637 3 638 4 639 5 640 6 641 7 642 8 643 9 644 10 645 11 646 12 647 13 648 14 649 15 650 16 651 17 652 18 653 19 654 20 655
[0525] 41 TABLE 41 656 No. R1 1 657 2 658 3 659 4 660 5 661 6 662 7 663 8 664 9 665 10 666 11 667 12 668 13 669 14 670 15 671 16 672 17 673 18 674 19 675 20 676
[0526] 42 TABLE 42 677 No. R1 1 678 2 679 3 680 4 681 5 682 6 683 7 684 8 685 9 686 10 687 11 688 12 689 13 690 14 691 15 692 16 693 17 694 18 695 19 696 20 697
[0527] 43 TABLE 43 698 No. R1 1 699 2 700 3 701 4 702 5 703 6 704 7 705 8 706 9 707 10 708 11 709 12 710 13 711 14 712 15 713 16 714 17 715 18 716 19 717 20 718
[0528] 44 TABLE 44 719 No. R1 1 720 2 721 3 722 4 723 5 724 6 725 7 726 8 727 9 728 10 729 11 730 12 731 13 732 14 733 15 734 16 735 17 736 18 737 19 738 20 739
[0529] 45 TABLE 45 740 No. R1 1 741 2 742 3 743 4 744 5 745 6 746 7 747 8 748 9 749 10 750 11 751 12 752 13 753 14 754 15 755 16 756 17 757 18 758 19 759 20 760
[0530] 46 TABLE 46 761 No. R1 1 762 2 763 3 764 4 765 5 766 6 767 7 768 8 769 9 770 10 771 11 772 12 773 13 774 14 775 15 776 16 777 17 778 18 779 19 780 20 781
[0531] 47 TABLE 47 782 No. R1 1 783 2 784 3 785 4 786 5 787 6 788 7 789 8 790 9 791 10 792 11 793 12 794 13 795 14 796 15 797 16 798 17 799 18 800 19 801 20 802
[0532] 48 TABLE 48 803 No. R1 1 804 2 805 3 806 4 807 5 808 6 809 7 810 8 811 9 812 10 813 11 814 12 815 13 816 14 817 15 818 16 819 17 820 18 821 19 822 20 823
[0533] 49 TABLE 49 824 No. R1 1 825 2 826 3 827 4 828 5 829 6 830 7 831 8 832 9 833 10 834 11 835 12 836 13 837 14 838 15 839 16 840 17 841 18 842 19 843 20 844
[0534] 50 TABLE 50 845 No. R1 1 846 2 847 3 848 4 849 5 850 6 851 7 852 8 853 9 854 10 855 11 856 12 857 13 858 14 859 15 860 16 861 17 862 18 863 19 864 20 865
[0535] 51 TABLE 51 (I-M-2) 866 No. R1 No. R1 1 867 11 868 2 869 12 870 3 871 13 872 4 873 14 874 5 875 15 876 6 877 16 878 7 879 17 880 8 881 18 882 9 883 19 884 10 885 20 886
[0536] 52 TABLE 52 (I-M-3) 887 No. R1 No. R1 1 888 11 889 2 890 12 891 3 892 13 893 4 894 14 895 5 896 15 897 6 898 16 899 7 900 17 901 8 902 18 903 9 904 19 905 10 906 20 907
[0537] 53 TABLE 53 (I-N-1) 908 No. R1 No. R1 1 909 11 910 2 911 12 912 3 913 13 914 4 915 14 916 5 917 15 918 6 919 16 920 7 921 17 922 8 923 18 924 9 925 19 926 10 927 20 928
[0538] 54 TABLE 54 (I-N-2) 929 No. R1 No. R1 1 930 11 931 2 932 12 933 3 934 13 935 4 936 14 937 5 938 15 939 6 940 16 941 7 942 17 943 8 944 18 945 9 946 19 947 10 948 20 949
[0539] 55 TABLE 55 (I-N-3) 950 No. R1 No. R1 1 951 11 952 2 953 12 954 3 955 13 956 4 957 14 958 5 959 15 960 6 961 16 962 7 963 17 964 8 965 18 966 9 967 19 968 10 969 20 970
[0540] 56 TABLE 56 (I-N-4) 971 No. R1 No. R1 1 972 11 973 2 974 12 975 3 976 13 977 4 978 14 979 5 980 15 981 6 982 16 983 7 984 17 985 8 986 18 987 9 988 19 989 10 990 20 991
[0541] 57 TABLE 57 (I-O-1) 992 No. R1 No. R1 1 993 11 994 2 995 12 996 3 997 13 998 4 999 14 1000 5 1001 15 1002 6 1003 16 1004 7 1005 17 1006 8 1007 18 1008 9 1009 19 1010 10 1011 20 1012
[0542] 58 TABLE 58 (I-O-2) 1013 No. R1 No. R1 1 1014 11 1015 2 1016 12 1017 3 1018 13 1019 4 1020 14 1021 5 1022 15 1023 6 1024 16 1025 7 1026 17 1027 8 1028 18 1029 9 1030 19 1031 10 1032 20 1033
[0543] 59 TABLE 59 (I-O-3) 1034 No. R1 No. R1 1 1035 11 1036 2 1037 12 1038 3 1039 13 1040 4 1041 14 1042 5 1043 15 1044 6 1045 16 1046 7 1047 17 1048 8 1049 18 1050 9 1051 19 1052 10 1053 20 1054
[0544] 60 TABLE 60 (I-P-1) 1055 No. R1 No. R1 1 1056 11 1057 2 1058 12 1059 3 1060 13 1061 4 1062 14 1063 5 1064 15 1065 6 1066 16 1067 7 1068 17 1069 8 1070 18 1071 9 1072 19 1073 10 1074 20 1075
[0545] 61 TABLE 61 (I-P-2) 1076 No. R1 1 1077 2 1078 3 1079 4 1080 5 1081 6 1082 7 1083 8 1084 9 1085 10 1086 11 1087 12 1088 13 1089 14 1090 15 1091 16 1092 17 1093 18 1094 19 1095 20 1096
[0546] 62 TABLE 62 (I-P-3) 1097 No. R1 1 1098 2 1099 3 1100 4 1101 5 1102 6 1103 7 1104 8 1105 9 1106 10 1107 11 1108 12 1109 13 1110 14 1111 15 1112 16 1113 17 1114 18 1115 19 1116 20 1117
[0547] 63 TABLE 63 (I-A-1) 1118 No. R1 21 1119 22 1120 23 1121 24 1122 25 1123 26 1124 27 1125 28 1126 29 1127 30 1128 31 1129 32 1130 33 1131 34 1132 35 1133 36 1134 37 1135 38 1136 39 1137 40 1138 41 1139 42 1140 43 1141 44 1142
[0548] 64 TABLE 64 (I-A-1) 1143 No. R1 45 1144 46 1145 47 1146 48 1147 49 1148 50 1149 51 1150 52 1151 53 1152 54 1153 55 1154 56 1155 57 1156 58 1157 59 1158 60 1159 61 1160 62 1161 63 1162 64 1163 65 1164 66 1165 67 1166
[0549] 65 TABLE 65 (I-A-2) 1167 No. R1 21 1168 22 1169 23 1170 24 1171 25 1172 26 1173 27 1174 28 1175 29 1176 30 1177 31 1178 32 1179 33 1180 34 1181 35 1182 36 1183 37 1184 38 1185 39 1186 40 1187 41 1188 42 1189 43 1190 44 1191
[0550] 66 TABLE 66 (I-A-2) 1192 No. R1 45 1193 46 1194 47 1195 48 1196 49 1197 50 1198 51 1199 52 1200 53 1201 54 1202 55 1203 56 1204 57 1205 58 1206 59 1207 60 1208 61 1209 62 1210 63 1211 64 1212 65 1213 66 1214 67 1215
[0551] 67 TABLE 67 (I-A-3) 1216 No. R1 21 1217 22 1218 23 1219 24 1220 25 1221 26 1222 27 1223 28 1224 29 1225 30 1226 31 1227 32 1228 33 1229 34 1230 35 1231 36 1232 37 1233 38 1234 39 1235 40 1236 41 1237 42 1238 43 1239 44 1240
[0552] 68 TABLE 68 (I-A-3) 1241 No. R1 45 1242 46 1243 47 1244 48 1245 49 1246 50 1247 51 1248 52 1249 53 1250 54 1251 55 1252 56 1253 57 1254 58 1255 59 1256 60 1257 61 1258 62 1259 63 1260 64 1261 65 1262 66 1263 67 1264
[0553] 69 TABLE 69 (I-A-4) 1265 No. R1 21 1266 22 1267 23 1268 24 1269 25 1270 26 1271 27 1272 28 1273 29 1274 30 1275 31 1276 32 1277 33 1278 34 1279 35 1280 36 1281 37 1282 38 1283 39 1284 40 1285 41 1286 42 1287 43 1288 44 1289
[0554] 70 TABLE 70 (I-A-4) 1290 No. R1 45 1291 46 1292 47 1293 48 1294 49 1295 50 1296 51 1297 52 1298 53 1299 54 1300 55 1301 56 1302 57 1303 58 1304 59 1305 60 1306 61 1307 62 1308 63 1309 64 1310 65 1311 66 1312 67 1313
[0555] 71 TABLE 71 (I-N-1) 1314 No. R1 No. R1 21 1315 33 1316 22 1317 34 1318 23 1319 35 1320 24 1321 36 1322 25 1323 37 1324 26 1325 38 1326 27 1327 39 1328 28 1329 40 1330 29 1331 41 1332 30 1333 42 1334 31 1335 43 1336 32 1337 44 1338
[0556] 72 TABLE 72 (I-N-1) 1339 No. R1 No. R1 45 1340 57 1341 46 1342 58 1343 47 1344 59 1345 48 1346 60 1347 49 1348 61 1349 50 1350 62 1351 51 1352 63 1353 52 1354 64 1355 53 1356 65 1357 54 1358 66 1359 55 1360 67 1361 56 1362
[0557] 73 TABLE 73 (I-N-2) 1363 No. R1 No. R1 21 1364 33 1365 22 1366 34 1367 23 1368 35 1369 24 1370 36 1371 25 1372 37 1373 26 1374 38 1375 27 1376 39 1377 28 1378 40 1379 29 1380 41 1381 30 1382 42 1383 31 1384 43 1385 32 1386 44 1387
[0558] 74 TABLE 74 (I-N-2) 1388 No. R1 No. R1 45 1389 57 1390 46 1391 58 1392 47 1393 59 1394 48 1395 60 1396 49 1397 61 1398 50 1399 62 1400 51 1401 63 1402 52 1403 64 1404 53 1405 65 1406 54 1407 66 1408 55 1409 67 1410 56 1411
[0559] 75 TABLE 75 (I-N-3) 1412 No. R1 No. R1 21 1413 33 1414 22 1415 34 1416 23 1417 35 1418 24 1419 36 1420 25 1421 37 1422 26 1423 38 1424 27 1425 39 1426 28 1427 40 1428 29 1429 41 1430 30 1431 42 1432 31 1433 43 1434 32 1435 44 1436
[0560] 76 TABLE 76 (I-N-3) 1437 No. R1 No. R1 45 1438 57 1439 46 1440 58 1441 47 1442 59 1443 48 1444 60 1445 49 1446 61 1447 50 1448 62 1449 51 1450 63 1451 52 1452 64 1453 53 1454 65 1455 54 1456 66 1457 55 1458 67 1459 56 1460
[0561] 77 TABLE 77 (I-N-4) 1461 No. R1 No. R1 21 1462 33 1463 22 1464 34 1465 23 1466 35 1467 24 1468 36 1469 25 1470 37 1471 26 1472 38 1473 27 1474 39 1475 28 1476 40 1477 29 1478 41 1479 30 1480 42 1481 31 1482 43 1483 32 1484 44 1485
[0562] 78 TABLE 78 (I-N-4) 1486 No. R1 No. R1 45 1487 57 1488 46 1489 58 1490 47 1491 59 1492 48 1493 60 1494 49 1495 61 1496 50 1497 62 1498 51 1499 63 1500 52 1501 64 1502 53 1503 65 1504 54 1505 66 1506 55 1507 67 1508 56 1509
[0563] [Methods for Preparation of the Compounds of the Present Invention]
[0564] The compounds of the present invention of the formula (I) of the present invention may be prepared by the following methods or the methods described in examples.
[0565] Among the compounds of the present invention of the formula (I), the compounds of the present invention of the formula (I-1) 1510
[0566] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the known methods or the following methods [1]˜14].
[0567] [1] The compounds of the present invention of the formula (I-1) in which n is 1 or 2 may be also prepared by the following methods (a)˜(b).
[0568] (a) The compounds of the present invention of the formula (I-1) in which n is 1, i.e., the compounds of the present invention of the formula (I-1-1a) 1511
[0569] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the compounds of the formula (I-1-1c) 1512
[0570] (wherein all the symbols are the same meanings as hereinbefore described.)
[0571] The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an 1-1.2 equivalent amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at -40° C.˜0° C.
[0572] (b) The compounds of the present invention of the formula (I-1) in which n is 2, i.e., the compounds of the present invention of the formula (I-1-1b) 1513
[0573] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the said the compounds of the formula (I-1-1c).
[0574] The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an excess amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at 20° C.˜60° C.
[0575] [2] The compounds of the present invention of the formula (I-1) in which at least one of R1 (s) is a substituted oxy group or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-1-2) 1514
[0576] (wherein, R1-1-2 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2(s) is a substituted oxy group or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.)
[0577] may be also prepared by the following methods (a)˜(b).
[0578] (a) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (I-1 -2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2a) 1515
[0579] (wherein, R R1-1-2a is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
[0580] This etherification is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of hydroxide of an alkalimetal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0˜100° C.
[0581] (b) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (1-1 -2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2b) 1516
[0582] (wherein, R R1-1-2b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-2b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
[0583] This etherification is well known. For example, it may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene etc.) in the presence of azo compounds (diethyl azodicaroxylate, diisopropyl azodicaroxylate, 1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide) etc.) and phosphine compounds (triphenylphosphine , tributylphosphine , trimethylphosphine etc.), with the corresponding alcohol compounds at 0˜60° C.
[0584] [3] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-1-3) 1517
[0585] (wherein, R1-1-3 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.)
[0586] may be prepared by the following methods (a)˜(d).
[0587] (a) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R1(s) is halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-1-3a) 1518
[0588] (wherein, R R1-1-3 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
[0589] and the corresponding compounds containing amino.
[0590] This reaction is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran, acetonitrile etc.) in the presence or absence of base (triethylamine, pyridine etc.) at 0˜100° C.
[0591] (b) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3b) 1519
[0592] (wherein, R R1-1-3b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
[0593] This reaction may be carried out by the same procedure for the preparation of the said compounds of the formula (I-1-3a).
[0594] (c) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3c) 1520
[0595] (wherein, R R1-1-3c is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carbonyl.
[0596] This reductive amidation is well known. For example, it may be carried out in an organic solvent (methanol, ethanol, dimethylformamide, dimethylsulfoxide etc,) in the presence of reductant (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, Pd-C etc.) and in the presence of acid (acetic acid, hydrochlolride solution etc.), if necessary, at −20˜60° C.
[0597] (d) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R1(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-1-3d) 1521
[0598] (wherein, R R1-1-3d is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-3d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.)
[0599] with the corresponding compounds containing amino.
[0600] This reductive amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-3c).
[0601] [4] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-1-4) 1522
[0602] (wherein, R1-1-4 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0603] (a) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R1(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-4a) 1523
[0604] (wherein, R R1-1-4a is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
[0605] The amidation is well known. For example, it may be carried out
[0606] (1) by the method with using acid halide,
[0607] (2) by the method with using mixed acid anhydride,
[0608] (3) by the method with using conducing agent etc.
[0609] Concrete description of these methods are as follows:
[0610] (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from −20° C. to a refluxing temperature to give an acid halide. The obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C.
[0611] (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C.
[0612] (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40° C. (etc.)
[0613] Preferably, the above reactions (1), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition.
[0614] (b) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-4b) 1524
[0615] (wherein, R R1-1-4b is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-4b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.)with the corresponding compounds containing carboxy.
[0616] The above amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-4a).
[0617] [5] The compounds of the present invention of the formula (1-1) in which at least one of R1(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-1-5) 1525
[0618] (wherein, R1-1-5 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0619] (a) The compounds of the present invention of the formula (I-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-1-5a) 1526
[0620] (wherein, R1-1-5a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
[0621] Esterification is well known. For example, it may be carried out
[0622] (1) by the method with using acid halide,
[0623] (2) by the method with using mixed acid anhydride,
[0624] (3) by the method with using conducing agent etc.
[0625] Concrete description of the above methods are as follows:
[0626] (1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride -etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from −20° C. to a refluxing temperature to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40° C.
[0627] (2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40° C. to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0-40° C.
[0628] (3) method with using condensing agent may be carried out, for example; a carboxylic acid and an alcohol are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1′-carbonydimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40° C.
[0629] Preferably, the reactions (1), (2) and (3) described above are carried out under an atmosphere of inert gas (argon, nitrogen etc.) on anhydrous condition.
[0630] (b) The compounds of the present invention of the formula (1-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-5b) 1527
[0631] (wherein, R1-1-5b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carboxy.
[0632] The esterification may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-5a).
[0633] [6] The compounds of the present invention of the formula (1-1) in which at least one of R1(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-1-6) 1528
[0634] (wherein, R1-1-6 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6(s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0635] (a) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (I-1) in which at least one of R1(s) is a —SO3H or a group containing —SO2H, i.e., the compounds of the formula (II) 1529
[0636] (wherein, R1-1-6a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6a(s) is a —SO3H or a group containing —SO3H and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
[0637] The sulfonamidation is well known. For example, it may be carried out by reacting sulfonic acid with acid halide (oxazolyl chloride, thionyl chloride etc.) in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) or without solvent, at −20° C. refluxing temperature to obtain sulfonylhalide and then by reacting the obtained sulfonylhalide with an amine in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0˜40° C.
[0638] (b) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (1-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-6b) 1530
[0639] (wherein, R1-1-6b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing sulfo.
[0640] The sulfonamidation may be carried out the same procedure for preparation of the said compounds of the formula (I-1-6a).
[0641] [7] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-7) 1531
[0642] (wherein, R R1-1-7 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-7(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-7a) 1532
[0643] (wherein, R1-1-7a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-7a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
[0644] This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (1,8-diazabicyclo[5.4.0]undec-7-en (DBU), triethylamine, sodium hydride etc.) at 0˜100° C.
[0645] [8] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-8) 1533
[0646] (wherein, R1-1-8 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-8(s) is a substituted aminocarbonyl or a group containing a substituted aminocarbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-8a) 1534
[0647] (wherein, R R1-1-8 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-8a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
[0648] This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-7).
[0649] [9] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-9) 1535
[0650] (wherein, R R1-1-9 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-9(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-9a) 1536
[0651] (wherein, R R1-1-9a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-9a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
[0652] This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (triethylamine, pyridine etc.) at −78˜40° C.
[0653] [10] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-10) 1537
[0654] (wherein, R1-1-10 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-10a) 1538
[0655] (wherein, R1-1-10a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
[0656] This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-9).
[0657] [11] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-1-11) 1539
[0658] (wherein, R1-1-11 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0659] (a) The compounds of the present invention of the formula (I-1-11) in which n is 0, i.e., the compounds of the present invention of the formula (I-1-11a) 1540
[0660] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is a formyl i.e., the compounds of the formula (1-1-11 aa) 1541
[0661] (wherein, R1-1-11aa is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.)
[0662] with the corresponding Grignard's reagents or corresponding derivatives containing lithium.
[0663] This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, diethyl ether etc.) at −78˜0° C.
[0664] (b) The compounds of the present invention of the formula (I-1-11) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-1-11b) 1542
[0665] (wherein, n-1-11b is an integer of 1˜2 and the other symbols are the same meaning as hereinbefore described.)
[0666] may be prepared by oxidizing the said compounds of the formula (I-1-11a) as described in [1].
[0667] [12] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted carbonyl or a group containing substituted carbonyformyl, i.e., the compounds of the present invention of the formula (I-1-12) 1543
[0668] (wherein, R1-1-12 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-12(s) is an substituted carbonyl or a group containing substituted carbonyl and the other symbols are the same meaning as hereinbefore described.)
[0669] may be prepared by oxidizing the said compounds of the formula (I-1-11).
[0670] This oxidation is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform etc.) using oxidant (manganese dioxide, oxazolyl chloride, pyridinium dichromate etc.) at −78˜40° C.
[0671] [13] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-1 -13) 1544
[0672] (wherein, R1-1-13 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reducing nitro in the compounds of the formula of (I-1) in which at least one of R1(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-1-13a) 1545
[0673] (wherein, R R1-1-13a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
[0674] The reduction of nitro is well known. For example, it may be carried out by hydrogenolysis and reduction using organic metal.
[0675] This hydrogenolysis is well known. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol , ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas or in the presence of ammonium formate at 0˜200° C. When an acid is used, its salt may be used.
[0676] The reduction using an organic metal is well known. For example, it may be carried out in a water-admissible solvent (ethanol , methanol etc.) in the presence or absence of an aqueous hydrochloric acid solution, using an organic metal (Zn, Fe, Sn, SnCl2, FeCl2 etc.) at 50˜150° C.
[0677] [14] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-1-14) 1546
[0678] (wherein, R1-1-14 is the same meanings as hereinbefore described for R1, provided that at least one of R R1-1-14(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-1) containing a protected COOH, hydroxy or amino, i.e., the compounds of the formula (I-1-14a) 1547
[0679] (wherein, R1-1-14a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-14a(s) is a protected COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group, and the other symbols are the same meaning as hereinbefore described.) according to alkaline hydrolysis, removal of protecting group in an acidic condition, removal of silyl or hydrogenolysis.
[0680] The removal of a protecting group according to alkaline hydrolysis is well known. For example, it may be carried out in an organic solvent (methanol, tetrahydrofuran, dioxane etc.), using hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide , lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0˜40° C.
[0681] The removal of a protecting group in an acidic condition is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.), organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid etc.) or a mixture thereof (bromohydroacetic acid etc.) at 0˜100° C.
[0682] The removal of silyl is well known. For example, it may be carried out in a water-admissible organic solvent (tetrahydrofuran, acetonitrile etc.), using tetrabutylammonium fluoride at 0˜40° C.
[0683] The removal of protecting group according to hydrogenolysis may be carried out by the same procedure of hydrogenolysis described in [13].
[0684] Among the compounds of the formula (I), the compounds of the formula (I-2) 1548
[0685] may be prepared by the following methods [15]˜[17].
[0686] [15] The compounds of the present invention of the formula (I-2) in which m is 0, i.e., the compounds of the present invention of the formula (I-2-15) 1549
[0687] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0688] (a) The compounds of the present invention of the formula (I-2-15) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-15a) 1550
[0689] (wherein, n-2-15a is an integer of 1˜2 and the other symbols are the same meanings as hereinbefore described.) may be prepared by reacting the said compounds of the formula (I-1-1a) or the compounds of the formula (I-1-1b) and the compounds of the formula (III) 1551
[0690] (wherein all the symbols are the same meanings as hereinbefore described.).
[0691] This reaction is known one (to see J. Am. Chem. Soc., 72, 1985 (1950), J. Org. Chem., 54, 4232 (1989). For example, it may be carried out in an inert organic solvent (tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide, acetonitrile etc.) using hydride of an alkaline metal, hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) or an aqueous solution thereof, or a mixture thereof at 0˜40° C.
[0692] (b) The compounds of the present invention of the formula (I-2-15) in which n is 0, i.e., the compounds of the present invention of the formula (I-2-15b) 1552
[0693] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds obtained by the. above mentioned method in which m is 0, n is 1, i.e., the compounds of the formula (I-2-15ab) 1553
[0694] (wherein all the symbols are the same meanings as hereinbefore described.).
[0695] This reduction reaction is well known. For example, this reaction may be carried out in an organic solvent (diethyl ether, tetrahydrofuran etc.) using reductant (lithium aluminum hydride, aluminum diisobutylhydride etc.) at 0˜80° C.
[0696] [16] The compounds of the present invention of the formula (I-2) in which m is 1, i.e., the compounds of the present invention of the formula (I-2-16) 1554
[0697] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-15).
[0698] This oxidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1a) in [1].
[0699] [17] The compounds of the present invention of the formula (I-2) in which m is 2, i.e., the compounds of the present invention of the formula (I-2-17) 1555
[0700] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)˜(c).
[0701] (a) The compounds of the present invention of the formula (I-2-17) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-17a) 1556
[0702] (wherein, n-2-17a is an integer of 1˜2 and the other symbols are the same meaning as hereinbefore described.)
[0703] may be prepared by reacting the said compounds of the formula (I-11-a) or the compounds of the formula (I-1-1b) and the compounds of the formula (IV) 1557
[0704] (wherein all the symbols are the same meanings as hereinbefore described.).
[0705] This reaction may be carried out by the same procedure described in the reaction of the compounds of the formula (I-2-15a) and the compounds of the formula (III) in [15].
[0706] (b) The compounds of the present invention of the formula (I-2-17) in which n is 0, i.e., the compounds of the formula (I-2-17b) 1558
[0707] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds of the formula (V) 1559
[0708] (wherein all the symbols are the same meanings as hereinbefore described.).
[0709] This reduction is known one. For example, it may be carried out by hydrogenation or by the method using triethylsilane.
[0710] This hydrogenation is known reaction. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol, ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pd-C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonici acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas, or in the presence of ammonium formate at 0˜200° C. When an acid is used, its salt may be used.
[0711] This reduction using triethylsilane is well known. For example, it may be carried out in trifluoroacetic acid, in the presence of triethylsilane at 0˜100° C.
[0712] (c) The compounds of the present invention of the formula (I-2-17) in which n is 2, i.e., the compounds of the present invention of the formula (I-2-17c) 1560
[0713] (wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the compounds obtained by the above mentioned method in which m is 0 and n is 2, i.e., the compounds of the formula (I-2-15ac) 1561
[0714] (wherein all the symbols are the same meanings as hereinbefore described.).
[0715] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1b) in [1].
[0716] The compounds of the present invention of the formula (I-2) may be also prepared by not only the methods described in [15]˜[17] but also the following methods [18]˜[30].
[0717] [18] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted oxy or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-2-18) 1562
[0718] (wherein, R1-2-18 and R2-2-18 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18(s) and R2-2-18(s) is a substituted oxy or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0719] (a) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18a) 1563
[0720] (wherein, R1-2-18a and R2-2-18a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18a(s) and R2-2-18a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.)
[0721] and the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
[0722] This eterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-2a) in [2].
[0723] (b) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18b) 1564
[0724] (wherein, R1-2-18b and R2-2-18b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18b(s) and R2-2-18b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.)
[0725] with corresponding compounds containing hydroxy.
[0726] This eterification may be carried out by the procedure for preparation of the compounds of the formula (I-1-2b) in [2].
[0727] [19] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-2-19) 1565
[0728] (wherein, R1-2-19 and R2-2-19 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19(s) and R2-2-19(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(d).
[0729] (a) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-2-19a) 1566
[0730] (wherein, R1-2-19a and R2-2-19a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19a(s) and R2-2-19a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.)
[0731] and the compounds containing amino.
[0732] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3].
[0733] (b) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19b) 1567
[0734] (wherein, R1-2-19b and R2-2-19b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19b(s) and R2-2-19b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
[0735] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3].
[0736] (c) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19c) 1568
[0737] (wherein, R1-2-19c and R2-2-19c are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19c(s) and R2-2-19c(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carbonyl.
[0738] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in (3].
[0739] (d) The compounds of the present invention of the formula (I-2-19) may be prepared by reductive amidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-2-19d) 1569
[0740] (wherein, R1-2-19d and R2-2-19d are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19d(s) and R2-2-19d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
[0741] This reductive amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in [3].
[0742] [20] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-2-20) 1570
[0743] (wherein, R1-2-20 and R2-2-20 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20(s) and R2-2-20(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0744] (a) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of at least one of R1(s) or R2(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-20a) 1571
[0745] (wherein, R1-2-20a and R2-2-20a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-1-20a(s) and R2-2-20a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
[0746] The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
[0747] (b) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-20b) 1572
[0748] (wherein, R1-2-20b and R2-2-20b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20b(s) and R2-2-20b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
[0749] The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
[0750] [21] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-2-21) 1573
[0751] (wherein, R1-2-21 and R2-2-1 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-2(s) and R2-2-21(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0752] (a) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a —COOH or a group containing —COOH, i.e., the compounds of the formula (I-2-21a) 1574
[0753] (wherein, R1-2-21a and R2-2-21a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21a(s) and R2-2-21a(s) is a —COOH or a group containing —COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing hydroxy.
[0754] This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5].
[0755] (b) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i e., the compounds of the formula (I-2-21b) 1575
[0756] (wherein, R1-2-21 and R2-2-21b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21b(s) and R2-2-21b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
[0757] This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5].
[0758] [22] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-2-22) 1576
[0759] (wherein, R1-2-22 and R2-2-22 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22(s) and R2-2-22(s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)˜(b).
[0760] (a) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a —SO3H or a group containing —SO3H, i.e., the compounds of the formula (VI) 1577
[0761] (wherein, R1-2-22a and R2-2-22a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22a(s) and R2-2-22a(s) is a —SO3H or a group containing —SO3H and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
[0762] The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6].
[0763] (b) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-22b) 1578
[0764] (wherein, R1-2-22b and R2-2-22b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22b(s) and R2-2-22b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing sulfo.
[0765] The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6].
[0766] [23] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-23) 1579
[0767] (wherein, R1-2-23 and R2-2-23 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23(s) and R2-2-23(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described,) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-23a) 1580
[0768] (wherein, R1-2-23a and R2-2-23a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23a(s) and R2-2-23a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
[0769] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7].
[0770] [24] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-24) 1581
[0771] (wherein, R1-2-24 and R2-2-24 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24(s) and R2-2-24(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-24a) 1582
[0772] (wherein, R1-2-24a and R2-2-24a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24a(s) and R2-2-24a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
[0773] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7].
[0774] [25] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-25) 1583
[0775] (wherein, R1-2-25 and R2-2-25 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25(s) and R2-2-25 (s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-25a) 1584
[0776] (wherein, R1-2-25a and R1-2-25a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25a(s) and R2-2-25a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
[0777] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9].
[0778] [26] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) or R2(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-26) 1585
[0779] (wherein, R1-2-26 and R2-2-26 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26(s) and R2-2-26(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-26a) 1586
[0780] (wherein, R1-2-26a and R2-2-26a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26a(s) and R2-22-6a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
[0781] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9].
[0782] [27] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted (hydroxy)methyl or a group containing substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-2-27) 1587
[0783] (wherein, R1-2-27 and R2-2-27 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27(s) and R2-2-27(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a formyl, i.e., the compounds of the formula (I-2-27a) 1588
[0784] (wherein, R1-2-27a and R2-2-27a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27a(s) and R2-2-27a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.) and Grignard's reagents or corresponding derivatives containing lithium.
[0785] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-11a) in (11].
[0786] [28] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted carbonyl or a group containing a substituted carbonyl, i.e., the compounds of the present invention of the formula (I-2-28) 1589
[0787] (wherein, R1-2-28 and R2-2-28 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-28(s) and R2-2-28(s) is a substituted carbonyl or a group containing a substituted carbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-27).
[0788] This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-12) in [12].
[0789] [29] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-2-29) 1590
[0790] (wherein, R1-2-29 and R2-22-29 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29(s) and R2-2-29(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reduce of nitro in the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-2-29a) 1591
[0791] (wherein, R2-2-29a and R2-2-29a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29a(s) and R2-2-29a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
[0792] The reduction of nitro may be carried out by the same procedure for preparation of the compounds of the formula (I-1-13) in [13].
[0793] [30] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-2-30) 1592
[0794] (wherein, R1-2-30 and R2-2-30 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30(s) and R2-2-30(s) is a —COOH, hydroxy or amino or a group containing —COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-2) in which —COOH, hydroxy or amino which is protected by a protecting group or a group containing —COOH, hydroxy or amino which is protected by a protecting group, i.e., the compounds of the formula (I-2-30a) 1593
[0795] (wherein, R1-2-30a and R2-2-30a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30a(s) and R2-2-30a(s) is a protected —COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group and the other symbols are the same meaning as hereinbefore described.) by an alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by removal of protecting group based on hydrogenelysis. An alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by hydrogenolysis may be carried out by same procedure for preparation of the compounds of the formula (I-1-14) in [14].
[0796] Reaction for removal of protecting group in the present invention means an ordinal one which is well known to the person in the art, for example, alkaline hydrolysis, removal of protecting group in an acidic condition and hydrogenolysis. The aimed compounds of the present invention may be prepared easily by choice of these reactions.
[0797] As well known to the person in the art, a protecting group of carboxy includes, for example, methyl, ethyl, t-butyl and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
[0798] A protecting group of hydroxy includes, for example, methoxymethyl, tetrahydropyranyl, t-butyidimethylsilyl, acetyl, and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
[0799] A protecting group of amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991.
[0800] The compounds of the formula (V) are known per se or may be prepared according to the following Reaction Scheme or by known methods easily.
[0801] In Reaction Scheme, X is halogen. 1594
[0802] The compounds of the formulae (III), (IV), (VI), (VII) or (VIII) used as starting materials have been known per se or may be prepared by known methods easily.
[0803] Further, the compounds of the formula (I-1-1 c) in which A is benzene, R1 is carboxy, p is 1 and R1 is bonded at 4-position, i.e., the compounds of the formula (XI) are important intermediates of the compounds of the formula (I) of the present invention. The methods for preparation of the compounds of the formula (XI) are shown in the mentioned Reaction Scheme 5. Next, each step is explained in detail.
[0804] The reaction to synthesis of the compounds of the formula (XIII) from the compounds of the formula (XII) is well known. For example, it may be carried out in an inert organic solvent (acetonitrile, benzene, toluene, xylene, methyhlene chloride, chloroform, dimethoxy ethane, tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, acetone etc.) or mixture thereof, in the presence of Lewis acid (Znl2, ZnCl2, aluminum chloride, TiCl2, lithium hypochloric acid, lithium borotetrafluoride, lithium hexafluoride etc.) and cyanide derivatives (trimethylsilylcyanide, diethyl aluminum cyanide, or diethyl cyanophosphonate etc.) at 0˜40°C.
[0805] The reaction to synthesis of the compounds of the formula (XIV) from the compounds of the formula (XIII) is well known. For example, it may be carried out in an inert organic solvent (benzene, toluene, ethyl acetate, dioxane, dimethoxy ethane, diethyl ether, tetrahydrofuran, tetrahydropyran, the mixture thereof etc.) in the presence of oxidant (2,3-dichloro-5,6-dicyano-1,4-benzoquinon, chloranil (2,3,5,6-tetrachloro-1,4-benzoquinon) etc.) at room temperature to refluxing temperature. Or it may be carried out, for example, in an organic solvent (ethylene glycol, oleic acid, diethylene glycol, dimethyl ether, toluene, benzene, xylene etc.) in the presence of hydrogen acceptor (nitrobenzene, maleic acid, cyclohexen, oleic acid, 1,5-cycloctadien, phenylacetylene, 2-butylic acid etc.) and in the presence of metal catalyst (Pd—C, palladium hydroxide, palladium black, Pd, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.) at 60° C.˜refluxing temperature.
[0806] The reaction to synthesis of the compounds of the formula (XI) from the compounds of the formula (XIV) is well known. For example, it may be carried out in alcohol solvent (ethylene glycol, t-butanol, benzyl alcohol, methanol ethanol , propanol, isopropanol etc.) in the presence of alkali (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.) at 60° C.˜refluxing temperature.
[0807] In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
[0808] In addition, the optical isomers of the compounds of the present invention of the formula (I) may be obtained by an ordinal optical separation (e.g., separation by gas chromatography or by high performance liquid chromatography, separation by crystallization to diastermeric salt or clathrate compounds or separation by preferential crystallization etc.) or by ordinal method for preparation of racemic compound.
[0809] [Pharmacological Activities]
[0810] According to the following experiments, it has been proved that the compounds of the present invention of the formula (I) possess inhibitory activities of producing IL-6 and/or IL-12.
[0811] (1) Assaying Inhibitory Activity on IL-6 production and cellular toxicity
[0812] [Experimental Method]
[0813] 1.5×104 of A549 cells (human lung epithelial cell line) were suspended in dalbeco-modified eagle medium (DMEM) containing 0.5% fetus bovine serum (abbreviated as FBS) (100 &mgr;l) and incubated in 96 well-microplate over day and night. The test compound dissolved in various kinds of solvents at various concentrations (20 &mgr;l) and Tumor Necrosis Factor-&agr; (TNF-&agr; (Genzyme Co, Cat. No. TNF-H)) dissolved in DMEM at the concentration of 12.5 ng/ml (80 &mgr;l) were added thereto. After incubation for 24 hours, the supernatant (200 &mgr;l) was recovered to assay the quantity of IL-6 using Enzyme Linked Immuno Solvent Assay (ELISA) Method (R&D Systems Co., Cat. No. D6050), to calculate inhibitory activity of the test compound and determine 50 % inhibitory concentration (IC50). To the cells from which the supernatant was removed, a solution of brom 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolinium (abbreviated as MTT (Dojin Chemical Laboratory, Cat. No. 345-01821)) dissolved in DMEM containing 1 0% FBS at the concentration of 0.5mg/ml (100 &mgr;l) was added and incubated for 3 hours. After removing MTT solution, methanol (100 &mgr;l) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a result, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-6 production with an IC50 value of 20 &mgr;M or less. For example, free compound of the compound of
EXAMPLE 20(4) possessed an inhibitory activity on IL-6 production with an IC50 value of 4.4 &mgr;M and showed no cellular toxicity at 10 &mgr;M.[0814] (2) Assaying Inhibitory Activity on IL-12 Production and Cellular Toxicity
[0815] [Experimental Method]
[0816] 2.0×105 of peripheral monocyte prepared from healthy human blood by Ficole gravity centrifugation method (Pharmacia Biotech Co, Cat. No. 17-1440-02) were suspended in RPMI1640 medium containing 10% FBS (170 &mgr;l). The test compound dissolved in various kinds of solvents at the various concentrations (10 &mgr;l) and 6000 units/ml of Interferon-&ggr; (IFN-&ggr; (Serotec Co, Cat. No. PHP050)) (10 &mgr;l) dissolved in RPMI1640 medium containing 10% FBS. After incubation for 24 hours in 96 well-microplate, lipopolysaccharide (6 &mgr;g/ml) dissolved in RPMI1640 medium containing 10% FBS (LPS (Difco Co., Cat. No. 3120-25-0)) (10 &mgr;l) was added thereto. After incubation for 20 hours, the supernatant (150 &mgr;l) was recovered to assay the quantity of IL-12 using ELISA Method (R&D Systems Co, Cat. No. D1200), calculate for inhibitory activity of the test compound and determine 50% inhibitory concentration (IC50) (see J. Exp. Med., 183, 147 (1996)). To the cells from which the supernatant (150 &mgr;l) was removed, a solution of MTT dissolved in RPMI1640 medium containing 10% FBS at 1 mg/ml (50 &mgr;l) was added and incubated for 3 hours. 2-Propanol containing 0.04N HCl (100 &mgr;l) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a results, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-12 production with an IC50 value of 10 &mgr;M or less. For example, hydrochloride of the compound of Example 20(4) possessed an inhibitory activity on IL-12 production with an IC50 of 0.11 &mgr;M and showed no cellular toxicity at 1 &mgr;M.
[0817] [Toxicity]
[0818] The toxicity of the compounds of the present invention is very low and therefore, it is confirmed that these compounds are safe for use as medicine.
[0819] [Application for Pharmaceuticals]
[0820] The compounds of the present invention possess an inhibitory activity of producing IL-6 and/or IL-12 in animal, especially human, so they are useful for prevention and/or treatment of, for example, various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, gammopathy, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmune diseases, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, infectious diseases.
[0821] For the purpose above described, the compounds of the general formula (I) of the present invention, non-toxic salts, acid addition salts, or hydrates thereof may be normally administered systematically or locally, usually by oral or parenteral administration.
[0822] The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
[0823] As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
[0824] The compounds of the present invention may be administered as inner solid composition's or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
[0825] Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules contain hard capsules and soft capsules.
[0826] In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
[0827] Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents and preserving agents.
[0828] Injections for parenteral administration include solutions, suspensions and emulsions, and solid injections. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80 (registered trade mark) etc. Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
[0829] Other compositions for parenteral administration include liquids for external use, and endermic liniments, ointments, spray, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods.
[0830] Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.
BEST MODE FOR CARRYING OUT THE INVENTION[0831] The following reference Examples and Examples are intended to illustrate, but do not limit the present invention.
[0832] The solvents in parenthesis show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. The solvents in parentheses in NMR show the solvents used for measurement.
EXAMPLE 1 3-Phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0833] 1595
[0834] To asolution of benzothiophene-1,1-dioxide (1 g) in tetrahydrofuran (10 ml) were added triethylamine (1.55 ml) and thiophenol (798 mg). The reaction mixture was stirred for 4 hours at room temperature. To the reaction mixture was water added. The mixture was extracted with ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with chromatography on silica gel (hexane:ethyl acetate=1:1). The obtained compound was then recrystallized from ethanol to give the title compound (1.18 g) having the following physical data.
[0835] TLC: Rf 0.46 (hexane:ethyl acetate=2:1);
[0836] NMR (CDCl3): &dgr; 7.85-7.18 (9H, m), 4.98 (1H, t, J=7 Hz), 3.80 (1H, dd, J=14, 7 Hz), 3.51 (1H, dd, J=14, 7 Hz).
EXAMPLES 1(1)˜1(18)[0837] By the same procedure as described in Example 1 using a corresponding thiol instead of thiophenol, the following compounds of the present invention were obtained.
EXAMPLE 1 (1) 3-(Thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0838] 1596
[0839] TLC: Rf 0.53 (hexane:ethyl acetate=1:1);
[0840] NMR (CDCl3):&dgr; 7.81-7.66 (m, 3H), 7.58-7.51 (m, 1H), 7.42 (dd, J=5.4, 1.4 Hz, 1H), 7.14 (dd, J=3.6, 1.4 Hz, 1H), 7.00 (dd, J=5.4, 3.6 Hz, 1H), 4.78 (t-like, J=6.9 Hz, 1H), 3.80 (dd, J=14.0, 7.2 Hz, 1H), 3.51 (dd, J=14.0, 6.6 Hz, 1H).
EXAMPLE 1 (2) 3-(4-Methylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0841] 1597
[0842] TLC: Rf 0.40 (hexane:ethyl acetate=2:1);
[0843] NMR (CDCl3): &dgr; 7.85-7.57 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.80 (t-like, J=6.5 Hz, 1H), 3.85 (dd, J=14.0, 7.5 Hz, 1H), 3.38 (dd, J=14.0, 6.0 Hz, 1H).
EXAMPLE 1 (3) 3-(4-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0844] 1598
[0845] TLC: Rf 0.38 (hexane:ethyl acetate=2:1);
[0846] NMR (CDC3): &dgr; 7.82-7.45 (4H, m), 7.36 (2H, d, J=7 Hz), 6.85 (2H, d, J=7 Hz), 4.83 (1 H, t, J=7 Hz), 3.83 (3H, s), 3.74 (1 H, dd, J=13, 7 Hz), 3.46 (1 H, dd, J=13, 7 Hz).
EXAMPLE 1 (4) 3-(4-Chlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0847] 1599
[0848] TLC: Rf 0.37 (hexane ethyl acetate=2:1);
[0849] NMR (CDCl3): &dgr; 7.88-7.67 (m, 4H), 7.32 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.83 (t-like, J=7.0 Hz, 1H), 3.83 (dd, J=14.5, 6.5 Hz, 1H), 3.52 (dd, J=14.5, 7.8 Hz, 1H).
EXAMPLE 1 (5) 3-(4-Fluorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0850] 1600
[0851] TLC Rf 0.36 (hexane:ethyl acetate=2:1);
[0852] NMR (CDCl3): &dgr; 7.80-7.32 (m, 6H), 7.04 (t-like, J=8.8 Hz, 2H), 4.90 (t-like, J=6.6 Hz, 1H), 3.78 (dd, J=13.6, 7.6 Hz, 1H), 3.50 (dd, J=13.6, 6.4 Hz, 1H).
EXAMPLE 1 (6) 3-(4-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0853] 1601
[0854] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);
[0855] NMR (CDCl3): &dgr; 3.45 (dd, J=15, 7.5Hz, 1H), 3.75 (dd, J15, 7.5Hz, 1H), 4.80 (t, J=7.5 Hz, 1H), 5.60 (s, 1H), 6.75 (d, J=7.5 Hz, 2H), 7.30 (d, J=7.5 Hz, 2H), 7.45-7.80 (m, 4H).
EXAMPLE 1 (7) 3-(3-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0856] 1602
[0857] TLC: Rf 0.36 (hexane:ethyl acetate=1:1);
[0858] NMR (CDCl3): &dgr; 3.50 (dd, J=15, 7.5 Hz, 1H), 3.85 (dd, J=15, 7.5 Hz, 1H), 5.00 (t, J=7.5 Hz, 1H), 5.65 (s, 1H), 6.75-7.00 (m, 3H), 7.10-7.30 (m, 1H), 7.50-7.80 (m, 4H).
EXAMPLE 1 (8) 3-(2-Hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0859] 1603
[0860] TLC: Rf 0.33 (hexane ethyl acetate=1:1);
[0861] NMR (CDCl3): &dgr; 3.45 (dd, J=12.5, 5.0 Hz, 1H), 3.70 (dd, J=12.5, 7.5 Hz, 1H), 4.80 (dd, J=7.5, 5.0 Hz, 1H), 6.65 (s, 1H), 6.90 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.30 -7.80 (m, 6H).
EXAMPLE 1 (9) 3-(Pyridin-4-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0862] 1604
[0863] TLC: Rf 0.45 (ethyl acetate)
[0864] NMR (CDCl3): &dgr; 3.58 (dd, J=13, 6 Hz, 1H), 4.00 (dd, J=13, 6 Hz, 1H), 5.22 (t, J=6 Hz, 1H), 7.20 (m, 2H), 7.69 (m, 4H), 8.51 (m, 2H)
EXAMPLE 1 (10) 3-(Pyrimidin-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0865] 1605
[0866] TLC: Rf 0.55 (hexane:ethyl acetate=1:2);
[0867] NMR (CDCl3): &dgr; 3.71 (dd, J=14, 7 Hz, 1H), 4.24 (dd, J=14, 7 Hz, 1H), 5.70 (t, J=7 Hz, 1H), 7.10 (t, J=5 Hz, 1H), 7.52-7.85 (m, 4H), 8.58 (d, J=5 Hz, 2H).
EXAMPLE 1 (11) 3-(Thiazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0868] 1606
[0869] TLC: Rf 0.52 (hexane:ethyl acetate=1:1);
[0870] NMR (CDCl3): &dgr; 3.55 (dd, J=13.4 Hz, 1H), 3.81 (dd, J=13, 7 Hz, 1H), 5.60 (dd, J=7, 4 Hz, 1H), 7.57-7.80 (m, 6H).
EXAMPLE 1 (12) 3-(3-Methylfuran-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0871] 1607
[0872] TLC: Rf 0.45 (hexane ethyl acetate=4:1);
[0873] NMR (CDCl3): &dgr; 2.27 (s, 3H), 3.39 (dd, J=14.0 Hz, 6.0 Hz, 1H), 3.75 (dd, J=14.0 Hz, 6.0 Hz, 1H), 4.69 (t, J=6.0 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.48-7.77 (m, 4H).
EXAMPLE 1 (13) 3-(3-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0874] 1608
[0875] TLC: Rf 0.44 (hexane:ethyl acetate=1:1);
[0876] NMR (CDCl3): &dgr; 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.75 (s, 3H), 3.80 (dd, J=12.5, 7.5 Hz, 1H), 5.00 (t, J=7.5 Hz, 1H), 6.85-7.05 (m, 3H), 7.20-7.30 (m, 1H), 7.50-7.80 (m, 4H).
EXAMPLE 1 (14) 3-(2-Methoxycarbonylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0877] 1609
[0878] TLC: Rf 0.40 (hexane ethyl acetate=1:1);
[0879] NMR (CDCl3): &dgr; 3.60 (dd, J=15, 7.5 Hz, 1H), 3.90 (s, 3H), 3.95 (dd, J=15, 7.5 Hz, 1H), 5.25 (t, J=7.5 Hz, 1H), 7.30-7.80 (m, 7H), 7.95-8.05 (m, 1H).
EXAMPLE 1 (15) 3-Cyclohexylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0880] 1610
[0881] TLC: Rf 0.32 (hexane:ethyl acetate=3:1);
[0882] NMR (CDCl3): &dgr; 1.26-2.10 (m, 10H), 2.80-2.93 (m, 1H), 3.52 (dd, J=13.4, 7.4 Hz, 1H), 3.92 (dd, J=13.4, 7.4 Hz, 1H), 4.68 (t, J=7.4 Hz, 1H), 7.47-7.54 (m, 1H), 7.59-7.67 (m, 1H), 7.70-7.75 (m, 2H).
EXAMPLE 1 (16) 3-(Naphthalen-1-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0883] 1611
[0884] TLC: Rf 0.36 (hexane:ethyl acetate=2:1);
[0885] NMR (CDCl3): &dgr; 3.51 (dd, J=13.6, 5.8 Hz, 1H), 3.64 (dd, J=13.6 Hz, 7.3 Hz, 1H), 5.01 (t-like, J=6.4 Hz, 1H), 7.40-7.79 (m, 8H), 7.90-7.94 (m, 2H), 8.52-8.56 (m, 1H).
EXAMPLE 1 (17) 3-(2-Methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0886] 1612
[0887] TLC: Rf 0.49 (hexane:ethyl acetate=1:1);
[0888] NMR (CDCl3): &dgr; 3.55 (dd, J=12.5, 7.5 Hz, 1H), 3.75 (dd, J=12.5, 7.5 Hz, 1H), 3.90 (s, 3H), 5.10 (t, J=7.5 Hz, 1H), 6.90-7.00 (m, 2H), 7.30-7.80 (m, 6H).
EXAMPLE 1 (18) 3-(1-Methylimidazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0889] 1613
[0890] TLC: Rf 0.50 (hexane:ethyl acetate=1:2); NMR (CDCl3):5 3.54 (dd, J=14, 3 Hz, 1H), 3.65 (s, 3H), 4.04 (dd, J=14, 9 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 6.65 (d, J=2.7 Hz, 1H), 6.95 (dd, J=9,3 Hz, 1H), 7.56 (m, 1H), 7.67 (m, 2H), 7.85 (m, 1H).
EXAMPLE 2 3-Phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0891] 1614
[0892] To potassium peroxymonosulfate (“OXONE” (trade name) marketed from Aldrich Co., abbreviated as OXONE®; 2.14 g), water (10 ml) was added. To a solution of a compound prepared in Example 1 (0.961 g) in methanol (50 ml), thus obtained aqueous solution of OXONE® (5.5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (twice) and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the title compound (361 mg) having the following physical data.
[0893] TLC: Rf 0.13 (hexane:ethyl acetate=1:1);
[0894] NMR (CDCl3): &dgr; 7.85-7.45 (9H, m), 4.57 (1H, t, J=7 Hz), 3.98 (1H, dd, J=14, 7 Hz), 3.19 (1H, dd, J=14, 7 Hz).
EXAMPLES 2 (1)˜2 (2)[0895] By the same procedure as described in Example 2 using the compounds prepared in Example 1 (1) and Example 1 (14) instead of the compound prepared in Example 1, the following compounds of the present invention were obtained.
EXAMPLE 2 (1) 3-(Thiophen-2-yl)sulfinyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene[0896] 1615
[0897] TLC: Rf 0.01 (hexane:ethyl acetate=1:1);
[0898] NMR (CDCl3): &dgr; 7.95-7.50 (4.5H m), 7.50-7.25 (1.5H, m), 7.25-7.10 (1H, m), 4.99 (0.5H, dd, J=8.4, 4 Hz), 4.81(0.5H, dd, J=8.4, 4 Hz), 4.02 (0.5H, dd, J=14.2, 4.4 Hz), 3.72-3.40 (1.5H, m).
EXAMPLE 2 (2) 3-(2-Methoxycarbonylphenyl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0899] 1616
[0900] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);
[0901] NMR (CDCl3): &dgr; 2.90 (dd, J=12.5, 7.5 Hz, 1H), 4.00 (s, 3H), 4.00(dd, J=12.5, 7.5 Hz, 1H), 5.05 (t, J=7.5 Hz, 1H), 7.55-7.90 (m, 5H), 8.10-8.25 (m, 3H).
EXAMPLE 3 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0902] 1617
[0903] To OXONE® (2.14 9), water (10 ml) was added. To a solution of the compound prepared in Example 1 (0.961 g) in methanol (50 ml),was added thus obtained aqueous solution of OXONE® at room temperature. The reaction mixture was stirred for 2 hours at room temperature. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (twice) and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (1.54 g) having the following physical data.
[0904] TLC: Rf 0.45 (hexane:ethyl acetate=1:1);
[0905] NMR (CDCl3): &dgr; 3.65-3.85 (m, 2H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.40-7.80 (m, 8H), 8.05 (d, J=10 Hz, 1H).
EXAMPLES 3 (1)˜3 (17)[0906] By the same procedure as described in Example 3 using the compounds prepared in Examples 1 (1)˜1 (17) instead of the compound prepared in Example 1, or using 3-chloroperbenzoic acid instead of OXONE® as an oxidant, the following compounds of the present invention were obtained.
EXAMPLE 3 (1) 3-(Thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0907] 1618
[0908] TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
[0909] NMR (CDCl3): &dgr; 8.08 (d, J=5.0 Hz, 1H), 7.82-7.66 (m, 5H), 7.20 (dd, J=5.0, 3.8Hz, 1H), 5.82 (dd, J=9.4, 3.1 Hz, 1H), 4.07 (dd, J=15.4, 9.4 Hz, 1H), 3.83 (dd, J=15.4, 3.1 Hz, 1H).
EXAMPLE 3 (2) 3-(4-Methylphenyl)sulfonyl-2,3-dihidro-1,1 -dioxidebenzo[b]thiophene[0910] 1619
[0911] TLC. Rf 0.11 (hexane:ethyl acetate=2:1);
[0912] NMR (CDCl3): &dgr; 8.04 (1H, d, J=8 Hz), 7.82-7.58 (3H, m), 7.53 (2H, d, J=9 Hz), 7.28 (2H, d, J=9 Hz), 5.08 (1 H, dd, J=1H, 8 Hz), 3.86-3.55 (2H, m), 2.42 (3H, s).
EXAMPLE 3 (3) 3-(4-Methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0913] 1620
[0914] TLC: Rf 0.23 (hexane:ethyl acetate=1:1);
[0915] NMR (CDCl3): &dgr; 8.04 (1H, d, J=8 Hz), 7.88-7.60 (3H, m), 7.54 (2H, d, J=7 Hz), 6.91 (2H, d, J=7 Hz), 5.06 (1 H, t, J=7 Hz), 3.85 (3H, s), 3.80-3.60 (2H, m).
EXAMPLE 3 (4) 3-(4-Chlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0916] 1621
[0917] TLC: Rf 0.26 (hexane:ethyl acetate=2:1);
[0918] NMR (CDCl3): &dgr; 8.02 (1H, d, J=8 Hz), 7.85-7.58 (3H, m), 7.58-7.32 (4H, m), 5.09 (1 H, t, J=7 Hz), 3.90-3.65 (2H, m).
EXAMPLE 3 (5) 3-(4-Fluorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0919] 1622
[0920] TLC: Rf 0.41 (hexane:ethyl acetate=1:1)
[0921] NMR (CDCl3): &dgr; 8.03 (1H, d, J=8 Hz), 7.90-7.45 (5H, m), 7.20-7.00 (2H, m), 5.08 (1H, t, J=7 Hz), 3.80-3.75 (2H, m).
EXAMPLE 3 (6) 3-(4-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0922] 1623
[0923] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);
[0924] NMR (CD3OD+CDCl3): &dgr; 7.97 (1 H, d, J=7 Hz), 7.85-7.55 (3H, m), 7.46 (2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz), 5.09 (1H, t, J=7 Hz), 3.90-3.60 (2H, m).
EXAMPLE 3(7) 3-(3-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0925] 1624
[0926] TLC: Rf 0.22 (hexane:ethyl acetate=1:1);
[0927] NMR (CDCl3+DMSO-d6): &dgr; 9.83 (1H, brs), 7.90-7.78 (1 H, m), 7.78-7.50 (3H, m), 7.42-7.08 (4H, m), 5.28-5.10 (1H, m), 3.90-3.58 (2H, m).
EXAMPLE 3 (8) 3-(2-Hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0928] 1625
[0929] TLC: Rf 0.15 (hexane:ethyl acetate=1:1);
[0930] NMR (CDCl3+DMSO-d6): &dgr; 7.90-7.42 (6H, m), 7.13 (1H, d, J=8 Hz), 6.98 (1H, t, J=7 Hz), 5.71 (1H, dd, J=9, 5 Hz), 3.86 (1H, dd, J=14, 5 Hz), 3.65 (1H, dd, J=14, 9 Hz).
EXAMPLE 3 (9) 3-(Pyridin-4-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0931] 1626
[0932] TLC: Rf 0.25 (hexane:ethyl acetate=1:2);
[0933] NMR (DMSO-d6): &dgr; 3.87 (dd, J=15, 3 Hz, 1H), 4.03 (dd, J=15, 9Hz, 1H), 5.94 (dd, J=9, 3 Hz, 1H), 7.70 (dd, J=4, 2 Hz, 2H), 7.81 (m, 4H), 8.88 (dd, J=4, 2 Hz, 2H).
EXAMPLE 3 (10) 3-(Pyrimidin-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0934] 1627
[0935] TLC: Rf 0.15 (methylene chloride);
[0936] NMR (DMSO-d6): &dgr; 4.00 (dd, J=16, 4 Hz, 1H), 4.12 (dd, J=16, 9 Hz, 1H), 6.17 (dd, J=9, 4 Hz, 1H), 7.78 (m, 3H), 7.90 (m, 2H), 9.09 (dd, J=5, 1 Hz, 2H).
EXAMPLE 3 (11) 3-(Thiazol-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0937] 1628
[0938] TLC: Rf 0.40 (hexane:ethyl acetate=1:1);
[0939] NMR (CDCl3): &dgr; 3.87 (dd, J=15, 9 Hz, 1H), 4.20 (dd, J=15, 5 Hz, 1H), 5.39 (dd, J=9, 5 Hz, 1H), 7.61-7.81 (m, 4H), 7.99-8.08 (m, 2H).
EXAMPLE 3 (12) 3-(3-Methylfuran-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]furan[0940] 1629
[0941] TLC: Rf 0.50 (hexane:ethyl acetate=3:2);
[0942] NMR (CDCl3): &dgr; 2.39 (s, 3H), 3.78 (dd, J=15, 4 Hz, 1H), 3.88 (dd, J=15, 8 Hz, 1H), 5.00 (dd, J=8, 4 Hz, 1H), 5.98 (d, J=2 Hz, 1H), 7.18 (d, J=2 Hz, 1H), 7.60-7.80 (m, 3H), 8.02 (m, 1H).
EXAMPLE 3 (13) 3-(3-Methyoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0943] 1630
[0944] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);
[0945] NMR (CDCl3): &dgr; 3.65-3.90 (m, 2H), 3.75 (s, 3H), 5.10 (dd, J=10, 5.0Hz, 1H), 7.10-7.50 (m, 4H), 7.60-7.80 (m, 3H), 8.00 (d, J=7.5 Hz, 1H).
EXAMPLE 3 (14) 3-(2-Methoxycarbonylphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0946] 1631
[0947] TLC: Rf 0.59 (methylene chloride:ethyl acetate=9:1);
[0948] NMR (CDCl3): &dgr; 8.01-7.97 (m, 1H), 7.84-7.63 (m, 7H), 6.06 (dd, J=9.0, 4.5 Hz, 1H), 4.04 (s, 3H), 3.92 (dd, J=14.0, 4.5 Hz, 1H), 3.63 (dd, J=14.0, 9.0 Hz, 1H).
EXAMPLE 3 (15) 3-Cyclohexylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0949] 1632
[0950] TLC: Rf 0.37 (hexane:ethyl acetate=1:1);
[0951] NMR (CDCl3): &dgr; 1.13-1.68 (m, 8H), 1.90-1.96 (m, 1H), 2.15-2.19 (m, 1H), 3.07-3.23 (m, 1H), 3.87 (dd, J=14.5, 8.2 Hz, 1H), 3.95 (dd, J=14.5, 5.2 Hz, 1H), 4.96 (dd, J=8.2, 5.2 Hz, 1H), 7.63-7.83 (m, 3H), 7.96-8.00 (m, 1H).
EXAMPLE 3 (16 ) 3-(Naphthalen-1-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0952] 1633
[0953] TLC: Rf 0.40 (hexane:ethyl acetate=1:1);
[0954] NMR (CDCl3): &dgr; 3.38 (dd, J=14.4, 8.8 Hz, 1H), 3.77 (dd, J=14.4, 5.0 Hz, 1H), 5.31 (dd, J=8.8, 5.0 Hz, 1H), 7.60-7.81 (m, 7H), 8.00-8.05 (m, 1H), 8.22-8.28 (m, 2H), 8.72-8.77 (m, 1H).
EXAMPLE 3 (17) 3-(2-Methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0955] 1634
[0956] TLC: Rf 0.20 (hexane:ethyl acetate=1:1);
[0957] NMR (CDCl3+DMSO-d6): &dgr; 3.65 (dd, J=15, 10 Hz, 1H), 3.80 (dd, J=15, 5.0 Hz, 1H), 4.00 (s, 3H), 5.55 (dd, J=10, 5.0 Hz, 1H), 7.05-7.20 (m, 2H), 7.60-7.95 (m, 6H).
EXAMPLE 4 3-(4-(2-(Piperidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0958] 1635
[0959] To a solution of the compound prepared in Example 3 (6) (283 mg) in dimetyhylformamide (5 ml) were added N-chloroethylpiperidine (193 mg) and cesium carbonate (1.0 g). The reaction mixture was stirred at room temperature overnight. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (three times), a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (186 mg) having the following physical data.
[0960] TLC: Rf 0.54 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[0961] NMR (CDCl3):&dgr; 8.03 (1H, d, J=7 Hz), 7.85-7.55 (3H, m), 7.53 (2H, d, J=9 Hz), 6.92 (2H, d, J=9 Hz), 5.05 (1H, t, J=7 Hz), 4.13 (2H, t, J=6 Hz), 3.85-3.60 (2H, m), 2.76 (2H, t, J=6 Hz), 2.49 (4H, brt, J=6 Hz), 1.68-1.45 (6H, m).
EXAMPLES 4 (1)˜4 (4)[0962] By the same procedure as described in Example 4 by using the compounds prepared in Examples 3 (6)˜3 (8) and corresponding halogenated compounds, the following compounds of the present invention were obtained.
EXAMPLE 4 (1) 3-(4- (2-(pyrrolidin-1-yl)ethoxy) phenyl)sulfonyl)-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0963] 1636
[0964] TLC: Rf 0.35 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[0965] NMR (CDCl3): &dgr; 8.03 (1H, d, J=7 Hz), 7.90-7.40 (5H, m), 6.93 (2H, d, J=7 Hz), 5.18-4.95 (1H, m), 4.14 (2H, t, J=6 Hz), 3.90-3.60 (2H, m), 2.91 (2H, t, J=6 Hz), 2.75-2.40 (4H, m), 1.84-1.74 (4H, m).
EXAMPLE 4 (2) 3-(4-(2-(Morpholine-1-yl)ethoxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0966] 1637
[0967] TLC: Rf 0.44 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[0968] NMR (CDCl3): &dgr; 8.05 (1H, d, J=7 Hz), 7.85-7.40 (5H, m), 6.91 (2H, d, J=7 Hz), 5.06 (1H, t, J=7 Hz), 4.13 (2H, t, J=6 Hz), 3.95-3.50 (6H, m), 2.80 (2H, t, J=6 Hz), 2.70-2.40 (4H, m).
EXAMPLE 4 (3) 3-(3-Benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0969] 1638
[0970] TLC: Rf 0.55 (hexane:ethyl acetate=1:1);
[0971] NMR (CDCl3): &dgr; 8.02 (1H, d, J=7 Hz), 7.85-7.52 (3H, m), 7.52-7.10 (9H, m), 5.15-4.85 (3H, m), 3.80-3.45 (2H, m).
EXAMPLE 4 (4) 3-(2-Benzyloxyohenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0972] 1639
[0973] TLC: Rf 0.37 (hexane ethyl acetate=1:1);
[0974] NMR (CDCl3): &dgr; 7.93 (1H, dd, J=8, 2 Hz), 7.85-7.30 (10 H, m), 7.25-7.08 (2H, m), 5.52 (1H, dd, J=9, 5 Hz), 5.28 (2H, s), 3.79 (1H, dd, J=14, 5 Hz), 3.48 (1H, dd, J=14, 9 Hz).
EXAMPLE 5 3-(4-(Pyridin-2-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0975] 1640
[0976] By the same procedure as described in Example 4 using the compound prepared in Example 1 (6) instead of the compound prepared in Example 3 (6), and using a corresponding halogenated compound instead of N-chloroethylpiperidine, the compound of the present invention having the following physical data was obtained.
[0977] TLC: Rf 0.58 (ethyl acetate)
[0978] NMR (CDCl3): &dgr; 8.65-8.55 (1H, m), 7.80-7.20 (9H, m), 7.00-6.90 (2H, m), 5.20 (2H, s), 4.85 (1H, t, J=7.5 Hz), 3.75 (1H, dd, J=12.5, 7.5 Hz), 3.45 (1H, dd, J=12.5, 7.5 Hz).
EXAMPLES 5 (1)˜5 (9)[0979] By the same procedure as described in Example 5 using the compounds prepared in Examples 1 (6)˜1 (8), the following compounds of the present invention were obtained.
EXAMPLE 5 (1) 3-(4-Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0980] 1641
[0981] TLC: Rf 0.42 (ethyl acetate);
[0982] NMR (CDCl3): &dgr; 8.70-8.60 (2H, m), 7.80-7.30 (8H, m), 7.00-6.90 (2H, m), 5.05 (2H, s), 4.85 (1H, t, J=5 Hz), 3.75 (1H, dd, J=15, 5 Hz), 3.45 (1H, dd, J=15, 5 Hz).
EXAMPLE 5 (2) 3-(4-(Pyridin-4-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0983] 1642
[0984] TLC: Rf 0.33 (ethyl acetate);
[0985] NMR (CDCl3): &dgr; 8.65-8.60 (2H, m), 7.80-7.30 (8H, m), 7.00-6.90 (2H, m), 5.10 (2H, s), 4.85 (1H, t, J=5 Hz), 3.75 (1H, dd, J=15, 5 Hz), 3.45 (1H; dd, J=15, 5 Hz)
EXAMPLE 5 (3) 3-(4-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0986] 1643
[0987] TLC: Rf 0.14 (hexane:ethyl acetate=1:1);
[0988] NMR (CD3OD): &dgr; 1.90-2.10 (m, 2H), 3.30-3.50 (m, 1H), 3.50-4.00 (m, 3H), 4.00-4.20 (m, 2H), 4.90-5.10 (m, 1H), 6.80-7.00 (m, 2H), 7.30-7.50 (m, 2H), 7.50-7.80 (m, 4H).
EXAMPLE 5(4) 3-(3-(Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo [b] thiophene[0989] 1644
[0990] TLC: Rf 0.44 (ethyl acetate);
[0991] NMR (CDCl3): &dgr; 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.80 (dd, J=12.5, 7.5 Hz, 1H), 4.95-5.10 (m, 1H), 5.00 (s, 2H), 6.90-7.10 (m, 3H), 7.20-7.40 (m, 2H), 7.50-7.80 (m, 5H), 8.50-8.70 (m, 2H).
EXAMPLE 5(5) 3-(3-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0992] 1645
[0993] TLC: Rf 0.17 (hexane:ethyl acetate=1:1);
[0994] NMR (CDCl3): &dgr; 1.95-2.05 (m, 2H), 3.50 (dd, J=12.5, 7.5 Hz, 1H), 3.80 (dd, J=12.5,7.5 Hz, 1H), 3.85 (t, J=7.5 Hz, 2H), 4.05 (t, J=7.5 Hz, 2H), 5.00 (t, J=7.5 Hz, 1H), 6.80-7.05 (m, 3H), 7.20-7.30 (m, 1H), 7.50-7.80 (m, 4H)).
EXAMPLES 5 (6) 3-(2-(Pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0995] 1646
[0996] TLC: Rf 0.16 (hexane:ethyl acetate=1:1);
[0997] NMR (CD3OD): &dgr; 3.50 (dd, J=15, 5.0 Hz, 1H), 3.85 (dd, J=15, 7.5 Hz, 1H), 5.20 (dd, J=7.5, 5.0 Hz, 1H), 5.25 (s, 2H), 7.00 (t, J=7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.35-7.70 (m, 7H), 8.00 (d, J=7.5 Hz, 1H), 8.50 (dd, J=5.0, 2.5 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H).
EXAMPLES 5 (7) 3-(2-(3-Hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[0998] 1647
[0999] TLC: Rf 0.30 (hexane:ethyl acetate=1:2);
[1000] NMR (CDCl3): &dgr; 2.05-2.10 (m, 2H), 2.30-2.60 (m, 1H), 3.50 (dd, J=15, 5.0 Hz, 1H), 3.70 (dd, J=5, 7.5 Hz, 1H), 3.90 (t, J=5.0 Hz, 2H), 4.20-4.40 (m, 2H), 5.10 (dd, J=7.5, 5.0 Hz, 1H), 6.90-7.00 (m, 2H), 7.30 -7.80 (m, 6H).
EXAMPLE 5 (8) 3-(4-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1001] 1648
[1002] TLC: Rf 0.30 (toluene:ethyl acetate=4:1);
[1003] NMR (CDCl3): &dgr; 7.80-7.10 (6H, m), 6.80 (2H, d, J=10 Hz), 5.10-4.70 (2H, m), 4.00 (2H, t, J=5 Hz), 3.75 (1H, dd, J=15, 7.5 Hz), 3.60-3.40 (3H, m), 1.45 (9H, s).
EXAMPLE 5 (9) 3-(3-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1004] 1649
[1005] TLC: Rf 0.40 (hexane ethyl:acetate=1:1);
[1006] NMR (CDCl3): &dgr; 7.80-7.50 (4H, m), 7.40-7.20 (1H, m), 7.05-6.70 (3H, m), 5.05-4.90 (2H, m), 3.95 (2H, t, J=5 Hz), 3.80 (1H, dd, J=15, 5 Hz), 3.60-3.40 (3H, m), 1.45 (9H, s).
EXAMPLE 6 3-(4-(Pyridin-2-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1007] 1650
[1008] By the same procedure as described in Example 3 using the compound prepared in Example 5 instead of the compound prepared in Example 1, and then by converting into the corresponding hydrochloride by a known method, the compound of the present invention having the following physical data was obtained.
[1009] Free Compound:
[1010] TLC: Rf 0.44 (ethyl acetate);
[1011] NMR (DMSO-d6): &dgr; 8.60-8.55 (1H, m), 7.90-7.60 (7H, m), 7.50 (1H, d, J=7.5 Hz), 7.40-7.30 (1H, m), 7.20 (2H, d, J=7.5 Hz), 5.70 (1H, dd, J=10, 2.5 Hz), 5.30 (2H, s), 4.00 (1H, dd, J=15, 10 Hz), 3.75 (1H, dd, J=15, 2.5 Hz).
[1012] Hydrochloride:
[1013] TLC: Rf 0.49 (ethyl acetate:triethylamine=19:1);
[1014] NMR (CD3OD): &dgr; 3.80 (dd, J=15, 25 Hz, 1H), 3.95 (dd J-15, 10 Hz, 1H), 5.50 (dd, J=10, 2.5 Hz, 1H), 5.60 (s, 2H), 7.20 (d, J=7.5 Hz, 2H), 7.55-8 00 (m, 4H), 7.70 (d, J=7.5 Hz, 2H), 8.05-8.25 (m, 2H), 8.60-8.95 (m, 2H).
EXAMPLES 6 (1)˜6 (9)[1015] Using the compounds prepared in Examples 5 (1)˜5 (9) instead of the compound prepared in Example 5, by the same procedure as described in Example 5, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE® as an oxidant, and if necessary, by converting into corresponding salts, the following compounds of the present invention were obtained.
EXAMPLE 6 (1) 3-(4-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1016] 1651
[1017] Free Compound:
[1018] TLC: Rf 0.27 (ethyl acetate);
[1019] NMR (CDCl3): &dgr; 8.70-8.55 (2H, m), 8.10-8.00 (1H, m), 7.80-7.50 (6H, m), 7.40-7.30 (1H, m), 7.10-6.90 (2H, m), 5.15 (2H, s), 5.20-5.00 (1H, m), 3.90-3.70 (2H, m).
[1020] Hydrochloride:
[1021] TLC: Rf 0.38 (ethyl acetate:triethylamine=19:1);
[1022] NMR (CD3OD): &dgr; 3.80 (dd,J=15,2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.45 (s, 2H), 5.45-5.55 (m, 1H), 7.20 (d, J=10 Hz, 2H), 7.60-8.00 (m, 4H), 7.60(d, J=10 Hz, 2H), 8.10-8.20 (m, 1H), 8.70-9.00 (m, 3H).
EXAMPLE 6 (2) 3-(4-(Pyridin-4-ylmethyloxy)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1023] 1652
[1024] Free Compound:
[1025] TLC: Rf 0.22 (ethyl acetate);
[1026] NMR (DMSO-d6): &dgr; 8.60 (2H, d, J=5 Hz), 7.90-7.65 (6H, m), 7.45 (2H, d, J=5 Hz), 7.20 (2H, d, J=7.5 Hz), 5.75 (1 H, dd, J=7.5, 2.5 Hz), 5.30 (2H, s), 4.00 (1 H, dd, J=15, 7.5 Hz), 3.80 (1 H, dd, J=15, 2.5 Hz).
[1027] Hydrochloride:
[1028] TLC: Rf 0.35 (ethyl acetate:triethylamine=19:1);
[1029] NMR (DMSO-d6): &dgr; 3.80 (dd, J=15, 2.5 Hz, 1H), 4.00 (dd, J=15, 10 Hz, 1H), 5.55 (s, 2H), 5.75 (dd, J=10, 2.5 Hz, 1H), 7.25 (d, J=10 Hz, 2H), 7.65-7.90 (m, 4H), 7.70 (d, J=10 Hz, 2H), 7.95 (d, J=7.5 Hz, 2H), 8.90 (d, J=7.5 Hz, 2H).
EXAMPLE 6 (3) 3-(4-(3-Hydroxypropylpxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1030] 1653
[1031] TLC: Rf 0.33 (ethyl acetate );
[1032] NMR (CDCl3): &dgr; 2.05 (quint., J=5.0 Hz, 2H), 3.70-3.90 (m, 2H), 3.85 (t, J=5.0 Hz, 2H), 4.15 (t, J=5.0 Hz, 2H), 5.05 (t, J=7.5 Hz, 1H), 6.90 (d, J=10 Hz, 2H), 7.50 (d, J=10 Hz, 2H), 7.60-7.80 (m, 3H), 8.05 (d, J=7.5 Hz, 1H).
EXAMPLE 6 (4) 3-(3-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1033] 1654
[1034] TLC: Rf 0.60 (ethyl acetate methanol:triethylamine=16:2:1);
[1035] NMR (CD3OD): &dgr; 3.85 (dd, J=15, 5.0 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.35 (d, J=12.5 Hz, 1H), 5.45 (d, J=12.5 Hz, 1H), 5.55 (dd, J=10, 5.0 Hz, 1H), 7.20-7.85 (m, 7H), 7.95 (d, J=7.5 Hz, 1H), 8.15 (dd, J=10, 7.5 Hz, 1H), 8.75 (d, J=7.5 Hz, 1H), 8.85 (d, J=5.0 Hz, 1H), 9.00 (s, 1H).
EXAMPLE 6 (5) 3-(3-(3-Hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1036] 1655
[1037] TLC: Rf 0.33 (ethyl acetate );
[1038] NMR (CDCl3): &dgr; 1.90-2.20 (m, 2H), 3.65-3.90 (m, 4H), 3.95-4.20 (m, 2H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.10-7.30 (m, 3H), 7.30-7.45 (m, 1H), 7.60-7.80 (m, 3H), 8.00 (d, J=5.0 Hz, 1H).
EXAMPLE 6 (6) 3-(2-(Pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1039] 1656
[1040] TLC: Rf 0.51 (ethyl acetate:methanol triethylamine=16:2:1);
[1041] NMR (DMSO-d6): &dgr; 3.70 (dd, J=15, 2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 5.60 (s, 2H) 5.75 (dd, J=10, 2.5 Hz, 1H), 7.20-7.35 (m, 1H), 7.40-7.60 (m, 2H), 7.60-7.90 (m, 5H), 7.95-8.10 (m, 1H), 8.60 (d, J=7.5 Hz, 1H), 8.90 (d, J=5.0 Hz, 1H), 9.05 (s, 1H).
EXAMPLE 6 (7) 3-(2-(3-Hydroxypropylpxy)phenyl)sulfonyl-2,3-dyhydro-1,1-dioxidebenzo[b]thiophene[1042] 1657
[1043] TLC: Rf 0.37 (ethyl acetate);
[1044] NMR (CDCl3): &dgr; 5 2.00-2.30 (m, 2H), 2.50-2.80 (m, 1H), 3.55 (dd, J=15, 10 Hz, 1H), 3.80 (dd, J=15, 5.0 Hz, 1H), 3.95 (t, J=5.0 Hz, 2H), 4.25-4.50 (m, 2H), 5.65 (dd, J=10, 5.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.60-7.80 (m, 4H), 7.80-7.95 (m, 2H).
EXAMPLE 6 (8) 3-(4-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1045] 1658
[1046] TLC: Rf 0.40 (hexane ethyl:acetate=1:2);
[1047] NMR (DMSO-d6): &dgr; 1.40 (s, 9H), 3.80 (dd, J=15, 2.5 Hz, 1H), 3.90-4.15 (m, 5H), 5.75 (dd, J=10, 2.5 Hz, 1H), 6.90-7.10 (m, 1H), 7.10 (d, J=7.5 Hz, 2H), 7.60-7.85 (m, 4H), 7.65 (d, J=7.5 Hz, 2H).
EXAMPLE 6 (9) 3-(3-(2-(t-Butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1048] 1659
[1049] TLC: Rf 0.13 (hexane:ethyl acetate=1:1); NMR (CDCl3): &dgr; 1.45 (s, 9H), 3.45-3.55 (m, 2H), 3.70-4.00 (m, 4H), 4.85-5.00 (m, 1H), 5.10 (dd, J=10, 5.0 Hz, 1H), 7.00-7.50 (m, 4H), 7.60-7.80 (m, 3H), 8.05 (d, J=7.5 Hz, 1H).
EXAMPLE 7 3-(4-(2-Aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1050] 1660
[1051] To a solution of the compound prepared in Example 6 (8) (200 mg) in dioxane (25 ml) and methanol (5 ml), was added a solution of 4N hydrochloric acid in dioxane (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give the compound of the present invention (160 mg) having the following physical data.
[1052] TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=16:3:1);
[1053] NMR (CD3OD): &dgr; 3.35 (t, J=5.0 Hz, 2H), 3.80 (dd, J=15, 5.0 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 4.30 (t, J=5.0 Hz, 2H), 5.45 (dd, J=10, 5.0 Hz, 1H), 7.10 (d, J=7.5 Hz, 2H), 7.60 (d, J=7.5 Hz, 2H), 7.60-8.00 (m, 4H).
EXAMPLE 7 (1) 3-(3-(2-Aminoethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1054] 1661
[1055] By the same procedure as described in Example 7 using the compound prepared in Example 6 (9) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained.
[1056] TLC: Rf 0.60 (ethyl acetate:methanol triethylamine=14:3:1);
[1057] NMR (CD3OD): &dgr; 3.25-3.45 (m, 2H), 3.80-4.00 (m, 2H), 4.15-4.35 (m, 2H), 5.55 (dd, J=7.5, 2.5 Hz, 1H), 7.20-7.50 (m, 4H), 7.60-8.00 (m, 4H).
EXAMPLE 8 3-(4-(2-(N,N-Dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1058] 1662
[1059] To a solution of the compound prepared in Example 7 (105 mg) and 90% paraformaldehyde (87 mg) in a mixture of acetic acid (3 ml) and methanol (3 ml), was added sodium cyanoborohydride (86 mg) at 0° C. The reaction mixture was stirred at room temperature overnight. To the reaction mixture, a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted by ethyl acetate. The extract was washed by water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:methanol:triethylamine=16:3:1). Then to a solution of the obtained compound in dioxane (25 ml) and methanol (5 ml), was added a solution of 4N hydrochloric acid-dioxane (10 ml) at room temperature. The reaction mixture was stirred for 30 minutes and concentrated to give the compound of the present invention (35 mg) having the following physical data.
[1060] TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=16:3:1); NMR (CD3OD): &dgr; 3.10(s, 6H), 3.60 (t, J=5.0 Hz, 2H), 3.80 (dd, J=15, 2.5 Hz, 1H), 3.95 (dd, J=15, 10 Hz, 1H), 4.45 (t, J=5.0 Hz, 2H), 5.50 (dd, J=10, 2.5 Hz, 1H), 7.10 (d, J=7.5 Hz; 2H), 7-60 (d, J=7.5 Hz, 2H), 7.60-8.00 (m, 4H).
EXAMPLE 8 (1) 3-(3-(2-(N,N-Dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1061] 1663
[1062] By the same procedure as described in Example 8 using the compound prepared in Example 7 (1) instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained.
[1063] TLC: Rf 0.44 (ethyl acetate:methanol:triethylamine=16:2:1);
[1064] NMR (DMSO-d6): &dgr; 2.80 (s, 6H), 3.50 (t, J=5.0 Hz, 2H), 3.85 (dd, J=15, 2.5 Hz, 1H), 4.00 (dd, J=15, 10 Hz, 1H), 4.30-4.55 (m, 2H), 5.90 (dd, J=10, 2.5 Hz, 1H), 7.30-7.60 (m, 4H), 7.70-7.90 (m, 4H).
EXAMPLE 9 5-Nitro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1065] 1664
[1066] By the same procedure as described in Example 1 using 5-nitrobenzothiophene-1,1-dioxide instead of benzothiophene-1,1-dioxide, the compound of the present invention having the following physical data was obtained.
[1067] TLC: Rf 0.35 (hexane:ethyl acetate=2:1);
[1068] NMR (CDCl3): &dgr; 8.52 (1 H, d, J=2 Hz), 8.38 (1 H, dd. J=8.4, 2.0 Hz), 7.89 (1 H, d, J=8.4 Hz), 7.48-7.36 (5H, m), 4.97 (1H, dd, J=7.2, 6.8 Hz), 3.92 (1H, dd, J=13.6, 7.2 Hz), 3.60 (1H, dd, J=13.6, 6.8 Hz).
EXAMPLES 9 (1)˜9 (17)[1069] By the same procedure as described in Example 9 using a corresponding benzothiophene-1,1-dioxide instead of 5-nitrobenzothiophene-1,1-dioxide, the following compounds were obtained.
EXAMPLE 9 (1)[1070] 6-Methoxy-3-phenylthio-2,3-dihydro-1,1-di oxidebenzo[b]thiophene 1665
[1071] TLC: Rf 0.60 (hexane:ethyl acetate=1:1);
[1072] NMR (CDCl3): &dgr; 3.52 (dd, J=13.6 Hz, 6.8 Hz, 1H), 3.81 (dd, J=13.6 Hz, 6.8 Hz, 1H), 3.86 (s, 3H), 4.92 (t, J=6.8 Hz, 1H), 7.14-7.21 (m, 2H), 7.32-7.40 (m, 3H), 7.40-7.43 (m, 2H), 7.57-7.61 (m, 1H).
EXAMPLE 9 (2) 4-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo [b]thiophene[1073] 1666
[1074] TLC: Rf 0.21 (hexane:methylene chloride=1:4);
[1075] NMR (CDCl3): &dgr; 3.60 (dd, J=14.0 Hz, 1.8 Hz, 1H), 3.71 (dd, J=14.0 Hz, 6.9 Hz, 1H), 3.91 (s, 3H), 5.05 (dd, J=6.9 Hz, 1.8 Hz, 1H), 7.07 (dd, J=8.1 Hz, 0.7 Hz, 1H), 7.29-7.37 (m, 4H), 7.48-7.56 (m, 3H).
EXAMPLE 9 (3) 5-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1076] 1667
[1077] TLC: Rf 0.62 (hexane:ethyl acetate=1:1);
[1078] NMR (CDCl3): &dgr; 3.51 (dd, 1H, J=14, 5 Hz), 3.79 (dd, 1H, J=14, 5 Hz), 3.88 (s, 3H), 4.92 (t, 1H, J=5 Hz), 7.04 (dd, 1H, J=5 Hz, 2 Hz), 7.13 (d, 1H, J=2 Hz), 7.35 (m, 3H), 7.44 (m, 2H), 7.63 (d, 1 H, J=5 Hz).
EXAMPLE 9 (4) 7-Methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1079] 1668
[1080] TLC: Rf 0.42 (hexane:ethyl acetate=1:1);
[1081] NMR (CDCl3): &dgr; 7.62-7.38 (1H, m), 7.58-7.28 (6H, m), 6.79 (1H, d, J=8.4 Hz), 4.89 (1H, t, J=7.6 Hz), 3.97 (3H, s), 3.78 (1H, dd, J=13.5, 7.6 Hz), 3.52 (1H, dd, J=13.5, 7.6 Hz).
EXAMPLE 9 (5) 4-Chloro-3-phenylthin-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1082] 1669
[1083] TLC: Rf 0.31 (hexane:ethyl acetate=2:1);
[1084] NMR (CDCl3): &dgr; 3.68 (dd, J=14.2, 3.0 Hz, 1H), 3.75 (dd, J=14.2, 5.6 Hz, 1H), 5.00 (dd, J=5.6, 3.0 Hz, 1H), 7.35-7.40 (m, 3H), 7.49-7.59 (m, 3H), 7.64-7.69 (m, 2H).
EXAMPLE 9 (6) 5-(t-Butoxycarbonylamino)methyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1085] 1670
[1086] TLC: Rf 0.44 (hexane:ethyl acetate=1:1);
[1087] NMR (CDCl3): &dgr; 1.45 (s, 9H), 3.60 (dd, J=12.5, 2.5 Hz, 1H), 3.75 (dd, J=12.5 Hz, 7.5 Hz, 1H), 4.50 (dd, J=15, 5.0 Hz, 1H), 4.85 (dd, J=15, 7.5 Hz, 1H), 5.00-5.20 (m, 2H) 7.30-7.45 (m, 3H), 7.50-7.75 (m, 5H).
EXAMPLE 9 (7) 4,7-Dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1088] 1671
[1089] TLC: Rf 0.45 (hexane:ethyl acetate=2:1);
[1090] NMR (CDCl3): &dgr; 7.50-7.30 (5H, m), 7.20 (1H, d, J=7.8 Hz), 4.89 (1H, dd, J=5.8, 2.2Hz), 3.75-3.55 (2H, m), 2.60 (3H, s), 2.54 (3H, s).
EXAMPLE 9 (8) 4,6-Dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1091] 1672
[1092] TLC: Rf 0.50 (hexane:ethyl acetate=2:1);
[1093] NMR (CDCl3): &dgr; 5 7.56-7.24 (7H, m), 4.90 (1H, dd, J=6.0, 1.8 Hz), 3.80-3.66 (2H, m 2.56 (3H, s), 2.42 (3H, s).
EXAMPLE 9 (9) 4-Ethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1094] 1673
[1095] TLC: Rf 0.44 (hexane:ethyl acetate=2:1);
[1096] NMR (CDCl3): &dgr; 5 7.65-7.30 (8H, m), 4.99 (1H, dd, J=5.9, 2.4 Hz), 3.75-3.57 (2H, m 2.98 (2H, q, J=7.6 Hz), 1.37 (3H, t, J=7.6 Hz).
EXAMPLE 9 (10) 4-Methoxy-5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1097] 1674
[1098] TLC: Rf 0.44 (hexane:ethyl acetate=2:1);
[1099] NMR (CDCl3): &dgr; 7.99 (1H, d, J=8.0 Hz), 7.60-7.50 (3H, m), 7.45-7.35 (3H, m), 5.11 (1H, dd, J=5.9, 2.8 Hz), 4.45 (2H, q, J=7.0 Hz), 4.09 (3H, s), 3.75-3.60 (2H, m), 1.44 (3H, t, J=7.0 Hz).
EXAMPLE 9 (11) 4-Bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1100] 1675
[1101] TLC: Rf 0.20 (hexane:ethyl acetate=3:1);
[1102] NMR (CDCl3): &dgr; 3.69 (dd, J=13.9, 2.8Hz, 1H), 3.74 (dd, J=13.9, 5.3Hz, 1H), 4.94 (dd, J=5.3, 2.8 Hz, 1H), 7.37-7.39 (m, 3H), 7.45 (t, J=7.8 Hz, 1H), 7.57-7.60 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz, 1H).
EXAMPLE 9 (12) 4-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1103] 1676
[1104] TLC: Rf 0.21 (hexane:ethyl acetate=1:1);
[1105] NMR (CDCl3): &dgr; 3.49 (dd, J=13.9, 5.9 Hz, 1H), 3.81 (dd, J=13.9, 7.5 Hz, 1H), 4.93 (dd, J=7.5, 5.9 Hz, 1H), 7.17 (dd, J=8.0, 0.5 Hz, 1H), 7.25-7.51 (m, 7H).
EXAMPLE 9 (13) 5-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1106] 1677
[1107] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[1108] NMR (CDCl3): &dgr; 3.51 (dd, J=14.0, 7.0 Hz, 1H), 3.78 (dd, J=14.0, 7.0 Hz, 1H), 4.89 (t, J=7.0 Hz, 1H), 6.32 (s, 1H), 6.94 (dd, J=5.0 Hz, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.35 (m, 3H), 7.43 (m, 2H), 7.58 (d, J=5.0 Hz, 1H).
EXAMPLE 9 (14) 6-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1109] 1678
[1110] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[1111] NMR (CDCl3): &dgr; 3.54 (dd, J=13.8, 5.9 Hz, 1H), 3.83 (dd, J=13.8, 7.4 Hz, 1H), 4.91 (t-like, J=6.6 Hz, 1H), 7.10-7.15 (m, 2H), 7.31-7.42 (m, 5H), 7.51-7.56 (m, 1H).
EXAMPLE 9 (15) 7-Hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1112] 1679
[1113] TLC: Rf 0.52 (hexane:ethyl acetate=2:1);
[1114] NMR (CDCl3): &dgr; 7.50-7.20 (5H, m), 7.11 (1 H, d, J=8.0 Hz), 6.85 (1 H, d, J=8.0 Hz), 6.68 (1H, dd, J=32.6, 6.6 Hz), 4.91 (1H, t, J=7.5 Hz), 3.79 (1H, dd, 14, 7.5 Hz), 3.50 (1H, dd, J=14, 7.5 Hz).
EXAMPLE 9 (16) 3-Phenylthio-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine[1115] 1680
[1116] TLC: Rf 0.50 (hexane: ethyl acetate=1:1);
[1117] NMR (CDCl3): &dgr; 3.49 (dd, J=14.0, 7.0 Hz, 1H), 3.85 (dd, J=14.0, 8.0 Hz, 1H), 4.91 (dd, J=8.0, 7.0 Hz, 1H), 7.40 (m, 5H), 7.58 (dd, J=8.0, 5.0 Hz, 1H), 8.08 (m, 1H), 8.76 (m, 1H).
EXAMPLE 9 (17) 4,7-dihydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1118] 1681
[1119] TLC: Rf 0.33 (methylene chloride:ethyl acetate=1:1);
[1120] NMR (CDCl3): &dgr; 9.25 (2H, brs), 7.55-7.45 (2H, m), 7.40-7.30 (3H, m), 6.96 (1H, d, J=8.8 Hz), 6.85 (1H, d, J=8.8 Hz), 5.09 (1 H, dd, J=7.4, 1.6 Hz), 3.71 (1H, dd, 13.9, 7.4 Hz), 3.50 (1H, dd, J=13.9, 1.6 Hz).
EXAMPLE 10 5-Nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1121] 1682
[1122] To a solution of the compound prepared in Example 9 (790 mg) in chloroform (45 ml) was added 3-chloroperbenzoic acid (70 % purity, 1.21 g). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by 2N aqueous solution of sodium hydroxide, water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=3:2) to give the compound of the present invention (497 mg) having the following physical data.
[1123] TLC: Rf 0.39 (hexane:ethyl acetate=1:1);
[1124] NMR (CDCl3): &dgr; 3.98 (dd, J=15.5, 3.0 Hz, 1H), 4.19 (dd, J=15.5, 9.3 Hz, 1H), 5.95 (dd, J=9.3, 3.0 Hz, 1H), 7.59-7.67 (m 2H), 7.78-7.84 (m, 3H), 8.11 (d, J=8.6 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.51 (dd, J=8.6, 2.0 Hz, 1H).
EXAMPLES 10 (1)˜10 (16)[1125] Using the compounds prepared in Examples 9 (1)˜9 (16) instead of the compound prepared in Example 9, by the same procedure as described in Example 10, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@, the following compounds of the present invention were obtained.
EXAMPLE 10 (1) 6-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene[1126] 1683
[1127] TLC: Rf 0.34 (hexane:ethyl acetate=1:1);
[1128] NMR (CDCl3): &dgr; 3.66-3.82 (m, 2H), 3.87 (s, 3H), 5.00 (dd, J=7.5, 5.5 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz, 1H), 7.46-7.54 (m, 2H), 7.63-7.71 (m, 3H), 7.86 (d, J=8.8 Hz, 1H).
EXAMPLE 10 (2) 4-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1 -dioxidebenzo[b]thiophene[1129] 1684
[1130] TLC: Rf 0.17 (hexane:ethyl acetate=1:1);
[1131] NMR (CDCl3): &dgr; 3.49 (s, 3H), 3.76 (dd, J=14.9, 9.2 Hz, 1H), 4.31 (dd, J=14.9, 1.3 Hz, 1H), 5.23 (dd, J=9.2, 1.3 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 7.31 (d, J=7.8 Hz; 1H) 745-7.54 (m, 3H), 7.58-7.68 (m, 1H), 7.72-7.77 (m, 2H).
EXAMPLE 10 (3) 5-Methoxy-3-phenylsulfonyl-2,3-dihydro-1, 1 -dioxidebenzo[b]thiophene[1132] 1685
[1133] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[1134] NMR (CDCl3): &dgr; 3.70(dd, J=12, 8 Hz, 1H), 3.77(dd, J=12, 4 Hz, 1H), 3.94(s, 3H), 5.01 (dd, J=8, 4 Hz, 1H), 7.12(d, J=8 Hz, 1H), 7.44(s, 1H), 7.53(m, 3H), 7.68(m, 3H).
EXAMPLE 10 (4) 7-Methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1135] 1686
[1136] TLC: Rf 0.40 (hexane:ethyl acetate=1:2);
[1137] NMR (DMSO-d6): &dgr; 7.80-7.55 (6H, m), 7.27 (1H, d, J=8.2 Hz), 7.15 (1H, d, J=8.2 Hz), 5.73(1H, dd, J=9.5, 3.4 Hz), 3.91 (1H, dd, J=15, 9.5 Hz), 3.87 (3H, s), 3.69 (1H, dd, J=15, 3.4 Hz).
EXAMPLE 10 (5) 4-Chioro-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1138] 1687
[1139] TLC: Rf 0.43 (methylene chloride:ethyl acetate=15:1);
[1140] NMR (CDCl3): &dgr; 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.24 (dd, J=15.0, 1.0 Hz, 1H), 5.26 (dd, J=9.2, 1.0 Hz, 1H), 7.46-7.66 (m, 6H), 7.77-7.81 (m, 2H).
EXAMPLE 10 (6) 4-(t-Butoxycarbonylamino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1141] 1688
[1142] TLC: Rf 0.26 (hexane:ethyl acetate=1:1);
[1143] NMR (CDCl3): &dgr; 1.45 (s, 9H), 3.75 (dd, J=15, 10 Hz, 1H), 3.85 (dd, J=15, 2.5 Hz, 1H), 4.40 (dd, J=5, 5.0 Hz, 1H), 4.95 (dd, J=15, 7.5 Hz, 1H), 5.35 (m, 2H), 7.45-7.90 (m, 8H).
EXAMPLE 10 (7) 4,7-Dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1144] 1689
[1145] TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
[1146] NMR (DMSO-d6): &dgr; 7.81-7.70 (3H, m), 7.70-7.55 (2H, m), 7.48 (1 H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 5.73 (1H, t, J=5.2 Hz), 3.84 (2H, d-like, J=5.2 Hz), 2.40 (3H, s), 2.36 (3H, s).
EXAMPLE 10 (8) 4,6-Dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1147] 1690
[1148] TLC: Rf 0.18 (hexane:ethyl acetate=2:1);
[1149] NMR (DMSO-d6): &dgr; 7.82-7.70 (3H, m), 7.70-7.55 (2H, m), 7.42 (2H, d, J=5.4 Hz), 5.73 (1 H, t, J=4.8 Hz), 3.86-3.80 (2H, m), 2.38 (6H, s).
EXAMPLE 10 (9) 4-Ethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1150] 1691
[1151] TLC: Rf 0.22 (hexane:ethyl acetate=2:1);
[1152] NMR (CDCl3): &dgr; 7.68-7.40 (8H, m), 5.22 (1H, d, J=9.2 Hz), 3.99 (1H, d, J=15.2 Hz), 3.76 (1 H, dd, J=15.2, 9.2 Hz), 3.07 (2H, dd, J=7.6, 2.2 Hz), 1.33 (3H, t, J=7.6 Hz).
EXAMPLE 10 (10) 4-Methoxy-5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1153] 1692
[1154] TLC: Rf 0.38 (hexane:ethyl acetate=1:1);
[1155] NMR (CDCl3): &dgr; 7.91 (1H, d, J=8.0 Hz), 7.83-7.45 (5H, m), 7.41 (1H, d, J=8.0 Hz), 5.28 (1H, d-like, J=8.0 Hz), 4.42 (2H, q, J=7.0 Hz), 4.17 (1H, dd, J=15, 1.6 Hz), 3.86 (3H, s), 3.75 (1H, dd, J=15, 8.0 Hz), 1.43 (3H, t, J=7.0 Hz).
EXAMPLE 10 (11) 4-Bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1156] 1693
[1157] TLC: Rf 0.35 (hexane:ethyl acetate=1:1);
[1158] NMR (CDCl3): &dgr; 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.23 (dd, J=15.0, 1.1 Hz, 1H), 5.23 (d-like, J=8.8 Hz, 1H), 7.44-7.54 (m, 3H), 7.62-7.70 (m, 2H), 7.78-7.83 (m, 3H).
EXAMPLE 10 (12) 4-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1159] 1694
[1160] TLC: Rf 0.22 (hexane:ethyl acetate=1:2);
[1161] NMR (DMSO-d6): &dgr; 3.96 (dd, J=15.0, 8.4 Hz, 1H), 4.08 (dd, J=15.0, 1.8 Hz, 1H), 5.51 (dd, J=8.4, 1.8 Hz, 1H), 7.00 (d-like, J=8.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.56-7.63 (m, 2H), 7.71-7.81 (m, 3H).
EXAMPLE 10 (13) 5-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1162] 1695
[1163] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[1164] NMR (DMSO-d6): &dgr; 3.66 (dd, J=14, 4 Hz, 1H), 3.90 (dd, J=14, 9 Hz, 1H), 5.71 (dd, J=9, 4 Hz, 1H), 7.07 (m, 2H), 7.55-7.82 (m, 6H), 10.80 (brs, 1H).
EXAMPLE 10 (14) 6-Hydroxy-3-phenylsulfonyl-2,3-dyhydro-1,1-dioxidebenzo[b]thiophene[1165] 1696
[1166] TLC: Rf 0.37 (hexane:ethyl acetate=1:2);
[1167] NMR (DMSO-d6): &dgr; 3.73 (dd, J=15.2, 3.2 Hz, 1H), 3.96 (dd, J=15.2, 9.2 Hz, 1H), 5.60 (dd, J=9.2, 3.2 Hz, 1H), 6.94 (s-like, 1H), 7.16 (d-like, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.57-7.64 (m, 2H), 7.71-7.76 (m, 3H).
EXAMPLE 10 (15) 7-Hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1168] 1697
[1169] TLC: Rf 0.31 (hexane:ethyl acetate 1:2);
[1170] NMR (DMSO-d6): &dgr; 7.80-7.45 (6H, m), 6.98 (2H, d, J=8.4 Hz), 5.66 (1H, dd, J=9.6, 3.2 Hz), 3.85 (1H, dd, J=15, 9.6 Hz), 3.68-3.58 (1H, m).
EXAMPLE 10 (16) 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine[1171] 1698
[1172] TLC: Rf 0.20 (hexane:ethyl acetate=1:1);
[1173] NMR (CDCl3): &dgr; 3.65 (dd, J=15, 8 Hz, 1H), 3.74 (dd, J=15, 6 Hz, 1H), 5.04 (dd, J=8, 6 Hz, 1H), 7.58 (m, 2H), 7.69 (m, 4H), 8.48 (m, 1H), 8.86 (m, 1H).
EXAMPLE 11 5-Amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1174] 1699
[1175] Under an atmosphere of argon, to a solution of the compound prepared in Example 10 (110 mg) in ethanol (7.5 ml) and ethyl acetate (7.5 ml), was added 5% palladium-carbon (20 mg). The reaction mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtrated through celite (trade name). The filtrate was concentrated. The residue was purified with column chromatography on silica gel (methylene chloride:ethyl acetate=2:1) to give the compound of the present invention (94 mg) having the following physical data. Then, it was converted into a corresponding salt by a known method to give the compound of the present invention having the following physical data.
[1176] Free Compound:
[1177] TLC: Rf 0.29 (hexane:ethyl acetate=1:2);
[1178] NMR (CDCl3): &dgr; 3.61 (dd, J=14.6, 8.3 Hz, 1H), 3.70 (dd, J=14.6, 5.6 Hz, 1H), 4.34 (brs, 2H), 4.94 (dd, J=8.3, 5.6 Hz, 1H), 6.79 (dd, J=8.0, 2.0 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.49-7.55 (m, 2H), 7.63-7.74 (m, 3H).
[1179] Hydrochloride:
[1180] TLC: Rf 0.47 (methylene chloride:methanol=18:1);
[1181] NMR (DMSO-d6): &dgr; 3.53 (dd, J=14.9, 3.8 Hz, 1H), 3.75 (dd, J=14.9, 9.4 Hz, 1H), 5.58 (dd, J=9.4, 3.8 Hz, 1H), 6.76 (dd, J=8.6, 2.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.57-7.65 (m, 2H), 7.72-7.79 (m, 3H).
EXAMPLE 12 5-Acetylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1182] 1700
[1183] To a solution of the compound prepared in Example 11 (91 mg) in pyridine (2 ml), was added acetic anhydride (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (86 mg) having the following physical data.
[1184] TLC: Rf 0.20 (hexane:ethyl acetate=1:2);
[1185] NMR (CDCl3): &dgr; 2.24 (s, 3H), 3.66 (dd, J=14.8, 8.3 Hz, 1H), 3.75 (dd, J=14.8, 5.2 Hz, 1H), 5.04 (dd, J=8.3, 5.2 Hz, 1H), 7.49-7.59 (m, 3H), 7.66-7.75 (m, 3H), 7.87-7.94 (m, 2H), 8.04 (s-like, 1H).
EXAMPLE 13 5-Aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1186] 1701
[1187] By the same procedure as described in Example 7 using the compound prepared in Example 10 (6) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained.
[1188] TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=16:2:1);
[1189] NMR (DMSO-d6): &dgr; 3.80-4.00 (m, 2H), 4.35 (d, J=15 Hz, 1H), 4.55 (d, J=15 Hz, 1H), 6.30-6.40 (m, 1H), 7.60-7.70 (m, 2H), 7.75-7.95 (m, 5H), 8.00-8.15 (m, 1H), 8.30-8.65 (m, 2H).
EXAMPLE 14 4-(N,N-dimethylamino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1190] 1702
[1191] By the same procedure as described in Example 8 using the compound prepared in Example 13 instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained.
[1192] TLC: Rf 0.50 (ethyl acetate:methanol:triethylamine=16:2:1);
[1193] NMR (DMSO-d6): &dgr; 2.65 and 2.70 (both s, total 3H), 2.85 and 2.90 (both s, total 3H), 3.80 (d, J=12.5 Hz, 1H), 4.05 (dd, J=12.5, 7.5 Hz, 1H), 4.50-4.70 (m, 1H), 4.70-4.90 (m, 1H), 6.35 (d, J=7.5 Hz, 1H), 7.60-8.00 (m, 7H), 8.20-8.35 (m, 1H), 10.85 (brs, 1H).
EXAMPLE 15 4-Methoxy-5-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1194] 1703
[1195] To a suspension of lithium aluminum hydride (54 mg) in tetrahydrofuran (10 ml), was added a solution of the compound prepared in Example 10 (10) (300 mg) in tetrahydrofuran (10 ml) at −78° C. dropwise. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was poured into ice-water. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (51 mg) having the following physical data.
[1196] TLC: Rf 0.27 (hexane:ethyl acetate=1:2);
[1197] NMR (CDCl3): &dgr; 3.80 (dd, J=15.2, 9.3 Hz, 1H), 4.05 (s, 3H), 4.14 (dd, J=15.2, 1.4 Hz, 1H), 5.28 (dd, J=9.3, 1.4 Hz, 1H), 7.46-7.54 (m, 3H), 7.63-7.78 (m, 3H), 8.05 (d, J=8.0 Hz, 1H), 10.33 (d, J=0.6 Hz, 1H).
EXAMPLE 16 4-Methoxy-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1198] 1704
[1199] By the same procedure as described in Example 1 using 2-thiophenthiol and 4-methoxybenzothiophen-1,1-diol, the compound of the present invention having the following physical data was obtained.
[1200] TLC: Rf 0.27 (methylene chloride:hexane=4:1);
[1201] NMR (CDCl3): &dgr; 3.66 (d, J=5.5, 5.4 Hz, 1H), 3.73 (dd, J=15.5, 4.2 Hz, 1H), 3.95 (s, 3H), 4.88 (dd, J=5.4, 4.2 Hz, 1H), 7.01 (dd, J=5.4, 3.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.19 (dd, J=3.6, 1.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.44 (dd, J=5.4, 1.2 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H).
EXAMPLE 17 4-Methoxy-3-(thioiphen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1202] 1705
[1203] By the same procedure using the compound prepared in Example 16 instead of the compound prepared in Example 9, the compound of the present invention having the following physical data was obtained.
[1204] TLC: Rf 0.46 (methylene chloride:ethyl acetate=10:1);
[1205] NMR (CDCl3): &dgr; 3.73 (s, 3H), 3.79 (dd, J=15.0, 9.2 Hz, 1H), 4.23 (dd, J=15.0, 1.2 Hz, 1H), 5.32 (dd, J=9.2, 1.2 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.11 (dd, J=4.9, 3.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.53 (dd, J=3.8, 1.4 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.73 (dd, J=4.9, 1.4 Hz, 1H).
EXAMPLE 18 4-(4-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1206] 1706
[1207] To a solution of a compound prepared in Example 9 (12) (1.0 g) in dimethylformamide (30 ml), were added 4-nitrobenzylbromide (947 mg) and potassium carbonate (1.0 g). The reaction mixture was stirred at room temperature overnight. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water (three times), a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (1.1 g) having the following physical data.
[1208] TLC: Rf 0.29 (hexane:ethyl acetate=1:1);
[1209] NMR (CDCl3): &dgr; 8.25 (2H, d, J=8.5 Hz), 7.71 (2H, d, J=8.5 Hz), 7.60-7.20 (7H, m), 7.10 (1H, d, J=8 Hz), 5.32 (2H, s), 5.11 (1H, dd, J=7, 2 Hz), 3.85-3.55 (2H, m).
EXAMPLES 18 (1)˜18 (40)[1210] By the sane procedure as described in Example 18 using compounds prepared in Examples 9 (12)˜9 (15) or Example 9 (17) and a corresponding halogenated compound, the following compounds of the present invention were obtained.
EXAMPLE 18 (1) 4-(3-Phenyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1211] 1707
[1212] TLC: Rf 0.27 (hexane ethyl acetate 2:1);
[1213] NMR (CDCl3): &dgr; 7.54-7.42 (3H, m), 7.32-7.19 (6H, m), 7.10 (1H, d, J=8.0 Hz), 6.95-6.84 (3H, m), 5.01 (1H, dd, J=6.6, 2.2 Hz), 4.31 (2H, t, J=6.0 Hz), 4.20 (2H, t, J=6.0 Hz), 3.69 (1H, dd, J=13.9, 6.6 Hz), 3.59 (1H, dd, J=13.9, 2.2 Hz), 2.31 (2H, quint, J=6.0 Hz).
EXAMPLE 18 (2) 4-Benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1214] 1708
[1215] TLC: Rf 0.45 (hexane:ethyl acetate=2:1);
[1216] NMR (CDCl3): &dgr; 7.54-7.26 (12H, m), 7.13 (1H, d, J=9.0 Hz), 5.22 (2H, s), 5.03 (1H, dd, J=6.0, 2.6 Hz), 3.71 (1H, dd, J=13.8, 6.0 Hz), 3.63 (1H, dd, J=13.8, 2.6 Hz).
EXAMPLE 18 (3) 4-(3-Benzyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1217] 1709
[1218] TLC: Rf 0.47 (hexane:ethyl acetate=1:1);
[1219] NMR (CDCl3): &dgr; 2.13 (quint, J=6.0 Hz, 2H), 3.58 (dd, J=14.0, 2.4 Hz, 1H), 3.67 (dd, J=14.0, 6.6 Hz, 1H), 3.69 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 4.44 (d, J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.92 (dd, J=6.6, 2.4 Hz, 1H), 7.08 (d-like, J=7.4 Hz, 1H), 7.26 (s, 5H), 7.30-7.35 (m, 4H), 7.43-7.54 (m, 3H).
EXAMPLE 18 (4) 4-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1220] 1710
[1221] TLC: Rf 0.46 (ethyl acetate);
[1222] NMR (CDCl3): &dgr; 3.62 (dd, J=14.0, 2.2Hz, 1H), 3.72 (dd, J=14.0, 6.2Hz, 1H), 5.04 (dd, J=6.2, 2.2 Hz, 1H), 5.23 (s, 2H), 7.15 (dd, J=8.0, 1.0 Hz, 1H), 7.26-7.45 (m, 7H), 7.54 (t, J=8.0 Hz, 1H), 7.85-7.92 (m, 1H), 8.63 (dd, J=4.7, 2.0 Hz, 1H), 8.76 (dd, J=2.0, 0.6 Hz, 1H).
EXAMPLE 18 (5) 4-(Quinolin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1223] 1711
[1224] TLC: Rf 0.25 (hexane:ethyl acetate=1:1);
[1225] NMR (CDCl3): &dgr; 8.18 (1H, d, J=8 Hz), 8.10 (1H, d, J=8 Hz), 7.92-7.68 (3H, m), 7.68-7.40 (4H, m), 7.40-7.22 (4H, m), 7.16 (1H, d, J=8 Hz), 5.53 (2H, s), 5.18 (1H, dd, J=7, 2 Hz), 3.76 (1H, dd, J=14, 7 Hz), 3.66 (1H, dd, J=14, 2 Hz).
EXAMPLE 18 (6) 4-(Pyridin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1226] 1712
[1227] TLC: Rf 0.33 (ethyl acetate);
[1228] NMR (CDCl3): &dgr; 8.62 (1H, d, J=5 Hz), 7.80-7.58 (2H, m), 7.58-7.38 (3H, m), 7.38-7.18 (5H, m), 7.11 (1H, d, J=8 Hz), 5.35 (2H, s), 5.15 (1H, dd, J=7, 2 Hz), 3.85-3.58 (2H, m).
EXAMPLE 18 (7) 4-(Pyridin-4-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1229] 1713
[1230] TLC: Rf 0.15 (ethyl acetate);
[1231] NMR (CDCl3): &dgr; 8.78-8.55 (2H, m), 7.65-7.18 (9H, m), 7.07 (1H, d, J=8 Hz), 5.23 (2H, s), 5.11 (1H, dd, J=7, 2 Hz), 3.82-3.53 (2H, m).
EXAMPLE 18 (8) 4-(3-(Pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1232] 1714
[1233] TLC: Rf 0.18 (ethyl acetate);
[1234] NMR (CDCl3): &dgr; 8.48-8.35 (m, 2H), 7.67-7.33 (m, 9H), 6.95 (d, J=8.0 Hz, 1H), 5.01 (d-like, J=8.5 Hz, 1H), 4.15-3.86 (m, 4H), 2.81 (t, J=7.0 Hz, 2H), 2.21-2.01 (m, 2H).
EXAMPLE 18 (9) 4-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1235] 1715
[1236] TLC: Rf 0.24 (hexane:ethyl acetate=1:2);
[1237] NMR (CDCl3): &dgr; 2.06-2.17 (m, 2H), 3.57 (dd, J=14.0, 2.2 Hz, 1H), 3.67 (dd, J=14.0, 6.6 Hz, 1H), 3.91 (br, 2H), 4.27 (t, J=5.8 Hz, 2H), 5.05 (dd, J=6.6, 2.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.30-7.38 (m, 4H), 7.49-7.56 (m, 3H).
EXAMPLE 18 (10) 5-Pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1238] 1716
[1239] TLC: Rf 0.70 (hexane:ethyl acetate=2:1);
[1240] NMR (CDCl3): &dgr; 0.95 (t, J=7.0 Hz, 3H), 1.38-1.47 (m, 4H), 1.82 (quint, J=6.8 Hz, 2H), 3.51 (dd, J=15, 7 Hz, 1H), 3.79 (dd, J=15, 7 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 4.89 (t, J=7.0 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 7.12 (d, J=2 Hz, 1H), 7.36-7.38 (m, 3H), 7.41-7.43 (m, 2H), 7.61 (d, J=8 Hz, 1H).
EXAMPLE 18 (11) 5-(2-Phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1241] 1717
[1242] TLC: Rf 0.75 (hexane:ethyl acetate=1:1);
[1243] NMR (CDCl3): &dgr; 7.65 (1H, d, J=8.5 Hz), 7.45-7.42 (2H, m), 7.34-7.29 (5H, m), 7.21 (1H, d, J=2.2 Hz), 7.09 (1 H, dd, J=8.5, 2.2 Hz), 7.00 (1 H, t, J=7.0 Hz), 6.95 (1 H, d, J=8.5 Hz), 4.93 (1H, t, J=7.0 Hz), 4.38 (4H, m), 3.78 (1H, dd, J=14.0, 7.0 Hz), 3.52 (1H, dd, J=14.0, 7.0 Hz).
EXAMPLE 18 (12) 5-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1244] 1718
[1245] TLC: Rf 0.25 (hexane:ethyl acetate=1:1);
[1246] NMR (CDCl3): &dgr; 2.10 (quint, J=6.5 Hz, 2H), 3.60 (dd, J=14, 6.7Hz, 1H), 3.82 (dd, J=14, 6.7 Hz, 1H), 3.89 (t, J=6.5 Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 4.98 (t, J=6.7 Hz, 1H), 7.20 (dd, J=8.5, 2.2 Hz, 1H), 7.35-7.47 (m, 6H), 7.61 (d, J=8.5 Hz, 1H).
EXAMPLE 18 (13) 5-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1247] 1719
[1248] TLC: Rf 0.40 (ethyl acetate);
[1249] NMR (CDCl3): &dgr; 3.51 (dd, J=9.0, 4.5 Hz, 1H), 3.79 (dd, J=9.0, 5.0 Hz, 1H), 4.91 (t-like, J=4.7 Hz, 1H), 5.14 (s, 2H), 7.11 (dd, J=5.6, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.33-7.42 (m, 6H), 7.65 (d, J=5.6 Hz, 1H), 7.77 (dt, J=5.4, 1.3 Hz, 1H), 8.63 (dd, J=3.2, 1.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H).
EXAMPLE 18 (14) 5-(3-(Pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1250] 1720
[1251] TLC: Rf 0.16 (ethyl acetate);
[1252] NMR (CDCl3): &dgr; 8.36-8.28 (m, 2H), 7.78-7.55 (m, 4H), 7.42-7.36 (m, 5H), 7.01 (d, J=8.0 Hz, 1H), 5.11 (d-like, J=9.0 Hz, 1H), 4.12 (t, J=7.0 Hz, 2H), 3.88-3.64 (m, 2H), 3.05 (t, J=7.0 Hz, 2H), 2.35-2.26 (m, 2H).
EXAMPLE 18 (15) 6-(3-Phenyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1253] 1721
[1254] TLC: Rf 0.42 (hexane:ethyl acetate=2:1);
[1255] NMR (CDCl3): &dgr; 7.61-7.56 (1H, m), 7.43-7.25 (7H, m), 7.19-7.15 (2H, m), 6.95-6.89 (3H, m), 4.91 (1H, t-like, J=6.6 Hz), 4.22 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.0 Hz), 3.80 (1H, dd, J=13.8, 7.3 Hz), 3.51 (1H, dd, J=13.8, 7.3 Hz), 2.28 (2H, quint, J=6.0 Hz).
EXAMPLE 18 (16) 6-Benzyloxy-3-phenylthio-2,3-dihydro-1,1-di oxidebenzo[b]thiophene[1256] 1722
[1257] TLC: Rf 0.58 (hexane:ethyl acetate=2:1);
[1258] NMR (CDCl3): &dgr; 7.63-7.58 (1 H, m), 7.45-7.31 (10H, m), 7.27-7.23 (2H, m), 5.10 (2H, s), 4.92 (1H, t-like, J=6.7 Hz), 3.81 (1H, dd, J=13.7, 7.5 Hz), 3.52 (1H, dd, J=13.7, 6.1 Hz).
EXAMPLE 18 (17) 6-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1259] 1723
[1260] TLC: Rf 0.51 (hexane:ethyl acetate=2:1);
[1261] NMR (CDCl3): 7.60-7.55 (1H, m), 7.43-7.31 (5H, m), 7.19-7.12 (2H, m), 4.91 (1H, t, J=6.8 Hz), 3.99 (2H, t, J=6.6 Hz), 3.80 (1H, dd, J=13.8, 7.3 Hz), 3.51 (1H, dd, J=13.8, 6.2 Hz), 1.80 (2H, quint, J=7.0 Hz), 1.50-1.30 (4H, m), 0.92 (3H, t, J=7.0 Hz).
EXAMPLE 18 (18) 6-(2-(Morpholin-4-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1262] 1724
[1263] TLC: Rf 0.41 (hexane:ethyl acetate: triethylamine=2:4:1);
[1264] NMR (CDCl3): &dgr; 7.60 (1H, d, J=8.4 Hz), 7.42-7.32 (5H, m), 7.22-7.16 (2H, m), 4.92 (1H, t-like, J=6.8 Hz), 4.15 (2H, t, J=5.8 Hz), 3.81 (1H, dd, J=13.8, 7.2 Hz), 3.73 (4H, t-like, J=4.6 Hz), 3.52 (1H, dd, J=13.8, 6.1 Hz), 2.82 (2H, t, J=5.8 Hz), 2.57 (4H, t-like, J=4.6 Hz).
EXAMPLE 18 (19) 6-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1265] 1725
[1266] TLC: Rf 0.33 (hexane:ethyl acetate 1:2);
[1267] NMR (CDCl3): &dgr; 2.06 (quint, J=6.1 Hz, 2H), 3.51 (dd, J=13.6, 6.2 Hz, 1H), 3.80 (dd, J=13.6, 7.4 Hz, 1H), 3.85 (t, J=6.1 Hz, 2H), 4.17 (t, J=6.1 Hz, 2H), 4.92 (t-like, J=6.8 Hz, 1H), 7.16-7.21 (m, 2H), 7.32-7.45 (m, 5H), 7.57-7.61 (m, 1H).
EXAMPLE 18 (20) 6-(Pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1268] 1726
[1269] TLC: Rf 0.31 (methylene chloride: ethyl acetate=2:1);
[1270] NMR (CDCl3): “ 3.53 (dd, J=13.6, 6.2 Hz, 1H), 3.82 (dd, J=13.6, 7.2 Hz, 1H), 4.93 (t-like, J=6.6 Hz, 1H), 5.12 (s, 2H), 7.23-7.28 (m, 2H), 7.33-7.46 (m, 6H), 7.61-7.65 (m, 1H), 7.75-7.79 (m, 1H), 8.63 (dd, J=5.0, 1.6 Hz, 1H), 8.70 (d, J=1.6 Hz, 1H).
EXAMPLE 18 (21) 6-(3-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1271] 1727
[1272] TLC: Rf 0.49 (hexane:ethyl acetate=1:1),
[1273] NMR (CDCl3): &dgr; 8.33 (1H, brs), 8.22 (1H, dd, J=8, 2 Hz), 7.76 (1H, d, J=7.8 Hz), 7.70-7.48 (2H, m), 7.48-7.16 (7H, m), 5.21 (2H, s), 4.93 (1H, t-like, J=6.8 Hz), 3.83 (1H, dd, J=13.6, 7.6 Hz), 3.54 (1H, dd, J=13.6, 6.2 Hz).
EXAMPLE 18 (22) 6-(3-Bromopropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1274] 1728
[1275] TLC: Rf 0.48 (hexane:ethyl acetate=3:1);
[1276] NMR (CDCl3). &dgr; 2.35 (quint, J=7.5 Hz, 2H), 3.55 (t, J=7.5 Hz, 2H), 3.59 (dd, J=15, 7 Hz, 1H), 3.80 (dd, J=15, 7 Hz, 1H), 4.18 (t, J=7.5 Hz, 2H), 4.92 (t, J=7 Hz, 1H), 7.20 (dd, J=9, 2 Hz, 1H), 7.34-7.43 (m, 6H), 7.60 (d, J=9 Hz, 1H).
EXAMPLE 18 (23) 7-Pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1277] 1729
[1278] TLC: Rf 0.80 (hexane:ethyl acetate=1:1);
[1279] NMR (CDCl3): &dgr; 5 7.54 (1H, t, J=7.8 Hz), 7.45-7.21 (6H, m), 6.91 (1H, d, J=8.6 Hz), 4.88 (1H, t, J=7.6 Hz), 4.11 (2H, t, J=7.0 Hz), 3.77 (1H, dd, J=13.6, 7.6 Hz), 3.50 (1H, dd, J=13.6, 7.6 Hz), 1.87 (2H, quint, J=7.0 Hz), 1.50-1.30 (4H, m), 0.92 (3H, t, J=7.2 Hz).
EXAMPLE 18 (24) 7-(2-Phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1280] 1730
[1281] TLC: Rf 0.55 (hexane:ethyl acetate=1:1);
[1282] NMR (CDCl3): &dgr; 7.58 (1H, t, J=7.8 Hz), 7.45-7.25 (8H, m), 7.06 (1H, d, J=8.4 Hz), 7.05-6.90 (3H, m), 4.89 (1 H, t, J=7.6 Hz), 4.58 -4.45 (2H, m), 4.45-4.35 (2H, m), 3.78 (1 H, dd, J=13.6, 7.6 Hz), 3.52 (1H, dd, J=13.6, 7.6 Hz).
EXAMPLE 18 (25) 7-(3-Hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1283] 1731
[1284] TLC: Rf 0.25 (hexane:ethyl acetate=1:2);
[1285] NMR (CDCl3): &dgr; 7.60-6.60 (8H, m), 4.90 (1 H, t, J=6.8 Hz), 4.36-4.26 (2H, m), 3.90 (2H, br) 3.79 (1H, d, J=13.8, 6.8 Hz), 3.52 (1H, dd, J=13.8, 6.8 Hz), 2.50-2.05 (2H, m).
EXAMPLE 18 (26) 7-(Pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1286] 1732
[1287] TLC: Rf 0.12 (hexane:ethyl acetate=1:2);
[1288] NMR (CDCl3): &dgr; 8.66 (1H, d, J=2.2 Hz), 8.57 (1H, dd, J=4.8, 1.8 Hz), 7.93 (1H, d, J=8.2 Hz), 7.56 (1H, t, J=8.2 Hz), 7.45-7.30 (4H, m), 6.97 (1H, d, J=8.2 Hz), 5.30 (2H, s), 4.92 (1H, t, J=7.0 Hz), 3.82 (1H, dd, J=13.8, 7.8 Hz), 3.54 (1H, dd, J=13.8, 7.8 Hz).
EXAMPLE 18 (27) 4-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1289] 1733
[1290] TLC: Rf 0.33 (hexane:ethyl acetate=2:1);
[1291] NMR (CDCl3): &dgr; 7.57-7.46 (3H, m), 7.37-7.32 (4H, m), 6.93 (1H, d-like, J=8.0 Hz), 5.16 (1H, dd, J=6.6, 2.0 Hz), 4.61 (2H, s), 3.72 (1H, dd, J=13.9, 6.6 Hz), 3.61 (1H, dd, J=13.9, 2.0 Hz), 1.49 (9H, s).
EXAMPLE 18 (28) 5-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1292] 1734
[1293] TLC: Rf 0.52 (hexane:ethyl acetate=2:1);
[1294] NMR (CDCl3): &dgr; 1.50 (s, 9H), 3.48 (dd, J=14, 6.7 Hz, 1H), 3.82 (dd, J=14, 6.7 Hz, 1H), 4.66 (s, 2H), 4.95 (t, J=6.7 Hz, 1H), 7.18 (dd, J=9, 2.3 Hz, 1H) 7.40-7.53 (m, 6H), 7.62 (d, J=9 Hz, 1H).
EXAMPLE 18 (29) 6-(t-Butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1295] 1735
[1296] TLC: Rf 0.44 (hexane:ethyl acetate 2:1);
[1297] NMR (CDCl3): &dgr; 7.61 (1H, d, J=8.7 Hz), 7.44-7.32 (5H, m), 7.24 (1H, dd, J=8.7, 2.6 Hz), 7.08 (1H, d, J=2.6 Hz), 4.91 (1H, t-like, J=6.7 Hz), 4.56 (2H, s), 3.80 (1H, dd, J=13.7, 7.3 Hz), 3.51 (1H, dd, J=13.7, 6.1 Hz), 1.49 (9H, s).
EXAMPLE 18 (30) 7-(t-Butoxycatbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1298] 1736
[1299] TLC: Rf 0.55 (hexane:ethyl acetate=1:1);
[1300] NMR (CDCl3): &dgr; 7.54 (1H, t, J=7.6 Hz), 7.45-7.27 (6H, m), 6.80 (1H, d, J=8.0 Hz), 4.90 (1H, t, J=7.6 Hz), 4.69 (2H, s), 3.79 (1H, dd, J=13.6, 7.6 Hz), 3.52 (1H, dd, J=13.6, 7.6 Hz), 1.46 (9H, s).
EXAMPLE 18 (31) 4-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1301] 1737
[1302] TLC: Rf 0.35 (hexane:ethyl acetate=1:2);
[1303] NMR (CDCl3): &dgr; 1.35 (s, 9H), 3.46-3.66 (m, 2H), 3.62 (dd, J=14.2, 2.2 Hz, 1H), 3.73 (dd, J=14.2, 6.8 Hz, 1H), 4.11-4.25 (m, 2H), 5.06 (dd, J=6.8, 2.2 Hz, 1H), 5.39 (br, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.31-7.39 (m, 4H), 7.44-7.57 (m, 3H).
EXAMPLE 18 (32) 4-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1304] 1738
[1305] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[1306] NMR (CDCl3): &dgr; 1.38 (s, 9H), 2.00-2.11 (m, 2H), 3.33-3.44 (m, 2H), 3.59 (dd, J=14.0, 2.2 Hz, 1H), 3.69 (dd, J=14.0, 6.6 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H), 4.90 (br, 1H), 5.08 (dd, J=6.6, 2.2 Hz, 1H), 7.08 (dd, J=8.1, 0.7 Hz, 1H), 7.29-7.38 (m, 4H), 7.48-7.56 (m, 3H).
EXAMPLE 18 (33) 5-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1307] 1739
[1308] TLC: Rf 0.40 (hexane:ethyl acetate=2:1);
[1309] NMR (CDCl3): &dgr; 1.46 (s, 9H), 3.52 (dd, J=15, 6 Hz, 1H), 3.56 (t, J=7.5 Hz, 2H), 3.80 (dd, J=15, 6 Hz, 1H), 4.10 (t, J=7.5 Hz, 2H), 4.88 (t, J=6 Hz, 1H), 4.99 (br, 1H), 7.03 (dd, J=9, 2 Hz, 1H), 7.12 (d, J=2 Hz, 1H), 7.35-7.47 (m, 5H), 7.64 (d, J=9 Hz, 1H).
EXAMPLE 18(34) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1310] 1740
[1311] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[1312] NMR (CDCl3): &dgr; 5 1.44 (s, 9H), 2.01 (quint, J=6.2 Hz, 2H), 3.32 (q, J=6.2 Hz, 2H), 3.51 (dd, J=13.6, 6.0 Hz, 1H), 3.80 (dd, J=13.6, 7.4 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 4.69 (br, 1H), 4.91 (t-like, J=6.8 Hz, 1H), 7.14-7.21 (m, 2H), 7.32-7.45 (m, 5H), 7.59 (d, J=8.4 Hz, 1H).
EXAMPLE 18(35) 6-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1313] 1741
[1314] TLC: Rf 0.47 (hexane:ethyl acetate=1:1);
[1315] NMR (CDCl3): &dgr; 1.46 (s, 9H), 3.51 (dd, J=13.8, 6.2 Hz, 1H), 3.55 (q, J=5.2 Hz, 2H), 3.81 (dd, J=13.8, 7.4 Hz, 1H), 4.06 (t, J=5.2 Hz, 2H), 4.92 (t-like, J=6.4 Hz, 1H), 4.96 (br, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.32-7.45 (m, 5H), 7.60 (d, J=8.5 Hz, 1H).
EXAMPLE 18(36) 7-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1316] 1742
[1317] TLC: Rf 0.60 (hexane ethyl acetate=1:2);
[1318] NMR (CDCl3): “ 7.60-7.24 (7H, m), 6.94 (1H, d, J=8.4 Hz), 5.38 (1H, bs), 4.90 (1H, t, J=7.4 Hz), 4.30-4.05 (2H, m), 3.79 (1H, dd, J=13.7, 7.4 Hz), 3.60-3.40 (3H, m), 1.42 (9H, s).
EXAMPLE 18(37) 4-(N-(t-Butoxycarbonyl)piperidin-4-yl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1319] 1743
[1320] TLC: Rf 0.41 (hexane:ethyl acetate=1:1);
[1321] NMR (CDCl3): &dgr; 7.60-7.42 (3H, m), 7.42-7.25 (4H, m), 7.04 (1 H, d, J=8.2 Hz), 5.05 (1 H, dd, J=6.6, 2.2 Hz), 4.80-4.60 (1H, m), 3.85-3.32 (6H, m), 2.15-1.65 (4H, m), 1.48 (9H, s).
EXAMPLE 18(38) 4,7-B is [(2-(t-butoxycarbonylamino)ethyl) oxy]-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1322] 1744
[1323] TLC: Rf 0.35 (hexane:ethyl acetate=1:2);
[1324] NMR (CDCl3): &dgr; 7.53-7.30 (5H, m), 7.20-6.85 (2H, m), 5.40 (2H, brs), 5.03-4.85 (1H, m), 4.25-4.00 (4H, m), 3.90-3.40 (6H, m), 1.43 (18H, s).
EXAMPLE 18(39) 4-(3-Nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1325] 1745
[1326] TLC: Rf 0.29 (hexane:ethyl acetate=1:1);
[1327] NMR (CDCl3): &dgr; 8.44 (1H, s), 8.24 (1 H, d, J=8.4 Hz), 7.86 (1H, d, J=8.0 Hz), 7.65-7.20, (8H, m), 7.14 (1H, d, J=7.2 Hz), 5.31 (2H, s), 5.13 (1H, dd, J=2.6 Hz, 6.6 Hz), 3.80-3.56 (2H, m).
EXAMPLE 18(40) 4,7-Bis(pyridin-3-ylmethyloxy)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1328] 1746
[1329] TLC: Rf 0.20 (ethyl acetate:methanol=10:1);
[1330] NMR (CDCl3): &dgr; 8.75-8.72 (1H, m), 8.70-8.50 (4H, m), 7.96-7.82 (2H, m), 7.46-7.24 (6H, m), 7.05 (1H, d, J=9.0 Hz), 6.93 (1H, d, J=9.0 Hz), 5.25 (2H, s), 5.15 (2H, s), 5.01-4.95 (1H, m), 3.81-3.59 (2H, m).
EXAMPLE 19 4-(3-Hydroxypropyl)oxy-3-phenylsulfynyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1331] 1747
[1332] By the same procedure as described in Example 2 using the compound prepared in Example 18 (9) instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained.
[1333] TLC: Rf 0.18 (hexane:ethyl acetate=1:1);
[1334] NMR (CDCl3): &dgr; 2.17 (quint, J=6.0 Hz, 2H), 3.08 (dd, J=14.0, 8.6 Hz, 1H), 3.94 (t, J=6.0 Hz, 2H), 3.98 (dd, J=14.0, 4.8 Hz, 1H), 4.32 (t, J=6.0 Hz, 2H), 4.15 (dd, J=8.6, 4.8 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.55-7.66 (m, 6H).
EXAMPLE 20 4-(4-Nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1335] 1748
[1336] By the same procedure as described in Example 10 using the compound prepared in Example 18 instead of the compound prepared in Example 9, the compound of the present invention having the following physical data was obtained.
[1337] TLC: Rf 0.67 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1338] NMR (DMSO-d6): &dgr; 8.25 (2H, d, J=9 Hz), 7.78-7.52 (6H, m), 7.52-7.20 (4H, m), 5.74 (1H, d, J=9 Hz), 5.26 (1H, d, J=14 Hz), 4.99 (1H, d, J=14 Hz), 4.19 (1H, d, J=15 Hz), 4.00 (1H, dd, J=15, 9 Hz).
EXAMPLES 20 (1)˜20 (39)[1339] Using the compounds prepared in Examples 18 (1)˜18 (39) instead of the compound prepared in Example 18 by the same procedure as described in Example 20, or by the same reaction using 3-chloroperbenzoic acid instead of OXONEO as an oxidizer, and, if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained.
EXAMPLE 20 (1) 4-(3-Phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1340] 1749
[1341] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);
[1342] NMR (CDCl3): &dgr; 2.20 (quint, J=6.0 Hz, 2H), 3.70 (dd, J=14.8, 9.3 Hz, 1H), 3.99-4.28 (m, 4H), 4.20 (dd, J=14.8, 1.2 Hz, 1H), 5.19 (dd, J=9.3, 1.2 Hz, 1H), 6.89-7.01 (m, 4H), 7.21-7.50 (m, 6H), 7.52-7.60 (m, 1H), 7.65-7.70 (m, 2H).
EXAMPLE 20 (2) 4-Benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1343] 1750
[1344] TLC: Rf 0.39 (hexane:ethyl=11);
[1345] NMR (CDCl6): &dgr; 3.73 (dd, J=15.0, 9.0 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 4.88 (d, J=11.7 Hz, 1H), 4.99 (d, J=11.7 Hz, 1H), 5.28 (d, J=9.0 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.26-7.40 (m, 8H), 7.49-7.58 (m, 2H), 7.64-7.69 (m, 2H).
EXAMPLE 20 (3) 4-(3-Benzyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1346] 1751
[1347] TLC: Rf 0.26 (hexane:ethyl acetate=1:1);
[1348] NMR (CDCl3): &dgr; 1.96 (quint, J=6.1 Hz, 2H), 3.57-3.67 (m, 2H), 3.67 (dd, J=14.9, 9.2 Hz, 1H), 3.82-3.92 (m, 1H), 3.98-4.09 (m, 1H), 4.21 (dd, J=14.9, 0.5 Hz, 1H), 4.46 (d, J=12.1 Hz, 1H), 4.56 (d, J=12.1 Hz, 1H). 5.05 (dd, J=9.2, 0.5 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.22-7.27 (m, 6H), 7.35-7.60 (m, 4H), 7.65-7.69 (m, 2H).
EXAMPLE 20 (4) 4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1349] 1752
[1350] free compound:
[1351] TLC: Rf 0.17 (ethyl acetate);
[1352] NMR (DMSO-d6): &dgr; 3.95 (dd, J=15.0, 8.8 Hz, 1H), 4.16 (dd, J=15.0, 1.2 Hz, 1H), 4.93 (d, J=12.5 Hz, 1H), 5.15 (d, J=12.5 Hz, 1H), 5.66 (d-like, J=8.0 Hz, 1H), 7.35-7.45 (m, 5H), 7.55-7.72 (m, 4H), 7.80 (dt, J=8.0, 1.4 Hz, 1H), 8.56 (dd, J=5.0, 1.4 Hz, 1H), 8.61 (d, J=1.4 Hz, 1H).
[1353] Hydrochloride:
[1354] TLC: Rf 0.17 (ethyl acetate);
[1355] NMR (DMSO-d6): &dgr; 3.98 (dd, J=15.2, 8.6 Hz, 1H), 4.16 (d, J=15.2 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 5.29 (d, J=12.8 Hz, 1H), 5.85 (d, J=8.6 Hz, 1H), 7.38-7.59 (m, 5H), 7.66-7.75 (m, 3H), 7.94 (dd, J=8.0, 5.4 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.88 (s, 1H).
[1356] Methanesulfonic Acid Salt:
[1357] TLC: Rf 0.31 (ethyl acetate:methanol=9:1);
[1358] NMR (DMSO-d6): &dgr; 2.37 (3H, s), 4.00 (dd, J=15.0, 8.8 Hz, 1H), 4.17 (d-like, J=15.4 Hz, 1H), 5.13 (d, J=13.0 Hz, 1H), 5.32 (d, J=13.0 Hz, 1H), 5.85 (d-like, J=8.0 Hz, 1H), 7.39-7.45 (m, 4H), 7.52-7.59 (m, 1H), 7.66-7.77 (m, 3H), 8.05 (dd, J=8.2, 5.8 Hz, 1H), 8.49 (d, J=8.2 Hz, 1H), 8.89-8.92 (m, 2H).
EXAMPLE 20 (5) 4-(N-Oxidequinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1359] 1753
[1360] TLC: Rf 0.38 (ethyl acetate:methanol: 28% ammonia water=100:10:1);
[1361] NMR (CDCl3): “ 8.77 (1H, d, J=8 Hz), 8.00-7.75 (4H, m), 7.75-7.63 (3H, m), 7.63-7.45 (2H, m), 7.45-7.22 (3H, m), 7.17 (1H, d, J=8 Hz), 5.72-5.25 (3H, m), 4.28 (1H, d, 15 Hz), 3.84 (1H, dd, J=15, 9 Hz).
EXAMPLE 20 (6a) 4-(Pyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1362] 1754
[1363] TLC: Rf 0.43 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1364] NMR (CDCl3): “ 8.61 (1H, d, J=4 Hz), 7.88-7.18 (10H, m), 7.04 (1H, d, J=8 Hz), 5.37 (1H, d, J=9 Hz), 5.11 (1 H, d, J=14 Hz), 4.98 (1 H, d, J=14 Hz), 4.24 (1 H, d, J=15 Hz), 3.78 (1H, dd, J=15, 9 Hz).
EXAMPLE 20 (6b) 4-(N-Oxidepyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1365] 1755
[1366] TLC: Rf 0.09 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1367] NMR (CDCl3+DMSO-d6): &dgr; 8.42-8.22 (1H, m), 7.90-7.20 (11H, m), 5.83 (1H, d, J=8.5 Hz), 5.18 (1H, d, J=15 Hz), 4.93 (1H, d, J=15 Hz), 4.21 (1H, d, J=15 Hz), 4.03 (1H, dd, J=15, 8.5 Hz).
EXAMPLE 20 (7) 4-(Pyridin-4-ylmethyl)oxy-3-phenylsulfonyl-2,3-di hydro-1,1-dioxidebenzo[b]thiophene[1368] 1756
[1369] Free Compound:
[1370] TLC: Rf 0.26 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1371] NMR (CDCl3+DMSO-d6): &dgr; 8.57 (2H, d, J=6 Hz), 7.80-7.15 (10H, m), 5.75 (1H, d, J=9 Hz), 5.15 (1H, d, J=14 Hz), 4.90 (1H, d, J=14 Hz), 4.19 (1H, d, J=15 Hz), 4.00 (1H, dd, J=15, 9 Hz).
[1372] Hydrochloride:
[1373] TLC: Rf 0.31 (ethyl acetate:methanol=9:1);
[1374] NMR (DMSO-d6): &dgr; 8.93 (d, J=6.5 Hz, 2H), 8.00 (d, J=6.5 Hz, 2H), 7.74-7.68 (m, 3H), 7.60-7.54 (m, 1H), 7.47-7.42 (m, 3H), 7.33 (d, J=8.0 Hz, 1H), 5.93 (d, J=9.0 Hz, 1H), 5.46 (d, J=16.0 Hz, 1H), 5.18 (d, J=16.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 4.03 (dd, J=15.0, 9.0 Hz, 1H).
[1375] Methanesulfonic Acid Salt:
[1376] TLC: Rf 0.31 (ethyl acetate:methanol=9:1);
[1377] NMR (DMSO-d6): &dgr; 8.94 (d, J=6.3 Hz, 2H), 8.03 (d, J=6.3 Hz, 2H), 7.74-7.68 (m, 3H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 5.92 (d, J=9.0 Hz, 1H), 5.46 (d, J=16.0 Hz, 1H), 5.19 (d, J=16.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 4.03 (dd, J=15.0, 9.0 Hz, 1H), 2.38 (s, 3H).
EXAMPLE 20 (8) 4-(3-(Pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene[1378] 1757
[1379] TLC: Rf 0.41 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1380] NMR (CDCl3+CD3OD): &dgr; 8.50-8.36 (2H. m), 7.80-7.23 (9H, m), 7.00 (1H, d, J=8 Hz), 5.27 (1H, d, J=9 Hz), 4.26-3.68 (4H, m), 2.88 (2H, t, J=7 Hz), 2.20-1.90 (2H, m).
EXAMPLE 20 (9) 4-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1381] 1758
[1382] TLC: Rf 0.26 (hexane:ethyl acetate=1:1);
[1383] NMR (CDCl3): &dgr; 2.02 (quint, J=5.6 Hz, 2H), 2.28 (t, J=5.6 Hz, 1H), 3.71 (dd, J=14.8, 9.2 Hz, 1H), 3.91 (m, J=5.6 Hz, 2H), 4.05 (dd, J=14.8, 1.0 Hz, 1H), 4.10-4.17 (m, 2H), 5.28 (d-like, J=8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.42-7.62 (m, 4H), 7.66-7.73 (m, 2H).
EXAMPLE 20 (10) 5-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1384] 1759
[1385] TLC: Rf 0.40 (hexane:ethyl acetate=2:1);
[1386] NMR (CDCl3): &dgr; 0.96 (t, J=8 Hz, 3H), 1.42 (m, 4H), 1.86 (m, 2H), 3.70 (dd, J=14, 8 Hz, 1H), 3.80 (dd, J=14,6 Hz, 1H), 4.07 (m, 2H), 5.00 (dd, J=8,6 Hz, 1H), 7.10 (dd, J=8,2 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.46-7.77 (m, 6H).
EXAMPLE 20 (11) 5-(2-Phenyloxyethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1387] 1760
[1388] TLC: Rf 0.25 (hexane:ethyl acetate=1:1);
[1389] NMR (CDCl3): (3.70 (dd, J=14, 8 Hz, 1H), 3.77 (dd, J=14, 6 Hz, 1H), 4.41 (m, 4H), 5.02 (dd, J=8, 6 Hz, 1H), 7.00 (m, 3H), 7.19 (dd, J=8, 2 Hz, 1H), 7.30-7.77 (m, 9H).
EXAMPLE 20 (12) 5-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1390] 1761
[1391] TLC: Rf 0.15 (hexane:ethyl acetate=1:1);
[1392] NMR (CDClo3): &dgr; 2.11 (m, 2H), 3.65 (dd, J=14, 8 Hz, 1H), 3.78 (dd, J=14, 5 Hz, 1H), 3.89 (m, 2H), 4.25 (m, 2H), 5.01 (dd, J=8, 5 Hz, 1H), 7.12 (dd, J=9, 2 Hz, 1H), 7.45-7.77 (m, 7H).
EXAMPLE 20 (13) 5-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1393] 1762
[1394] Free Compound:
[1395] TLC: Rf 0.30 (ethyl acetate);
[1396] NMR (DMSC-d6): &dgr; 3.79 (dd, J=15.1, 3.2 Hz, 1H), 4.00 (dd, J=15.1, 9.4 Hz, 1H), 5.27 (s, 2H), 5.74 (dd, J=9.4, 3.2 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (dd, J=7.8, 4.9 Hz, 1H), 7.57-7.65 (m, 2H), 7.71-7.82 (m, 4H), 7.91 (dt, J=7.8, 2.0 Hz, 1H), 8.58 (dd, J=4.9, 2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H).
[1397] Hydrochloride:
[1398] TLC: Rf 0.65 (ethyl acetate:triethylamine=10:1);
[1399] NMR (DMSO-d6): &dgr; 3.77 (dd, J=15.0, 3.4 Hz, 1H), 3.99 (dd, J=15.0, 9.6 Hz, 1H), 5.43 (s, 2H), 5.77 (dd, J=9.6, 3.4 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.8, 2.2 Hz, 1H), 7.59-7.66 (m, 2H), 7.74-7.82 (m, 4H), 8.02 (dd, J=8.4, 5.6 Hz, 1H), 8.57 (d-like, J=8.4 Hz, 1H), 8.88 (d-like, J=5.6 Hz, 1H), 9.04 (s-like, 1H).
[1400] Methanesulfonic Acid Salt:
[1401] TLC: Rf 0.30 (ethyl acetate);
[1402] NMR (DMSO-d6): &dgr; 2.37 (3H, s), 3.77 (dd, J=15.0, 3.3 Hz, 1H), 4.00 (dd, J=15.0, 9.3 Hz, 1H), 5.77 (dd, J=9.3, 3.3 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.41 (dd, J=8.7, 2.2 Hz, 1H), 7.59-7.66 (m, 2H), 7.74-7.83 (m, 4H), 8.06 (dd, J=8.0, 5.6 Hz, 1H), 8.61 (d-like, J=8.0 Hz, 1H), 8.91 (dd, J=5.6, 1.0 Hz, 1H), 9.07 (d, J=1.6 Hz, 1H).
EXAMPLE 20 (14) 5-(3-(Pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1403] 1763
[1404] TLC: Rf 0.32 (ethyl acetate:methanol=10:1);
[1405] NMR (CD3OD): &dgr; 8.80 (1H, s), 8.71 (1H, d, J=6 Hz), 8.56 (1H, d, J=8 Hz), 8.02 (1H, t, J=7 Hz), 7.85-7.42 (6H, m), 7.27 (1H, d, J=10 Hz), 7.14 (1H, s), 5.50-5.32 (1H, m), 4.16 (2H, t, J=6 Hz), 3.98-3.65 (2H, m), 3.10 (2H, t, J=7 Hz), 2.40-2.10 (2H, m).
EXAMPLE 20 (15) 6-(3-Phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1406] 1764
[1407] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[1408] NMR (CDCl3): &dgr; 2.29 (quint, J=6.0 Hz, 2H), 3.65-3.81 (m, 2H), 4.15 (t, J=6.0 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 4.99 (dd, J=7.3, 5.9 Hz, 1H), 6.89-6.99 (m, 3H), 7.08 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.8, 2.2 Hz, 1H), 7.25-7.33 (m, 2H), 7.45-7.52 (m, 2H), 7.62-7.70 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (16) 6-Benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1409] 1765
[1410] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[1411] NMR (CDCl3): &dgr; 3.71 (dd, J=14.7, 7.7 Hz, 1H), 3.80 (dd, J=14.7, 5.5 Hz, 1H), 5.00 (dd, J=7.7, 5.5 Hz, 1H), 5.10 (s, 2H), 7.15 (d, J=2.5 Hz, 1H), 7.30 (dd, J=8.5, 2.5 Hz, 1H), 7.40-7.53 (m, 7H), 7.63-7.71 (m, 3H), 7.87 (d, J=8.5 Hz, 1H).
EXAMPLE 20 (17) 6-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1412] 1766
[1413] TLC: Rf 0.26 (hexane:ethyl acetate 2:1);
[1414] NMR (CDCl3): &dgr; 0.94 (t, J=6.4 Hz, 3H), 1.42 (m, 4H), 1.81 (m, 2H), 3.70 (dd, J=14.9, 7.6 Hz, 1H), 3.79 (dd, J=14.9, 5.7 Hz, 1H), 3.99 (t, J=6.4 Hz, 2H), 5.00 (dd, J=7.6, 5.7 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 7.46-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (18) 6-(2-(Morpholin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1415] 1767
[1416] Free Compound:
[1417] TLC: Rf 0.27 (hexane:ethyl acetate: triethylamine=2:4:1);
[1418] NMR (CDCl3): &dgr; 2.56 (t, J=4.5 Hz, 4H), 2.81 (t, J=5.6 Hz, 2H), 3.70-3.77 (m, 6H), 4.14 (t, J=5.6 Hz, 2H), 5.01 (dd, J=7.5, 5.7 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 7.25 (dd, J=8.7, 2.3 Hz, 1H), 7.47-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.83 (d, J=8.7 Hz, 1H).
[1419] Hydrochloride:
[1420] TLC: Rf 0.27 (hexane ethyl acetate:triethylamine=4:8:1);
[1421] NMR (CD3OD): &dgr; 3.43-3.53 (m, 4H), 3.68 (t, J=4.8 Hz, 2H), 3.80 (dd, J=15.4, 8.4 Hz, 1H), 3.95 (dd, J=15.4, 4.0 Hz, 1H), 3.92-4.02 (m, 4H), 4.51 (t, J=4.8 Hz, 2H), 5.45 (dd, J=8.4, 4.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.42 (dd, J=8.8, 2.6 Hz, 1H), 7.55-7.63 (m, 2H), 7.71-7.81 (m, 4H).
EXAMPLE 20 (19) 6-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1422] 1768
[1423] TLC: Rf 0.22 (hexane:ethyl acetate=1:2);
[1424] NMR (CDCl3): &dgr; 2.06 (quint, J=6.0 Hz, 2H), 3.71 (dd, J=14.6, 7.5 Hz, 1H), 3.79 (dd, J=14.6, 5.6 Hz, 1H), 3.85 (t, J=6.0 Hz, 2H), 4.16 (t, J=6.0 Hz, 2H), 5.00 (dd, J=7.5, 5.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.55 (m, 2H), 7.64-7.71 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (20) 6-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1425] 1769
[1426] Free Compound:
[1427] TLC: Rf 0.39 (ethyl acetate);
[1428] NMR (DMSO-d6): &dgr; 3.78 (dd, J=15.2, 3.1 Hz, 1H), 4.01 (dd, J=15.2, 9.2 Hz, 1H), 5.29 (s, 2H), 5.69 (dd, J=9.2, 3.1 Hz, 1H), 7.42-7.47 (m, 3H), 7.58-7.66 (m, 3H), 7.74-7.82 (m, 3H), 7.89 (dt, J=8.0, 1.0 Hz, 1H), 8.57 (dd, J=4.8, 1.6 Hz, 1H), 8.69 (d, J=1.6 Hz, 1H).
[1429] Hydrochloride:
[1430] TLC: Rf 0.39 (ethyl acetate);
[1431] NMR (DMSO-d6): &dgr; 3.78 (dd, J=15.2, 3.0 Hz, 1H), 4.01 (dd, J=15.2, 9.4 Hz, 1H), 5.72 (dd, J=9.4, 3.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.59-7.66 (m, 3H), 7.75-7.83 (m, 3H), 7.99 (dd, J=8.0, 5.4 Hz, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.87 (dd, J=5.4, 1.2 Hz, 1H), 8.99 (d, J=1.2 Hz, 1H).
EXAMPLE 20 (21) 6-(3-Nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1432] 1770
[1433] TLC: Rf 0.55 (hexane:ethyl acetate=1:2);
[1434] NMR (DMSO-d6): &dgr; 8.36-8.34 (m, 1H), 8.25-8.20 (m, 1H), 7.93 (d-like, J=7.6 Hz, 1H), 7.82-7.72 (m, 4H), 7.68-7.58 (m, 3H), 7.50-7.43 (m, 2H), 5.70 (dd, J=9.4, 3.0 Hz, 1H), 5.40 (s, 2H), 4.02 (dd, J=15.2, 9.4 Hz, 1H), 3.79 (dd, J=15.2, 3.0 Hz, 1H).
EXAMPLE 20 (22) 6-(3-Bromopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1435] 1771
[1436] TLC: Rf 0.60 (hexane:ethyl acetate=1:1);
[1437] NMR (CDCl3): &dgr; 2.35 (m, 2H), 3.60 (t, J=6.0 Hz, 2H), 3.70-3.91 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 5.01 (dd, J=14, 7 Hz, 1H), 7.09 (d, J=3.0 Hz, 1H), 7.25 (m, 1H), 7.53 (m, 2H), 7.67 (m, 3H), 7.89 (m, 1H).
EXAMPLE 20 (23) 7-Pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1438] 1772
[1439] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[1440] NMR (CDCl3): &dgr; 7.70-7.43 (7H, m), 6.99 (1H, d, J=8.2 Hz), 5.01 (1H, dd, J=8.6, 5.4 Hz), 4.07 (2H, t, J=6.8 Hz), 3.73-3.68 (2H, m), 1.80 (2H, quint., J=6.8 Hz), 1.50-1.20 (4H, m), 0.89 (3H, t, J=6.8 Hz).
EXAMPLE 20 (24) 7-(2-Phenyloxyethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1441] 1773
[1442] TLC: Rf 0.27 (hexane:ethyl acetate=1:1)
[1443] NMR (CDCl3): &dgr;7.70-6.88 (13H, m), 5.01 (1H, dd, J=8.1, 5.4 Hz), 4.50-4.40 (2H, m), 4.40-4.31 (2H, m), 3.76-3.70 (2H, m).
EXAMPLE 20 (25) 7-(3-Hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1444] 1774
[1445] TLC: Rf 0.46 (ethyl acetate);
[1446] NMR (CDCl3): &dgr; 7.75-7.40 (7H, m), 7.07 (1H, d, J=8.0 Hz), 5.05 (1H, dd, J=8.4,5.4 Hz), 4.26 (2H, t, J=5.8 Hz), 3.85-3.65 (4H, m), 2.03 (2H, quint, J=5.8 Hz).
EXAMPLE 20 (26a) 7-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1447] 1775
[1448] TLC: Rf 0.30 (ethyl acetate:triethylamine=20:1);
[1449] NMR (DMSO-d6): &dgr; 8.85-8.75 (2H, m), 8.27 (1H, d, J=7.6 Hz), 7.92-7.55 (7H, m), 7.43 (1H, d, J=8.2 Hz), 7.26 (1H, d, J=7.6 Hz), 5.80 (1H, dd, J=9.4, 3.2 Hz), 5.51 (2H, s), 3.99 (1H, dd, J=15.3, 9.4 Hz), 3.77 (1H, dd, J=15.3, 3.2 Hz).
EXAMPLE 20 (26b) 7-(N-Oxidepyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1450] 1776
[1451] TLC: Rf 0.26 (ethyl acetate: methanol triethylamine 16 3 1);
[1452] NMR (DMSO-d6): &dgr; 5.38 (1H, s), 8.30 (1H, d, J=5.4 Hz), 7.90-7.42 (8H, m), 7.39 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=7.8 Hz), 5.78 (1H, dd, J=9.7, 3.4 Hz), 5.39 (2H, s), 3.99 (1 H, dd, J=15, 9.7 Hz), 3.78 (1H, dd, J=15, 3.4 Hz).
EXAMPLE 20 (27) 4-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1453] 1777
[1454] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[1455] NMR (CDCl3): &dgr; 1.48 (s, 9H), 3.76 (dd, J-14.9, 9.2 Hz, 1H), 4.16 (d, J=16.0 Hz, 1H), 4.25 (dd, J=1.9, 1.2 Hz, 1H), 4.31 (d, J=16.0 Hz, 1H), 5.36 (dd, J=9.2, 1.2 Hz, 1H), 6.82 (dd, J=8.1, 0.7 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.44-7.57 (m, 3H), 7.59-7.67 (m, 1H), 7.78-7.83 (m, 2H).
EXAMPLE 20 (28) 5-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1456] 1778
[1457] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[1458] NMR (CDCl3): &dgr; 1.53 (s, 9H), 3.74 (d-like, J=6 Hz, 2H), 4.67 (m, 2H), 5.00 (t, J=6 Hz, 1H), 7.17 (dd, J=8, 2Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.50 (m, 2H), 7.55 (d, J=8 Hz, 1H), 7.66 (m, 3H).
EXAMPLE 20 (31) 6-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1459] 1779
[1460] TLC: Rf 0.42 (hexane:ethyl acetate=1:1);
[1461] NMR (CDCl3): &dgr; 1.48 (s, 3H), 3.67-3.83 (m, 2H), 4.56 (s, 2H), 5.00 (dd, J=7.4, 5.6 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 7.29 (dd, J=8.8, 2.6 Hz, 1H), 7.46-7.53 (m, 2H), 7.61-7.70 (m 2H), 7.89 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (30) 7-(t-Butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1462] 1780
[1463] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[1464] NMR (CDCl3): &dgr; 7.70-7.47 (7H, m), 6.91-6.86 (lH, m), 5.02 (1H, dd, J=8.3, 5.6 Hz), 4.64 (2H, s), 3.76-3.72 (2H, m), 1.44 (9H, s).
EXAMPLE 20 (31) 4-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1465] 1781
[1466] TLC: Rf 0.35 (hexane:ethyl acetate=1:2);
[1467] NMR (CDCl3): 3.42-3.56 (m, 1H), 3.63-3.76 (m, 1H), 3.73 (dd, J=15.2, 9.6 Hz, 1H), 4.02-4.34 (m, 2H), 4.10 (dd, J=15.2, 1.2 Hz, 1H), 5.29 (dd, J=9.6, 1.2 Hz, 1H), 5.78 (br, 1H), 7.02 (d-like, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.40-7.64 (m, 4H), 7.21-7.76 (m, 2H).
EXAMPLE 20 (32) 4-(3-(t-Butoxycarbonylamino)propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1468] 1782
[1469] TLC: Rf 0.30 (hexane:ethyl acetate 1:2);
[1470] NMR (CDCl3): &dgr; 1.41 (s, 9H), 1.93 (m, 2H), 3.35 (m, 2H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.99 (t, J=6.1 Hz, 2H), 4.09 (d, J=15.0 Hz, 2H), 4.95 (br, 1H), 5.35 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.43-7.67 (m, 4H), 7.70-7.75 (m, 2H).
EXAMPLE 20 (33) 5-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1471] 1783
[1472] TLC: Rf 0.40 (hexane:ethyl acetate=1:1);
[1473] NMR (CDCl3): &dgr; 1.47 (s, 9H), 3.54 (m, 2H), 3.66 (dd, J=15, 8Hz, 1H), 3.80 (dd, J=15,5 Hz, 1H), 4.13 (t, J=5 Hz, 2H), 5.00 (dd, J=8, 5 Hz, 1H), 5.00 (br, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.44 (d, J-2 Hz, 1H), 7.55 (m, 3H), 7.72 (m, 3H).
EXAMPLE 20 (34) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1474] 1784
[1475] TLC: Rf 0.41 (hexane:ethyl acetate=1:2);
[1476] NMR (CDCl3): &dgr; 1.44 (s, 9H), 2.01 (quint, J=6.2 Hz, 2H), 3.32 (q, J=6.2 Hz, 2H), 3.71 (dd, J=14.6, 7.7 Hz, 1H), 3.79 (dd, J=14.6, 5.5 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 4.68 (br, 1H), 5.00 (dd, J=7.7, 5.5 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.54 (m, 2H), 7.64-7.72 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (35) 6-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1477] 1785
[1478] TLC: Rf 0.24 (hexane ethyl acetate=1:1);
[1479] NMR (CDCl3): &dgr; 1.46 (s, 9H), 3.56 (q, J=5.4 Hz, 2H), 3.71 (dd, J=14.8, 7.7 Hz, 1H), 3.79 (dd, J=14.8, 5.6 Hz, 1H), 4.06 (t, J=5.4 Hz, 2H), 4.97 (br, 1H), 5.00 (dd, J=7.7, 5.6 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 7.24 (dd, J=8.8, 2.6 Hz, 1H), 7.47-7.55 (m, 2H), 7.65-7.72 (m, 3H), 7.88 (d, J=8.8 Hz, 1H).
EXAMPLE 20 (36) 7-(2-(t-Butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1480] 1786
[1481] TLC: Rf 0.36 (hexane:ethyl acetate=2:1);
[1482] NMR (CDCl3): &dgr; 7.72-7.40 (7H, m), 7.04 (1H, d, J=8.2 Hz), 5.22 (1H, bs), 5.02 (1H, dd, J=8.7, 5.0 Hz), 4.25-4.10 (2H, m), 3.85-3.65 (2H, m), 3.60-3.46 (2H, m), 1.42 (9H, s).
EXAMPLE 20 (37) 4-(N-(t-Butoxycarbonyl)piperidin-4-yl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1483] 1787
[1484] TLC: Rf 0.19 (hexane:ethyl acetate=1:1);
[1485] NMR (CDCl3): &dgr; 7.80-7.38 (6H, m), 7.23 (1H, d, J=8 Hz), 7.05 (1H, d, J=8 Hz), 5.23 (1H, d, J=9 Hz), 4.70 -4.45 (1H, m), 4.08 (1H, d, J=15 Hz), 3.95-3.60 (2H, m), 3.72 (1H, dd, J=15, 9 Hz), 3.50-3.22 (2H, m), 2.15-1.58 (4H, m), 1.48 (9H, s).
EXAMPLE 20 (38) 4,7-Bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1486] 1788
[1487] TLC: Rf 0.25 (hexane:ethyl acetate=1:3);
[1488] NMR (CDCl3): &dgr; 7.77 (2H, d, J=8.2 Hz), 7.70-7.55 (1H, m), 7.55-7.40 (2H, m), 6.95 (2H, s), 5.71 (1H, brs), 5.40-5.15 (2H, m), 4.20-3.30 (10H, m), 1.43 (18H, s).
EXAMPLE 20 (39) 4-(3-Nitrophenylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1489] 1789
[1490] TLC: Rf 0.13 (hexane ethyl acetate=1:1);
[1491] NMR (CDCl3+CD30D): &dgr; 8.35 (1H, s), 8.27 (1H, d, J=8 Hz), 7.87 (1H, d, J=8 Hz), 7.80-7.50 (5H, m), 7.50-7.25 (3H, m), 7.13 (1H, d, J=8 Hz), 5.36 (1H, d-like, J=9 Hz), 5.25-4.98 (2H, m), 4.11 (1H, dd, J=15, 1 Hz), 3.76 (1H, dd, J=15, 9 Hz).
EXAMPLE 21 4-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1492] 1790
[1493] To a solution of the compound prepared in Example 20 (27) (105 mg) in methylene chloride (5 ml), was added trifluoroacetic acid (5 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from diethyl ether to give the compound of the present invention (63 mg) having the following physical data.
[1494] TLC: Rf 0.20 (chloroform:methanol=4:1);
[1495] NMR (CDCl3+CD3OD): &dgr; 3.79 (dd, J=14.9, 9.0 Hz, 1H), 4.23 (dd, J=14.9, 1.0 Hz, 1H), 4.26 (d, J=16.1 Hz, 1H), 4.43 (d, J=16.1 Hz, 1H), 5.45 (dd, J=9.0, 1.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.45-7.59 (m, 3H), 7.62-7.70 (m, 1H), 7.77-7.81 (m, 2H).
EXAMPLES 21 (1)˜21 (3)[1496] By the same procedure as described in Example 21 using the compounds prepared in Examples 20 (28)˜20 (30) instead of the compound prepared in Example 20 (27), the following compounds of the present invention were obtained.
EXAMPLE 21 (1) 5-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1497] 1791
[1498] TLC: Rf 0.30 (chloroform:methanol=4:1);
[1499] NMR (CDCl3+CD3OD): &dgr; 3.79 (d-like, J=6 Hz, 2H), 4.76 (s, 2H), 5.10 (t, J=6 Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.69 (m, 3H).
EXAMPLE 21 (2) 6-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1500] 1792
[1501] TLC: Rf 0.25 (chloroform:methanol=4:1);
[1502] NMR (CDCl3+CD3OD): &dgr; 3.70-3.85 (m, 2H), 4.68 (s, 2H), 5.07 (t-like, J=6.6 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 7.32 (dd, J=8.8, 2.5 Hz, 1H), 7.47-7.55 (m, 2H), 7.63-7.73 (m, 3H), 7.83 (d, J=8.8 Hz, 1H).
EXAMPLE 21 (3) 7-Carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1503] 1793
[1504] TLC: Rf 0.29 (ethyl acetate:acetic acid=10:1);
[1505] NMR (CDCl3+DMSO-d6): &dgr; 7.52-7.26 (6H, m), 7.20 (1H, d, J=7.8 Hz), 6.77 (1H, d, J=8.2 Hz), 4.98 (1H, dd, J=7.8, 5.6 Hz), 4.52 (2H, s), 3.58-3.54 (2H, m).
EXAMPLE 22 4-(N-Pyridin-3-ylmethyl)carbamoylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1506] 1794
[1507] A suspension of the compound prepared in Example 21 (480 mg) in thionyl chloride (10 ml) was refluxed for 15 minutes. After removing thionylchloride, the residue was dissolved in methylene chloride (5 ml). Thereto was added dropwise a solution of 3-(aminomethyl)pyridine (0.15 ml) and triethylamine (1 ml) in methylene chloride (10 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:triethylamine=100:1) to give the compound of the present invention (421 mg) having the following physical data.
[1508] Free Compound:
[1509] TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=8:1:1);
[1510] NMR (DMSO-d6): &dgr; 4.03 (dd, J=14.9, 8.4 Hz, 1H), 4.11 (d, J=14.5 Hz, 1H), 4.12 (dd, J=14.9, 1.6 Hz, 1H), 4.33 (dd, J=15.3, 6.0 Hz, 1H), 4.44 (dd, J=15.3, 6.0 Hz, 1H), 4.57 (d, J=14.5 Hz, 1H), 6.00 (dd, J=8.4, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.63-7.73 (m, 5H), 8.39 (t, J=6.0 Hz, 1H), 8.46 (dd, J=4.7, 1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H).
[1511] Hydrochloride:
[1512] TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=8:1:1);
[1513] NMR (DMSO-d6): &dgr; 4.04 (dd, J=15.0, 8.7 Hz, 1H), 4.12 (d, J=14.7 Hz, 1H), 4.13 (dd, J=1 5.0, 1.5 Hz, 1H), 4.49 (dd, J=1 5.8, 6.2 Hz, 1H), 4.57 (dd, J=15.8, 6.2 Hz, 1H), 4.60 (d, J=14.7 Hz, 1H), 6.15 (dd, J=8.7, 1.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.52-7.57 (m, 2H), 7.64 (d, J=8.2 Hz, 1H), 7.68-7.74 (m, 3H), 7.93 (dd, J=8.0, 5.5 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.68 (t, J=6.2 Hz, 1H), 8.78 (d, J=5.4 Hz, 1H), 8.81 (s 1H).
EXAMPLES 22 (1) And 22 (2)[1514] By the same procedure as described in Example 22 using a corresponding amine compound instead of 3-(aminomethyl)pyridine, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained.
EXAMPLE 22 (1) 4-((2-(N,N-Dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsuifonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1515] 1795
[1516] Free Compound:
[1517] TLC: Rf 0.29 (ethyl acetate:methanol: triethylamine=8:1:1);
[1518] NMR (CDCl3): &dgr; 2.24 (s, 6H), 2.51 (t-like, J=6.0 Hz, 2H), 3.49 (m, J=6.0 Hz, 2H), 3.77 (dd, J=15.3, 9.6 Hz, 1H), 4.05 (dd, J=15.3, 1.3 Hz, 1H), 4.53 (d, J=14.2 Hz, 1H), 4.64 (d, J=14.2 Hz, 1H), 5.39 (d-like, J=9.0 Hz, 1H); 7.04 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (t, J=8.0 Hz, 1H), 7.59-7.65 (m, 1H), 7.70-7.74 (m, 2H), 7.94 (br, 1H).
[1519] hydrochloride:
[1520] TLC: Rf 0.29 (ethyl acetate:methanol:triethylamine=8:1:1);
[1521] NMR (DMSO-d6): &dgr; 2.76 (s, 6H), 3.14-3.18 (m, 2H), 3.44-3.56 (m, 2H), 4.00 (dd, J=15.0, 9.3 Hz, 1H), 4.03 (d, J=14.4 Hz, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.50 (d, J=14.4 Hz, 1H), 6.24 (d-like, J=8.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.56-7.62 (m, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.70-7.77 (m, 3H), 8.23 (t, J=5.5 Hz, 1H).
EXAMPLE 22 (2) 4-((N-Benzyl-2-(N′,N′-dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1522] 1796
[1523] TLC: Rf 0.52 (ethyl acetate:methanol:triethylamine=9:1:1);
[1524] NMR (CDCl3): &dgr; 2.22 (s, 3H), 2.29 (s, 3H), 2.44-2.55 (m, 2H), 3.29-3.35 (m, 1H), 3.56-3.60 (m, 1H), 3.73-3.75 (m, 2H), 4.60 (d, J=15.0 Hz, 0.5H), 4.67 (s-like, 1H), 4.76 (d, J=15.0 Hz, 0.5H), 4.88 (s, 1H), 4.94-5.00 (m, 1H), 5.05 (d, J=15.0 Hz, 0.5H), 5.18 (d, J=15.0 Hz, 0.5H), 7.10-7.36 (m, 6H), 7.41-7.53 (m, 4H), 7.61-7.68 (m, 3H).
EXAMPLE 23 4-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[1525] 1797
[1526] By the same procedure as described in Example 7 using the compound prepared in Example 20 (31) instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained.
[1527] TLC: Rf 0.21 (ethyl acetate: methanol: triethylamine=8:2:1);
[1528] NMR (DMSO-d6): &dgr; 2.66-2.78 (m, 1H), 3.02-3.12 (m, 1H), 3.83-4.18 (m, 4H), 6.23 (d-like, J=6.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.58-7.68 (m, 3H), 7.72-7.79 (m, 3H), 8.02 (br, 2H).
EXAMPLES 23 (1)˜23 (7)[1529] By the same procedure as described in Example 23 using the compounds prepared in Examples 20 (32)˜20 (38) instead of the compound prepared in Example 20 (31), the following compounds of the present invention were obtained.
EXAMPLE 23 (1) 4-(3-Aminopropyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1530] 1798
[1531] TLC: Rf 0.12 (ethyl acetate:methanol: triethylamine=8:4:1);
[1532] NMR (DMSO-d6): &dgr; 1.85-1.93 (m, 2H), 2.93 (q, J=6.4 Hz, 2H), 3.87-4.08 (m, 2H), 3.97 (dd, J=15.0, 8.4 Hz, 1H), 4.11 (dd, J=15.0, 1.4 Hz, 1H), 5.65 (dd, J=8.4, 1.4 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.59-7.78 (m, 6H), 8.15 (br, 3H).
EXAMPLE 23 (2) 5-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1533] 1799
[1534] TLC: Rf 0.25 (ethyl acetate methanol triethylamine 8:2:1);
[1535] NMR (DMSO-d6): &dgr; 7.81-7.72 (m, 4H), 7.66-7.59 (m, 2H), 7.32-7.27 (m, 2H), 5.77 (dd, J=9, 3.5 Hz, 1H), 4.27 (m, 2H), 3.94 (dd, J=15, 9 Hz, 1H), 3.71 (dd, J=15, 3.5 Hz, 1H), 3.38-3.32 (m, 2H).
EXAMPLE 23 (3) 6-(3-Aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1536] 1800
[1537] TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=8:2 :1);
[1538] NMR (DMSO-d6): 5 2.05 (quint, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 3.76 (dd, J=15.2, 3.0 Hz, 1H), 4.00 (dd, J=15.2, 9.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 5.70 (dd, J=9.4, 3.0 Hz, 1H), 7.29-7.38 (m, 2H), 7.56-7.67 (m, 3H), 7.76-7.79 (m, 3H), 8.08 (br, 2H).
EXAMPLE 23 (4) 6-(2-Aminoethyl)oxy-3-phenylsulfonyl-1,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1539] 1801
[1540] TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=9:1:1);
[1541] NMR (DMSO-d6): &dgr; 3.22 (t, J=4.9 Hz, 2H), 3.79 (dd, J=15.1, 3.0 Hz, 1H), 4.01 (dd, J=15.1, 9.4 Hz, 1H), 4.32 (t, J=4.9 Hz, 2H), 5.73 (dd, J=9.4, 3.0 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.8, 2.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.64-7.66 (m, 2H), 7.76-7.81 (m, 3H), 8.35 (br, 3H).
EXAMPLE 23 (5) 7-(2-Aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[1542] 1802
[1543] TLC: Rf 0.38 (ethyl acetate:acetic acid:water=3:1:1);
[1544] NMR (DMSO-d6): &dgr; 8.18 (3H, brs), 7.83-7.60 (6H, m), 7.40 (1H, d, J=8 Hz), 7.22 (1H, d, J=8 Hz), 5.81 (1 H, dd, J=9.6, 3.2 Hz), 4.44-3.30 (2H, m), 3.96 (1 H, dd, J=15, 9.6 Hz), 3.76 (1H, dd, J=15, 3.2 Hz), 3.18 (2H, t, J=6 Hz).
EXAMPLE 23 (6) 4-(Piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[1545] 1803
[1546] TLC: Rf 0.47 (ethyl acetate:acetic acid:water=3:1:1);
[1547] NMR (DMSO-d6): &dgr; 8.91 (2H, brs), 7.90-7.52 (6H, m), 7.41 (1H, d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 5.71 (1H, d, J=7 Hz), 4.95-4.70 (1H, m), 4.20-3.80 (2H, m), 3.50-2.95 (4H, m), 2.30-1.60 (4H, m).
EXAMPLE 23 (7) 4,7-Bis[(2-aminoethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[1548] 1804
[1549] TLC: Rf 0.22 (ethyl acetate:methanol:triethylamine=4:1:1);
[1550] NMR (DMSO-d6): &dgr; 8.10 (6H, brs), 7.85-7.70 (3H, m), 7.70-7.50 (2H, m), 7.37 (1H, d, J=8.6 Hz), 7.23 (1H, d, J=8.6 Hz), 6.14 (1H, d, J=6.0 Hz), 4.50-4.15 (2H, m), 4.15-3.90 (4H, m), 3.85-3.65 (1H, m), 3.25-3.15 (2H, m), 3.15-2.90 (1H, m).
EXAMPLE 24 4-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1551] 1805
[1552] By the same procedure as described in Example 8 using the compound prepared in Example 23 instead of the compound prepared in Example 7, the compounds of the present invention having the following physical data were obtained.
[1553] Free Compound:
[1554] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:2:1);
[1555] NMR (CDCl3): &dgr; 2.33 (s, 6H), 2.52-2.77 (m, 2H), 3.72 (dd, J=15.0, 9.4 Hz, 1H), 3.79-3.89 (m, 1H), 4.00-4.12 (m, 1H), 4.18 (dd, J=15.0, 1.1 Hz, 1H), 5.35 (d-like, J=8.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.43-7.66 (m, 4H), 7.72-7.77 (m, 2H).
[1556] Hydrochloride:
[1557] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:2:1);
[1558] NMR (CD3OD): &dgr; 3.05 (s, 6H), 3.52-3.76 (m, 2H), 3.83-3.99 (m, 2H), 4.38-4.63 (m, 2H), 5.89 (t, J=5.4 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.51-7.59 (m, 2H), 7.66-7.78 (m, 4H).
EXAMPLES 24 (1)˜24 (5)[1559] By the same procedure as described in Example 14 using the compounds prepared in Examples 23 (1)˜23 (5) instead of the compound prepared in Example 23, and if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained, with the proviso that when compounds of Example 23 (1) and Example 23 (3) were used, compounds of Example 24 (1b) and Example 24 (3b) were also generated respectively.
EXAMPLE 24 (1a) 4-(3-(N,N-Dimethylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1560] 1806
[1561] Free Compound:
[1562] TLC: Rf 0.35 (ethyl acetate:methanol:triethylamine=8:2:1);
[1563] NMR (CDCl3): &dgr; 1.86 (quint, J=7.0 Hz, 2H), 2.26 (s, 6H), 2.47 (t, J=7.0 Hz, 2H), 3.74 (dd, J=5.0, 9.2 Hz, 1H), 3.83-4.03 (m, 2H), 4.21 (dd, J=15.0, 1.2 Hz, 1H), 5.25 (d-like, J=8.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.48-7.74 (m, 6H).
[1564] Hydrochloride:
[1565] TLC: Rf 0.35 (ethyl acetate:methanol:triethylamine=8:2:1);
[1566] NMR (DMSO-d6): &dgr; 2.15 (m, 2H), 2.80 (s, 6H), 3.31 (t, J=7.5 Hz, 2H), 3.75 (dd, J=15.2, 9.2 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 4.31 (dd, J=15.2, 1.1 Hz, 1H), 5.69 (dd, J=9.2, 1.1 Hz, 1H), 7.32-7.39 (m, 2H), 7.55-7.72 (m, 3H), 7.80-7.85 (m, 3H).
EXAMPLE 24 (1b) 4-(3-(N-Cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1567] 1807
[1568] TLC: Rf 0.36 (ethyl acetate:triethylamine=9:1);
[1569] NMR (CDCl3): &dgr; 1.88 (quint, J=6.6 Hz, 2H), 2.38 (s, 3H), 2.69 (m, 2H), 3.51 (d, J=17.0 Hz, 1H), 3.61 (d, J=17.0 Hz, 1H), 3.73 (dd, J=15.0, 9.4 Hz, 1H), 3.96 (m, 2H), 4.13 (dd, J=15.0, 1.0 Hz, 1H), 5.28 (d-like, J=8.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.42-7.74 (m, 6H).
EXAMPLE 24 (2) 5-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydeo-1,1-dioxidebenzo[b]thiophene[1570] 1808
[1571] Free Compound:
[1572] TLC: Rf 0.55 (ethyl acetate: methanol: triethylamine 8:2:1);
[1573] NMR (DMSO-d6): &dgr; 2.23 (s, 6H), 2.66 (t, J=6 Hz, 2H), 3.77 (dd, J=15, 3 Hz, 1H), 3.98 (dd, J=15, 10 Hz, 1H), 4.10 (m, 2H), 5.71 (dd, J=10, 3 Hz, 1H), 7.05 (d, J=2 Hz, 1H), 7.25 (dd, J=9, 2 Hz, 1H), 7.58-7.84 (m, 6H).
[1574] Hydrochloride:
[1575] TLC: Rf 0.55 (ethyl acetate:methanol:triethylamine=8:2:1);
[1576] NMR (DMSO-d6): &dgr; 2.84 (s, 6H), 3.56 (m, 2H), 3.75 (dd, J=15, 4 Hz, 1H), 3.97 (dd, J=15, 9 Hz, 1H), 4.45 (m, 2H), 5.76 (dd, J=9, 4 Hz, 1H), 7.22 (d, J=2 Hz, 1H), 7.33 (dd, J=9, 2 Hz, 1H), 7.64 (m, 2H), 7.79 (m, 4H).
EXAMPLE 24 (3a) 6-(3-(N,N-Dimethylamino) propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1577] 1809
[1578] Free Compound:
[1579] TLC: Rf 0.53 (ethyl acetate:methanol:triethylamine=8:2:1);
[1580] NMR (CDCl3): &dgr; 1.97 (quint, J=6.6 Hz, 2H), 2.25 (s, 6H), 2.44 (t, J=6.6 Hz, 2H), 3.71 (dd, J=14.6, 7.6 Hz; 1H), 3.79 (dd, J=14.6, 5.6 Hz, 1H), 4.07 (t, J=6.6 Hz, 2H), 5.00 (dd, J=7.6, 5.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.23 (dd, J=8.8, 2.6 Hz, 1H), 7.46-7.54 (m, 2H), 7.63-7.72 (m, 3H), 7.85 (d, J=8.8 Hz, 1H).
[1581] Hydrochloride:
[1582] TLC: Rf 0.53 (ethyl acetate:methanol:triethylamine=8:2:1);
[1583] NMR (DMSO-d6): &dgr; 2.17 (m, 2H), 2.78 (s, 6H), 3.20 (t, J=7.9 Hz, 2H), 3.77 (dd, J=15.4, 3.2 Hz, 1H), 4.00 (dd, J=15.4, 9.4 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 5.71 (dd, J=9.4, 3.2 Hz, 1H), 7.30-7.38 (m, 2H), 7.58-7.67 (m, 3H), 7.75-7.79 (m, 3H).
EXAMPLE 24 (3b) 6-(3- (N-Cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1584] 1810
[1585] TLC: Rf 0.33 (ethyl acetate:hexane:triethylamine=6:3:1);
[1586] NMR (CDCl3): &dgr; 1.97 (quint, J=6.5 Hz, 2H), 2.38 (s, 3H), 2.65 (t, J=6.5 Hz, 2H), 3.54 (s, 2H), 3.71 (dd, J=14.8, 7.8 Hz, 1H), 3.79 (dd, J=14.8, 5.2 Hz, 1H), 4.06 (t, J=6.5 Hz, 2H), 5.00 (dd, J=7.8, 5.2 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.23 (dd, J=9.0, 2.6 Hz, 1H), 7.47-7.55 (m, 2H), 7.65-7.72 (m, 3H), 7.84 (d, J=9.0 Hz, 1H).
EXAMPLE 24 (4) 6-(2-(N,N-Dimethylamino)ethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1587] 1811
[1588] Free Compound:
[1589] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine 9:1:1);
[1590] NMR (CDCl3): &dgr; 2.34 (s, 6H), 2.75 (t, J=5.4 Hz, 2H), 3.74 (dd, J=14.8, 7.8 Hz, 1H), 3.79 (dd, J=14.8, 5.4Hz, 1H), 4.09 (t, J=5.4 Hz, 2H), 5.00 (dd, J=7.8, 5.4Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.52 (m, 2H), 7.62-7.69 (m, 3H), 7.84 (d, J=8.8 Hz, 1H).
[1591] Hydrochloride:
[1592] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=9:1:1);
[1593] NMR (DMSO-d6): &dgr; 2.83 (d, J=4.5 Hz, 6H), 3.50-3.54 (m, 2H), 3.78 (dd, J=15.0, 3.0 Hz, 1H), 4.01 (dd, J=15.0, 9.4 Hz, 1H), 4.49 (t, J=5.1 Hz, 2H), 5.73 (dd, J=9.4, 3.0 Hz, 1H), 7.41-7.44 (m, 2H), 7.60-7.67 (m, 3H), 7.77-7.80 (m, 3H), 10.83 (br, 1H).
EXAMPLE 24 (5) 7-(2-(N,N-Dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzp[b]thiophene hydrochloride[1594] 1812
[1595] TLC: Rf 0.32 (ethyl acetate:methanol:triethylamine=16:3:1);
[1596] NMR (DMSO-d6): &dgr; 7.85-7.60 (6H, m), 7.37 (1H, d, J=8.2 Hz), 7.22 (1H, d, J=8.2 Hz), 5.81 (1 H, dd, J=9.4, 3.2 Hz), 4.65-4.56 (2H, m), 3.97 (1H, dd, J=15, 9.4 Hz), 3.75 (1 H, dd, J=15, 3.2 Hz), 3.56-3. 45 (2H, m), 2.82 (6H, s).
EXAMPLE 25 4-(3-Aminophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1597] 1813
[1598] By the same procedure as described in Example 11 using the compound prepared in Example 20 (39) instead of the compound prepared in Example 10, the compound of the present invention having the following physical data was obtained.
[1599] TLC: Rf 0.34 (chloroform:tetrahydrofuran:28% ammonia water=100:50:1);
[1600] NMR (DMSO-d6): &dgr; 7.80-7.55 (4H, m), 7.49 (2H, t, J=8 Hz), 7.31 (2H, dd, J=12, 8 Hz), 7.02 (1H, t, J=8 Hz), 6.60-6.45 (2H, m), 5.54 (1H, d, J=9 Hz), 5.10 (2H, bs), 4.91 (1H, d, J=12 Hz), 4.69 (1H, d, J=12 Hz), 4.20 (1H, d, J=15 Hz), 3.98 (1H, dd, J=15, 9 Hz).
EXAMPLE 26 4-(3-(Pyridin-3-ylcarbonylamino)phenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1601] 1814
[1602] To a solution of the compound prepared in Example 25 (143 mg) in pyridine (6 ml) was added nicotinyl chloride-hydrochloride (77 mg). The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water, a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethanol to give the compound of the present invention (127 mg) having the following physical data.
[1603] TLC: Rf 0.34 (ethyl acetate:methanol:28% ammonia water=100:10:1);
[1604] NMR (DMSO-d6): &dgr; 9.12 (1H, d, J=2 Hz), 8.77 (1H, dd, J=5,2 Hz), 8.31 (1H, d, J=8 Hz), 7.82 (1H, s), 7.78-7.52 (7H, m), 7.52-7.25 (5H, m), 7.19 (1H, d, J=7 Hz), 5.59 (1H, d, J=8.5 Hz), 5.11 (1H, d, J=12 Hz), 4.86 (1H, d, J=12 Hz), 4.20 (1H, d, J=15 Hz), 4.01 (1H, dd, J=15, 8.5 Hz).
EXAMPLE 26 (1) 4-(2-(Pyridin-3-ylcarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1605] 1815
[1606] By the same procedure as described in Example 26 using the compound prepared in Example 23 instead of the compound prepared in Example 25, and if necessary, by converting into the corresponding salt by known methods, the compounds of the present invention having the following physical data were obtained.
[1607] Free Compound:
[1608] TLC: Rf 0.43 (ethyl acetate:methanol:triethylamine=8:1:1);
[1609] NMR (DMSO-d6): &dgr; 3.36-3.55 (m, 2H), 3.81-3.88 (m, 1H), 4.02 (dd, J=15.0, 8.7 Hz, 1H), 4.04-4.10 (m, 1H), 4.13 (dd, J=15.0, 1.3 Hz, 1H), 5.61 (d-like, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.48 (dd, J=8.1, 4.8 Hz, 1H), 7.56-7.68 (m, 3H), 7.71-7.77 (m, 3H), 8.15 (dt, J=8.1, 1.8 Hz, 1H), 8.65-8.68 (m, 1H), 8.68 (dd, J=4.8, 1.8 Hz, 1H), 8.98 (d, J=1.8 Hz, 1H).
[1610] Hydrochloride:
[1611] TLC: Rf 0.43 (ethyl acetate:methanol:triethylamine=8:1:1);
[1612] NMR (DMSO-d6): &dgr; 3.41-3.56 (m, 2H), 3.83-3.89 (m, 1H), 4.01 (dd, J=15.0, 8.7 Hz, 1H), 4.07-4.12 (m, 1H), 4.12 (dd, J=15.0, 1.2 Hz, 1H), 5.67 (d-like, J=7.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.56-7.61 (m, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.83 (dd, J=8.1, 5.4 Hz, 1H), 8.59 (dt, J=8.1, 1.6 Hz, 1H), 8.87 (dd, J=5.4, 1.6 Hz, 1H), 9.10 (t, J=5.4 Hz, 1H), 9.19 (d, J=1.6 Hz, 1H).
EXAMPLE 27 5-Methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1613] 1816
[1614] To a solution of 5-methyl-1,1-dioxidebenzo[b]thiophene (353 mg) in ethanol (19.5 ml), were added water (0.5 ml), acetic acid (0.4 ml) and benzenesulfonic acid sodium salt (940 mg) successively. The reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature. The crystals that appeared were separated by filtration. The crystals were washed by water, ethanol and hexane, sucessively, to give the compound of the present invention (381 mg) having the following physical data.
[1615] TLC: Rf 0.32 (hexane:ethyl acetate=1:1);
[1616] NMR (CDCl3): &dgr; 2.52 (s, 3H), 3.66 (dd, J=14.6, 8.7 Hz, 1H), 3.77 (dd, J=14.6, 4.9 Hz, 1H), 5.02 (dd, J=8.7, 4.9 Hz, 1H), 7.41-7.57 (m, 4H), 7.64-7.69 (m, 3H), 7.80 (s-like, 1H).
EXAMPLES 27 (1)˜27 (5)[1617] By the same procedure as described in Example 27 using corresponding benzo[b]thiophene compounds instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained.
EXAMPLE 27 (1) 5-(4-Chlorophenylcarbonyl)amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1618] 1817
[1619] TLC: Rf 0.27 (methylene chloride ethyl acetate 8:1);
[1620] NMR (DMSO-d6): &dgr; 3.74 (dd, J=15.1, 3.7 Hz, 1H), 3.95 (dd, J=15.1, 9.3 Hz, 1H), 5.83 (dd, J=9.3, 3.7 Hz, 1H), 7.58-7.65 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.73-7.83 (m, 4H), 8.04 (d, J=8.7 Hz, 2H), 8.10 (dd, J=8.8, 2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 10.86 (s, 1H).
EXAMPLE 27 (2) 4-Cyano-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b][thiophene[1621] 1818
[1622] TLC: Rf 0.60 (methylene chloride:ethyl acetate=8:1);
[1623] NMR (DMSO-d6): &dgr; 3.95 (dd, J=15, 10 Hz, 1H), 4.15 (d, J=15 Hz, 1H), 5.80 (d, J=10 Hz, 1H), 7.60-7.80 (m, 2H), 7.80-7.90 (m, 3H), 7.95 (t, J=7.5 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 8.35 (d, J=7.5 Hz, 1H).
EXAMPLE 27 (3) 6-Nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1624] 1819
[1625] TLC: Rf 0.44 (hexane ethyl acetate=1:1);
[1626] NMR (DMSO-d6): &dgr; 3.97 (dd, J=15.3, 3.0 Hz, 1H), 4.16 (dd, J=15.3, 9.3 Hz, 1H), 6.00 (dd, J=9.3, 3.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.79-7.83 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 8.61 (s-like, 1H), 8.62 (dd, J=8.4, 2.1 Hz, 1H).
EXAMPLE 27 (4) 4,7-Dimethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1627] 1820
[1628] TLC: Rf 0.48 (ethyl acetate );
[1629] NMR (DMSO-d6): &dgr; 3.27 (s, 3H), 3.85 (s, 3H), 3.96 (dd, J=15.2, 8.8 Hz, 1H), 4.12 (dd, J=15.2, 1.5 Hz, 1H), 5.49 (dd, J=8.8, 1.5 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 7.60-7.78 (m, 5H).
EXAMPLE 27 (5) 4,7-Bis(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1630] 1821
[1631] TLC: Rf 0.34 (ethyl acetate:methanol=9:19;
[1632] NMR (DMSO-d6): 5 1.52-1.57 (m, 2H), 1.83 (quint, J_6.3 Hz, 2H), 3.43 (q, J=6.3 Hz, 2H), 3.55 (q, J=5.8 Hz, 2H), 3.60-3.67 (m, 1H), 3.80-3.87 (m, 1H), 3.96 (dd, J=14.8, 9.0 Hz, 1H), 4.09 (d-like, J=14.8 Hz, 1H), 4.08-4.21 (m, 2H), 4.46 (t, J=5.1 Hz, 1H), 4.52 (t, J=5.1 Hz, 1H), 5.45 (d-like, J=7.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.58-7.63 (m, 2H), 7.72-7.77 (m, 3H).
EXAMPLE 28 4-(Pyridin-3-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1633] 1822
[1634] To 4-carboxy-1,1-dioxidebenzo[b]thiophene (prepared by the method described in Example 107 hereafter) (270 mg), was added thionyl chloride (2.0 ml). The mixture was refluxed for 2 hours, and concentrated. To a solution of (pyridin-3-ylmethyl)amine (154 mg) dissolved in methylene chloride (6.0 ml) and triethylamine (260 mg), a solution of the said chloride in methylene chloride (4.0 ml) were added dropwise. The mixture was stirred for 2 hours at room temperature. To the reaction mixture, ice-water and a 1N aqueous solution of sodium hydroxide (1.5 ml) were added dropwise. The mixture was extracted by ethyl acetate (40 ml). The extract was washed by a saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the compound of the present invention (330 mg) having the following physical data.
[1635] TLC: Rf 0.48 (methylene chloride: methanol=10:1);
[1636] NMR (CDCl3): &dgr; 8.56 (d, J=2.1 Hz, 1H), 8.53 (dd, J=4.5, 2.1 Hz, 1H), 7.93 (dd, J=7.2, 0.6 Hz, 1H), 7.79-7.72 (m, 2H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.8, 4.5 Hz, 1H), 6.86 (t, J=6.3 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.65 (d, J=6.3 Hz, 2Hz.
EXAMPLES 28 (1)˜28 (33)[1637] By the same procedure as described in Example 28 using carboxylic acid corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivative corresponding to (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salt by a known method, the compounds of the present invention were obtained.
[1638] In the preparation of a compound of Example 28 (33), 4-aminomethyl-1,1-dioxidebenzo[b]thiophene and pyridin-3-ylcarboxylic acid were subjected to reaction.
EXAMPLE 28 (1) 4-(4-Benzylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene[1639] 1823
[1640] TLC: Rf 0.30 (ethyl acetate:methanol=50:1);
[1641] NMR (CDCl3): &dgr; 7.75 (d, J=7.4 Hz, 1H), 7.56 (t, J=7.4 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.40-7.20 (m, 6H), 6.78 (d, J=7.0 Hz, 1H), 3.83 (m, 2H), 3.55 (s, 2H), 3.34 (m, 2H), 2.55 (m, 2H), 2.37 (m, 2H).
EXAMPLE 28 (2) 4-(N-(2-(Pyridin-3-yl)ethyl)-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene[1642] 1824
[1643] MS (APCI, Pos.): m/z 361 (M+MeOH+H)+, 329 (M+H)+.
EXAMPLE 28 (3) 4-(2-(2-Hydroxyethoxy)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1644] 1825
[1645] MS (APCI, Pos.): m/z 330 (M+MeOH+H)+, 298 (M+H)+.
EXAMPLE 28 (4) 4-(2,4-Dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1646] 1826
[1647] TLC: Rf 0.68 (ethyl acetate);
[1648] NMR (CDCl3): &dgr; 7.90 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.25 (d, J=10 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.60-6.40 (m, 3H), 4.55 (d, J=7.5 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H).
EXAMPLE 28 (5) 4-(1-Benzylpiperidin-4-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1649] 1827
[1650] Free Aicd:
[1651] TLC: Rf 0.50 (ethyl acetate:methanol=8:1.5);
[1652] NMR (CDCl3): &dgr; 7.90 (d, J=7.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.20 (m, 5H), 6.75 (d, J=7.5 Hz, 1H), 6.05-5.95 (m, 1H), 4.10-3.90 (m, 1H), 3.55 (s, 2H), 3.00-2.90 (m, 2H), 2.30-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.70-1.50 (m, 2H).
[1653] Hydrochloride:
[1654] TLC: Rf 0.44 (methanol:ethyl acetate=1:10);
[1655] NMR (CD3OD): &dgr; 7.90-7.75 (m, 3H), 7.75-7.45 (m, 6H), 7.08 (d, J=7.0 Hz, 1H), 4.34 (s, 2H), 4.27-4.05 (m, 1H), 3.61-3.42 (m, 2H), 3.33-3.10 (m, 2H), 2.34-2.15 (m, 2H), 2.12-1.81 (m, 2H).
[1656] Methanesulfonic Acid Salt:
[1657] TLC: Rf 0.44 (methanol:ethyl acetate=1:10);
[1658] NMR (CD3OD): &dgr; 7.89-7.74 (m, 3H), 7.73-7.60 (m, 1H), 7.60-7.45 (m, 5H), 7.08 (d, J=7.0 Hz, 1H), 4.34 (s, 2H), 4.27-4.03 (m, 1H), 3.68-3.38 (m, 2H), 3.38-3.06 (m, 2H), 2.67 (s, 3H), 2.38-1.72 (m, 4H).
EXAMPLE 28 (6) 4-(Pyridin-4-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1659] 1828
[1660] TLC: Rf 0.29 (ethyl acetate:methanol=19:1);
[1661] NMR (CDCl3+CD3OD): &dgr; 8.50 (d, J=7 Hz, 2H), 8.25 (broad-t, J=7 Hz, 1H), 7.95 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 2H), 7.60 (t, J=8 Hz, 1H), 7.30 (d, J=7Hz, 2H), 6.80 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H).
EXAMPLE 28 (7) 4-(2-t-Butoxycarbonylethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene[1662] 1829
[1663] TLC: Rf 0.40 (ethyl acetate:hexane=3:2);
[1664] NMR (CDCl3): &dgr; 8.00 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 6.95 (broad-s, 1H), 6.80 (d, J=7 Hz, 1H), 3 70 (q, J=7 Hz, 7H), 2.60 (t, J=7 Hz, 2H), 1.45 (s, 9H).
EXAMPLE 28 (8) 4-(Thiophen-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1665] 1830
[1666] TLC: Rf 0.48 (chloroform:methanol=9:1);
[1667] NMR (CDCl3+DMSO-d6): &dgr; 8.50 (t, J=7 Hz, 1H), 7.95 (d, J=6 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.25 (d, J=6 Hz, 1H), 7.05 (d, J=3 Hz, 1H), 6.95 (dd, J=3 Hz and 6 Hz, 1H), 6.80 (d, J=6 Hz, 1H), 4.75 (d, J=7 Hz, 2H).
EXAMPLE 28 (9) 4-Benzylcarbamoyl-1,1-dioxidebenzo[b]thiophene[1668] 1831
[1669] TLC: Rf 040 (ethyl acetate hexane=1:1);
[1670] NMR (CDCl3+DMSO-d6): &dgr; 7.99 (d, J=7.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.43 (t, J=5.7 Hz, 1H), 7.40-7.27 (m, 5H), 6.78 (d, J=7.2 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H).
EXAMPLE 28 (10) 4-(Pyridin-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1671] 1832
[1672] TLC: Rf 0.30 (ethyl acetate:hexane=1:1);
[1673] NMR (CDCl3): &dgr; 8.56 (d, J=5.1 Hz, 1H), 8.05 (dd, J=7.2, 0.9 Hz, 1H), 7.84 (t, J=7.2 Hz, 1H), 7.73 (dt, J=0.9, 7.8 Hz, 1H), 7.68 (t, J=5.1 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.59-7.23 (m, 2H), 6.78 (d, J=6.9 Hz, 1H), 4.76 (d, J=5.1 Hz, 2H).
EXAMPLE 28 (11) 4-(2-(Piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1674] 1833
[1675] Free Aicd:
[1676] TLC: Rf 0.35 (methylene chloride:methanol=10:1);
[1677] NMR (CDCl3): &dgr; 8.04 (dd, J=7.2, 0.9 Hz, 1H), 7.80 (dt, J=7.8. 0.9 Hz, 1H), 7.72 (dd. J=7.8, 0.9 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.02 (bs, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.54 (q, J=5.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.50-2.40 (m, 4H), 1.76-1.43 (m, 6H).
[1678] Hydrochloride:
[1679] TLC: Rf 0.60 (methylene chloride:methanol:triethylamine=8:1.5:0.5);
[1680] NMR (DMSO-d6): &dgr; 10.20 (br. s, 1H), 9.25-9.10 (m, 1H), 8.01 (d, J=7.0 Hz, 1H), 7.99 (d, J=7.0 Hz, 1H), 7.93 (d, J=6.9 Hz, 1H), 7.73 (t, J=7.0 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H), 3.80-3.60 (m, 2H), 3.60-3.50 (m, 2H), 3.45-3.15 (m, 2H), 3.10-2.80 (m, 2H), 2.00-1.70 (m, 5H), 1.55-1.30 (m, 1H).
EXAMPLE 28 (12) 4-((1S)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1681] 1834
[1682] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[1683] NMR (CDCl3): &dgr; 7.95 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.64 (dd, J=8.4, 4.2 Hz, 1H), 2.36-2.27 (m, 1H), 1.51 (s, 9H), 1.02 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H).
EXAMPLE 28 (13) 4-(2-Fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1684] 1835
[1685] TLC: Rf 0.60 (chloroform:methanol=9:1);
[1686] NMR (CDCl3+DMSO-d6): &dgr; 7.95 (broad peak, 1H), 7.95 (d, J=7 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.50-7.20 (m, 2H), 7.20-7.00 (m, 2H), 6.77 (d, J=7 Hz, 1H), 4.62 (d, J=7 Hz, 2H).
EXAMPLE 28 (14) 4-(3-Fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1687] 1836
[1688] TLC: Rf 0.50 (chloroform:methanol=9:1);
[1689] NMR (CDCl3+DMSO-d6): &dgr; 8.40 (broad peak, 1H), 7.98 (d, J=7 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.40-7.25 (m, 1H), 7.20-6.90 (m, 3H), 6.80 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H).
EXAMPLE 28 (15) 4-(3-Methylphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1690] 1837
[1691] TLC: Rf 0.60 (chloroform: methanol=9:1); NMR (CDCl3): &dgr; 7.95 (d, J=7 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7.30-7.20 (m, 1H), 7.20-7.10 (m, 3H), 6.75 (d, J=7 Hz, 1H), 6.40 (broad peak, 1H), 4.60 (d, J=7 Hz, 2H), 2.40 (s, 3H).
EXAMPLE 28 (16) 4-(2-Methoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1692] 1838
[1693] TLC: Rf 0.64 (chloroform:methanol=9:1);
[1694] NMR (CDCl3+DMSO-d6): &dgr; 7.93 (d, J=7 Hz, 1H), 7.85-7.70 (m, 3H), 7.55 (t, J=8 Hz, 1H), 7.30 (m, 2H), 6.92 (m, 2H), 6.78 (d, J=7 Hz, 1H), 4.60 (d, J=7 Hz, 2H), 3.90 (s, 3H).
EXAMPLE 28 (17) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1695] 1839
[1696] TLC: Rf 0.63 (chloroform:methanol=9:1);
[1697] NMR (CDCl3+DMSO-d6): &dgr; 7.97 (d, J=7.2 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.73 (broad peak, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.00-6.85 (m, 2H), 6.77 (d, J=7.2 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H).
EXAMPLE 28 (18) 4-(3,4-Dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1698] 1840
[1699] TLC: Rf 0.53 (chloroform:methanol=9:1);
[1700] NMR (CDCl3+DMSO-d6): &dgr; 8.57 (t-like, J=5.8 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz,1H), 7.57 (t, J=7.8 Hz,1H), 7.00-6.80 (m, 4H), 4.53 (d, J=5.8 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H).
EXAMPLE 28 (19) 4-(2,5-Difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1701] 1841
[1702] TLC: Rf 0.45 (chloroform:methanol 9:1);
[1703] NMR (CDCl3+DMSO-d6): &dgr; 8.78 (t, J=6.0 Hz, 1H), 7.97 (dd, J=7.0 Hz and 1.0 Hz, 1H), 7.89 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.20-6.90 (m, 3H), 6.82 (d, J=7.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H).
EXAMPLE 28 (20) 4-(3,4,5-Trimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1704] 1842
[1705] TLC: Rf 0.33 (chloroform:methanol=9:1);
[1706] NMR (CDCl3, DMSO-d6): &dgr; 8.00 (broad peak, 1H), 7.98 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.82 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.61 (s, 2H), 4.54 (d, J=5.8 Hz, 2H), 3.86 (s, 6H), 3.83 (s, 3H).
EXAMPLE 28 (21) 4-(Benzimidazol-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1707] 1843
[1708] TLC: Rf 0.28 (chloroform:methanol=9:1);
[1709] NMR (CDCl3+DMSO-d6): &dgr; 8.97 (t, J=5.6 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.94 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.79 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.62-7.50 (m, 3H), 7.30-7.15 (m, 2H), 6.81 (d, J=7.2 Hz, 1H), 4.85 (d, J=5.6 Hz, 2H).
EXAMPLE 28 (22) 4-(3,5-Difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1710] 1844
[1711] TLC: Rf 0.57 (chloroform:methanol=9:1);
[1712] NMR (CDCl3+DMSO-d6): &dgr; 9.11 (t, J=5.8 Hz, 1H), 7.98 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.93 (dd, J=7.6 Hz and 1.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.00-6.90 (m, 2H), 6.90 (d, J=7.2 Hz, 1H), 6.80-6.68 (m, 1H), 4.55 (d, J=5.8 Hz, 2H).
EXAMPLE 28 (23) 4-(N-Benzyl-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene[1713] 1845
[1714] TLC: Rf 0.69 (chloroform:methanol=9:1);
[1715] NMR (CDCl3): &dgr; 7.80-7.70 (m, 1H), 7.65-7.47 (m, 2H), 7.47-7.25 (m, 5H), 7.15-7.00 (m, 1H), 6.80-6.72 (m, 1H), 4.78 and 4.44 (each s, total 2H), 3.12 and 2.84 (each s, total 3H).
EXAMPLE 28 (24) 4-(4-Nitrophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1716] 1846
[1717] TLC: Rf 0.44 (chloroform:methanol 9:1);
[1718] NMR (CDCl3+DMSO-d6): &dgr; 9.20 (t, J=5.8 Hz, 1H), 8.20 (d, J=8 Hz, 2H), 7.98 (d, J=7 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.57 (d, J=8 Hz, 2H), 6.89 (d, J=7 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H).
EXAMPLE 28 (25) 5-(2-Hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[1719] 1847
[1720] TLC: Rf 0.38 (ethyl acetate);
[1721] NMR (CDCl3+CD3OD): &dgr; 7.98 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.88 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.31 (d, J=6.8 Hz, 1H), 6.81 (d, J=6.8 Hz, 1H), 3.78 (t, J=4.8 Hz, 2H), 3.57 (t, J=4.8 Hz, 2H).
EXAMPLE 28 (26) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1722] 1848
[1723] MS (APCI, Pos.): m/z 363 (M+MeOH+H)+, 331 (M+H)+.
EXAMPLE 28 (27) 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1724] 1849
[1725] TLC: Rf 0.27 (methylene chloride:methanol=10:1);
[1726] NMR (CDCl3): &dgr; 8.23 (d, J=8.1 Hz,1H), 8.03 (t, J=5.7 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.41 (d, J=6.9 Hz, 1H), 6.76 (d, J=6.9 Hz, 1H), 3.94 (s, 3H), 3.57 (q, J=5.7 Hz, 2H), 2.53 (t, J=5.7 Hz, 2H), 2.30 (s, 6H).
EXAMPLE 28 (28) 5-Dimethylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1727] 1850
[1728] TLC: Rf 0.35 (methanol:ethyl acetate=5:95);
[1729] NMR (CDCl3): &dgr; 7.52-7.38 (m, 3H), 6.75 (d, J=7.4 Hz, 1H), 3.93 (s, 3H), 3.15 (s, 3H), 2.88 (s, 3H).
EXAMPLE 28 (29) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1730] 1851
[1731] TLC: Rf 0.60 (methylene chloride:methanol=10:1);
[1732] NMR (CDCl3): &dgr; 7.48 (dd, J=7.5,0.9Hz, 1H), 7.42 (dd, J=6.9, 0.9 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 3.95 (s, 3H), 3.80-3.56 (m, 2H), 3.30-3.20 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.40 (m, 6H).
EXAMPLE 28 (30) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1733] 1852
[1734] TLC: Rf 0.82 (methylene chloride:methanol=10:1);
[1735] NMR (CDCl3): &dgr; 8.31 (d, J=7.8 Hz, 1H), 7.54 (s, 2H), 7.45 (d, J=6.9 Hz, 1H), 7.33-7.20 (m, 2H), 7.20-7.07 (m, 1H), 6.77 (d, J=6.9 Hz, 1H), 3.97 (s, 3H), 3.90-3.66 (m, 2H), 3.25-3.10 (m, 2H).
EXAMPLE 28 (31) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1736] 1853
[1737] TLC: Rf 0.30 (ethyl acetate:hexane=1:1);
[1738] NMR (CDCl3): &dgr; 7.51 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.43-7.35 (m, 2H), 7.30-7.20 (m, 1H), 7.06-6.99 (m, 2H), 6.76 (d, J=6.9 Hz, 1H), 4.10-3.90 (m, 2H), 3.98 (s, 3H), 3.54-3.37 (m, 2H),3.20-2.90 (m, 4H).
EXAMPLE 28 (32) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1739] 1854
[1740] TLC: Rf 0.33 (ethyl acetate);
[1741] NMR (CDCl3): &dgr; 7.63 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.46-7.40 (m, 2H), 7.40-7.27 (m, 2H), 6.75 (d, J=7.5 Hz, 1H), 3.94 (s, 3H), 3.90-3.80 (m, 2H), 3.35-3.20 (m, 2H), 3.04-2.94 (m, 2H), 2.68-2.60 (m, 4H), 2.58-2.40 (m, 2H).
EXAMPLE 28 (33) 4-(Pyridin-3-ylcarbonyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[1742] 1855
[1743] MS (APCI, Pos.): m/z 333 (M+MeOH+H)+, 301 (M+H)+.
EXAMPLE 29 4-(3-(Pyrrol-1-yl)-propyl) oxy-1,1-dioxidebenzo[b]thiophene[1744] 1856
[1745] 4-Hydroxy-1,1-dioxidebenzo[b]thiophene (370 mg), triphenylphosphine (630 mg) and 1-(3-hydroxypropyl)pyrrole (300 mg) were dissolved in anhydrous tetrahydrofuran (15 ml). Under an atmosphere of argon to the mixture, was added a solution of diethylazodicarboxylate (323 mg) in anhydrous tetrahydrofuran (4 ml) dropwise. The mixture was stirred at room temperature for 2 hours. To the reaction mixture methanol was added. The mixture was stirred for 10 minutes. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention (473 mg) having the following physical data.
[1746] TLC: Rf 0.47 (hexane:ethyl acetate=1:1);
[1747] NMR (CDCl3): &dgr; 7.55-7.35 (m, 2H), 7.30 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 6.75-6.54 (m, 3H), 6.16 (t, J=2 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 4.00 (t, J=6 Hz, 2H), 2.27 (q, J=6 Hz, 2H).
EXAMPLES 30˜30 (13)[1748] By the same procedure as described in Example 18 using alcohol derivative corresponding to the compound prepared in Example 9 (12) and halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained.
EXAMPLE 30 4-(Quinolin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[1749] 1857
[1750] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);
[1751] NMR (CDCl3): &dgr; 8.23 (d, J=8 Hz, 1H), 8.09 (d, J=8Hz, 1H), 7.95-7.68 (m, 2H), 7.68-7.50 (m, 3H), 7.50-7.22 (m, 2H), 7.14 (d, J=8 Hz, 1H), 6.66 (d, J=7 Hz, 1H), 5.49 (s, 2H).
EXAMPLE 30 (1) 4-(2-(Pyrrol-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1752] 1858
[1753] TLC: Rf 0.50 (ethyl acetate:hexane=2:1);
[1754] NMR (CDCl3): &dgr; 7.55-7.22 (m, 3H), 6.94 (d, J=8 Hz, 1H), 6.73 (t, J=2 Hz, 2H), 6.62 (d, J=7 Hz, 1H), 6.19 (t, J=2 Hz, 2H), 4.32 (s, 4H).
EXAMPLE 30 (2) 4-(2-(4-Methylazol-5-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1755] 1859
[1756] TLC: Rf 0.15 (ethyl acetate:hexane=2:1);
[1757] NMR (CDCl3): &dgr; 8.63 (s, 1H), 7.58-7.37 (m, 2H), 7.31 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz,1H), 6.64 (d, J=8 Hz, 1H), 4.26 (t, J=6 Hz, 2H), 3.31 (t, J=6 Hz, 2H), 2.46 (s, 3H).
EXAMPLE 30 (3) 4-(3-(Pyridin-4-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene[1758] 1860
[1759] TLC: Rf 0.36 (ethyl acetate:methanol=10:1);
[1760] NMR (CDCl3): &dgr; 8.53 (dd, J=1.6, 4.5 Hz, 2H), 7.60-7.22 (m, 3H), 7.14 (d, J=5.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 6.62 (d, J=7.4 Hz, 1H), 4.09 (t, J=6.2 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.19 (quint, J=6.2 Hz, 2H).
EXAMPLE 30 (4) 4-(1-t-Butoxycarbonylpiperidin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[1761] 1861
[1762] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);
[1763] NMR (CDCl3): &dgr; 7.58-7.38 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.61 (d, J=7.0 Hz, 3.15-2.50 (m, 4H), 1.45 (s, 9H).
EXAMPLE 30 (5) 4-(2-(Pyrrolidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1764] 1862
[1765] TLC: Rf 0.36 (ethyl acetate:acetic acid:water=3:1:1);
[1766] NMR (CDCl3): &dgr; 7.55-7.35 (m, 2H), 7.29 (d, J=7 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.61 (d, J=7 Hz, 1H), 4.22 (t, J=6 Hz, 2H), 2.94 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz, 4H), 2.20-1.65 (m, 4H).
EXAMPLE 30 (6) 4-(2-(Piperidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1767] 1863
[1768] TLC: Rf 0.44 (ethyl acetate:acetic acid:water=3:1:1);
[1769] NMR (CDCl3): &dgr; 7.60-7.58 (m, 2H), 7.29 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.61 (d, J=7 Hz, 1H), 4.21 (t, J=6 Hz, 2H), 2.80 (t, J=6 Hz, 2H), 2.51 (t, J=6 Hz, 4H), 1.90-1.35 (m 6H).
EXAMPLE 30 (7) 4-(2-(2-Acetyloxyethoxy)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1770] 1864
[1771] TLC: Rf 0.46 (ethyl acetate:hexane=2:1);
[1772] NMR (CDCl3): &dgr; 5 7.58-7.38 (m, 2H), 7.31 (d, J=7 Hz, 1H), 7.08 (d, J=9 Hz, 1H), 6.62 (d, J=7 Hz, 1H), 4.25 (t, J=5 Hz, 4H), 3.88 (t, J=5 Hz, 2H), 3.76 (t, J=5 Hz, 2H), 2.07 (s, 3H).
EXAMPLE 30 (8) 4-(2-(4-Benzylpiperazin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[1773] 1865
[1774] TLC: Rf 0.57 (chloroform:methanol 5:1);
[1775] NMR (CDCl3): &dgr; 7.58-7.38 (m, 2H), 7.38-7.18 (m, 6H), 7.05 (d, J=8 Hz, 1H), 6.60 (d, J=7 Hz,1H), 4.35-4.05 (m, 2H), 3.52 (s, 2H), 2.85 (t, J=6 Hz, 2H), 2.78-2.35 (m, 8H).
EXAMPLE 30 (9) 4-Diethylcarbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene[1776] 1866
[1777] TLC: Rf 0.25 (hexane:ethyl acetate=1:2);
[1778] NMR (CDCl3): &dgr; 7.52 (d, J=7.0 Hz,1H), 7.46 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.63 (d, J=7.0 Hz, 1H), 4.80 (s, 2H), 3.41 (q, J=7.2 Hz, 2H), 3.36 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H).
EXAMPLE 30 (10) 4-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene[1779] 1867
[1780] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[1781] NMR (CDCl3): &dgr; 7.65-7.35 (m, 3H), 7.15 (d, J=7.5 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 4.90 (s, 2H).
EXAMPLE 30 (11) 5-(Pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[1782] 1868
[1783] MS (APCI, Pos.): m/z 336 (M+MeOH+H)+, 304 (M+H)+.
EXAMPLE 30 (12) 5-(2-t-Butoxycarbonylaminoethyl)oxy-4-nitro-1,1-dioxidebenzo[b]thiophene[1784] 1869
[1785] TLC: Rf 0.32 (hexane:ethyl acetate=1:1);
[1786] NMR (CDCl3) &dgr; 7.80 (d, J=8.6 Hz, 1H), 7.33 (d, J=7.0 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.93 (d, J=7.0 Hz, 1H), 5.00 (br, 1H), 4.24 (t, J=5.2 Hz, 2H), 3.57 (q, J=5.2 Hz, 2H), 1.45 (s, 9H).
EXAMPLE 30 (13) 5-((2E)-3-Ethoxycarbonyl-2-propenyl) oxy-1,1-dioxidebenzo[b]thiophene[1787] 1870
[1788] TLC: Rf 0.51 (hexane:ethyl acetate=1:1);
[1789] NMR (CDCl3): &dgr; 7.65 (d, J=8.8 Hz, 1H), 7.14 (d, J=6.8 Hz, 1H), 7.12-6.85 (m, 4H), 6.74 (d, J=6.8 Hz, 1H), 6.23-6.10 (m, 1H), 4.82-4.73 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H).
EXAMPLE 31 4-(2,4-Dimethoxyphenylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[1790] 1871
[1791] 4-Bromomethyl-1,1-dioxidebenzo[b]thiophene (198 mg) was dissolved in acetonitrile (10 ml). Thereto was added a solution of 2,4-dimethoxybenzylamine, hydrochloride (188 mg) and triethylamine (0.26 ml) in acetonitrile (6 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture a saturated aqueous solution of sodium bicarbonate was added. The mixture was extracted by ethyl acetate. The extract was washed by a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane 1:1→2:1) to give the compound of the present invention (113 mg) having the following physical data.
[1792] TLC: Rf 0.29 (ethyl acetate);
[1793] NMR (CDCl3): &dgr; 7.63-7.39 (m, 4H), 7.07 (d, J=8.0 Hz,1H), 6.66 (d, J=7.0 Hz,1H), 6.49-6.39 (m, 2H), 3.83 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.72 (s, 2H), 1.98 (s, 1H).
EXAMPLES 31 (1)˜31 (12)[1794] By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and an amine derivative corresponding to 2,4-dimethoxybenzylamine-hydrochloride, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained.
EXAMPLE 31 (1) 4-(Pyridin-3-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene-2hydrochloride[1795] 1872
[1796] TLC: Rf 0.37 (ethyl acetate:methanol=5:1);
[1797] NMR (CD3OD): &dgr; 9.11 (d, J=1.7 Hz, 1H), 8.92 (dd, J=5.5, 1.7 Hz, 1H), 8.73 (dt, J=8.2, 1.7 Hz, 1H), 8.10 (dd, J=8.2, 5.5 Hz, 1H), 7.94-7.90 (m, 2H), 7.84 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.4 Hz,. 1H), 7.18 (d, J=7.4 Hz, 1H), 4.68 (s, 2H), 4.63 (s, 2H).
EXAMPLE 31 (2) 4-(2-(Dimethylamino)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[1798] 1873
[1799] MS (APCI, Pos.): mlz 299 (M+MeOH+H)+, 267 (M+H)+.
EXAMPLE 31 (3) 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene[1800] 1874
[1801] MS (APCI, Pos.): m/z 316 (M+MeOH+H)+, 284 (M+H)+.
EXAMPLE 31 (4) 4-(2-(2-Hydroxyethoxy)ethyl)aminoethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[1802] 1875
[1803] MS (APCI, Pos.): m/z 599 (2M+MeOH+H)+, 567 (2M+H)+, 316 (M+MeOH+H)+, 284 (M+H)+.
EXAMPLE 31 (5) 4-(4-Benzylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene[1804] 1876
[1805] Free Compound:
[1806] TLC: Rf 0.27 (ethyl acetate:hexane=1:1);
[1807] NMR (CDCl3): &dgr; 7.71 (d, J=7.0 Hz, 1H), 7.62 (t, J=4.6 Hz, 1H), 7.44 (d, J=4.6 Hz, 2H), 7.35-7.25 (m, 5H), 6.68 (d, J=7.0 Hz, 1H), 3.60 (s, 2H), 3.51 (s, 2H), 2.46 (brs, 8H).
[1808] 2hydrochloride:
[1809] TLC: Rf 0.32 (ethyl acetate);
[1810] NMR (CD3OD): &dgr; 7.86 (d, J=7.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.58-7.47 (m, 5H), 7.07 (d, J=7.2 Hz, 1H), 4.38 (s, 2H), 4.13 (s, 2H), 3.41 (br, 4H), 3.13 (br, 4H).
EXAMPLE 31 (6) 4-(4-(Pyridin-2-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene[1811] 1877
[1812] MS (APCI, Pos.): m/z 374 (M+MeOH+H)+, 342 (M+H)+.
EXAMPLE 31 (7) 4-(4-Ethoxycarbonylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene[1813] 1878
[1814] MS (APCI, Pos.): m/z 369 (M+MeOH+H)+, 337 (M+H)+.
EXAMPLE 31 (8) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene[1815] 1879
[1816] MS (APCI, Pos.): m/z 649 (2M+MeOH+H)+, 617 (2M+H)+, 341 (M+MeOH+H)+, 309 (M+H)+.
EXAMPLE 31 (9) 4-(4-(Pyridin-4-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene[1817] 1880
[1818] MS (APCI, Pos.): m/z 374 (M+MeOH+H)+, 342 (M+H)+.
EXAMPLE 31 (10) 4-Benzylaminomethyl-1,1-dioxidebenzo[b]thiophene[1819] 1881
[1820] Free Compound:
[1821] TLC: Rf 0.66 (ethyl acetate);
[1822] NMR (CDCl3): &dgr; 7.62 (d, J=7.2 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.39-7.24 (m, 5H), 6.69 (d, J=7.2 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 2H), 1.59 (s, 1H).
[1823] Hydrochloride:
[1824] TLC: Rf 0.47 (ethyl acetate:hexane 2:1);
[1825] NMR (CD3OD): &dgr; 7.95-7.18 (m, 8H), 7.15 (d, J=7 Hz, 1H), 6.98 (d, J=7 Hz, 1H), 4.48 (s, 2H), 4.36 (s, 2H).
EXAMPLE 31 (11) 4-(1-Benzylpiperidin-4-yl)aminomethyl-1,1-dioxidebenzo[b]thiophene[1826] 1882
[1827] Free Compound:
[1828] TLC: Rf 0.27 (ethyl acetate:methanol=4:1);
[1829] NMR (CDCl3): &dgr; 7.65 (d, J=7.0 Hz, 1H), 7.61 (d, J=6.8 Hz, 1H), 7.56-7.40 (m, 2H), 7.34-7.22 (m, 5H), 6.68 (d, J=7.0 Hz, 1H), 3.91 (s, 2H), 3.50 (s, 2H), 2.91-2.77 (m, 2H), 2.60-2.43 (m, 1H), 2.12-1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.60-1.32 (m, 3H).
[1830] 2hydrochloride:
[1831] TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[1832] NMR (DMSO-d6+CD3OD): &dgr; 7.97 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.5 Hz,1H),7.65-7.55 (m, 3H), 7.50-7.40 (m, 4H), 4.42 (s, 2H), 4.33 (s, 2H), 3.80-3.40 (m, 3H), 3.10-2.95 (m, 2H), 2.50-2.35 (m, 2H), 2.35-2.05 (m, 2H).
EXAMPLE 31 (12) 4-(Morpholin-4-yl)methyl-1,1-dioxidebenzo[b]thiophene[1833] 1883
[1834] TLC: Rf 0.31 (ethyl acetate:methylene chloride=1:1);
[1835] NMR (CDCl3): &dgr; 7.69 (d, J=7.2 Hz, 1H), 7.64 (t, J=4.8 Hz, 1H), 7.46 (d, J=4.8 Hz, 2H), 6.71 (d, J=7.2 Hz, 1H), 3.68 (t, J=4.5 Hz, 4H), 3.60 (s, 2H), 2.44 (t, J=4.5 Hz, 4H).
EXAMPLE 32 4-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene[1836] 1884
[1837] To a solution of 4-Carboxy-1,1-dioxidebenzo[b]thiophene (2.42 g) in dimethylformamide (50 ml), were added potassium carbonate (3.10 g) and bromoethane (44.3 g). The mixture was stirred at room temperature overnight. To a reaction mixture, water was added. The mixture was extracted by ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (2.08 g) having the following physical data.
[1838] TLC: Rf 0.24 (ethyl acetate:hexane=1:4);
[1839] NMR (CDCl3). &dgr; 8.25 (d, J=7.4 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
EXAMPLE 32 (1) 4-Benzyloxycarbonyl-1,1-dioxidebenzo[b]thiophene[1840] 1885
[1841] By the same procedure as described in Example 32 using 4-carboxy-1,1-dioxidebenzo[b]thiophene and benzylbromide instead of bromoethane, the compound of the present invention having the following physical data was obtained.
[1842] MS (APCI, Pos.): m/z 301 (M+H)+.
EXAMPLE 33 4-(Pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene[1843] 1886
[1844] To a solution of 4-bromo-1,1-dioxidebenzo[b]thiophene (492 mg) in dimethylformamide (5.0 ml), were added diethyl(3-pyridyl)boran (440 mg) and trispotassium phosphate (637 mg) and tetrakis(triphenylphosphine)palladium (0) (116 mg). The mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=50:1) to give the compound of the present invention (490 mg) having the following physical data.
[1845] TLC: Rf 0.59 (chloroform:methanol=9:1);
[1846] MS (APCI, Pos.): m/z 276 (M+MeOH+H)+, 244 (M+H)+.
EXAMPLE 33 (1) 6-(Pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene[1847] 1887
[1848] By the same procedure as described in Example 33, using 6-bromo-1,1-dioxidebenzo[b]thiophene instead of 4-bromo-1,1-dioxidebenzo[b]thiophene, and diethyl(3-pyridyl)borane, the compound of the present invention having the following physical data was obtained.
[1849] MS (APCI, Pos.): m/z 276 (M+MeOH+H)+, 244 (M+H)+.
EXAMPLE 34 4-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene[1850] 1888
[1851] To the compound prepared in the following Example 72 (519 mg), was added thionyl chloride (2.1 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated to give the compound of the present invention (392 mg) having the following physical data.
[1852] TLC: Rf 0.42 (ethyl acetate:hexane=1:1);
[1853] NMR (CDCl3): &dgr; 8.43 (d, J=7.0 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 4.13 (s, 2H), 1.40 (s, 6H).
EXAMPLES 35˜35 (68)[1854] By the same procedure as described in Example 27, using the compounds prepared in Examples 28˜28 (33), 29, 30˜30 (13), 31˜31 (12), 32˜32 (1), 33˜33 (1), 34 or corresponding compounds instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and if necessary, by converting into the corresponding salt by a known method, the compounds of the present invention having the following physical data were obtained.
EXAMPLE 35 4-(Pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1855] 1889
[1856] Free Acid:
[1857] TLC: Rf 0.44 (methylene chloride:methanol=10:1);
[1858] NMR (DMSO-d6): &dgr; 9.41 (t, J=5.7 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.46 (dd. J=4.8, 1.8 Hz,1H), 8.06 (d, J=6.3 Hz,1H), 7.96 (d, J=6.9 Hz, 1H), 7.90-7.67 (m, 5H), 7.66-7.58 (m, 2H), 7.36 (dd, J=8.1, 5.1 Hz, 1H), 6.27 (d, J=6.9 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.10 (dd, J=15.6, 9.3 Hz, 1H), 3.98 (dd, J=15.6,1.5 Hz, 1H). hydrochloride:
[1859] TLC: Rf 0.45 (chloroform:methanol 9:1);
[1860] NMR (DMSO-d6): &dgr; 9.70-9.62 (br, 1H), 8.95 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.91-7.85 (m, 1H), 7.81-7.72 (m, 1H), 7.67-7.58 (m, 4H), 6.21 (d, J=9.0 Hz, 1H), 4.76 (dd, J=15.6, 6.0 Hz, 1H), 4.62 (dd, J=15.6, 5.1 Hz, 1H), 4.07 (dd, J=15.0, 9.0 Hz, 1H), 3.93 (d, J=15.0Hz, 1H).
EXAMPLE 35 (1) 4-(4-Benzylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[1861] 1890
[1862] TLC: Rf 0.46 (chloroform:methanol=19:1);
[1863] NMR (DMSO-d6): &dgr; 11.60-11.40 and 11.40-11.20 (each br, total 1H), 8.05-7.52 (m, 10H), 7.51-7.23 (m, 3H), 5.88 and 5.81 (each d, J=9.3 Hz, total 1H), 4.80-3.85 (m, 6H), 3.70-2.78 (m, 6H).
EXAMPLE 35 (2) 4-(N-(2-(Pyridin-3-yl)ethyl)-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-2,2-dioxidebenzo[b]thiophene.hydrochloride[1864] 1891
[1865] TLC: Rf 0.27 (chloroform: methanol=19:1);
[1866] NMR (DMSO-d6): &dgr; 8.96 and 8.81 (each s, total 1H), 8.75 and 8.73 (each d, J=5.4 Hz, total 1H), 8.55 and 8.32 (each d, J=7.5 Hz, total 1H), 7.95-7.62 (m, 9H), 5.81 and 5.79 (each d, J=8.4 Hz, total 1H), 4.15-3.84 and 3.73-3.62 (each m, total 4H), 3.50-3.05 (m, 2H), 3.16 and 3.13 (each s, total 3H).
EXAMPLE 35 (3) 4-(2-(2-Hydroxyethoxy)ethyl)carbamoyl-3-phenylSulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1867] 1892
[1868] TLC: Rf 0.55 (methylene chloride:methanol=9:1);
[1869] NMR (DMSO-d6): &dgr; 8.84 (t, J=5.4 Hz, 1H), 7.98-7.90 (m, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.81-7.73 (m, 3H), 7.69-7.60 (m, 2H), 6.36 (d, J=8.9 Hz, 1H), 4.58 t, J=5.1 Hz, 1H), 4.09 (dd, J=15.3, 8.9 Hz, 1H), 3.9 6 (d, J=15.3 Hz, 1H), 3.67-3.53 (m, 2H), 3.53-3.35 (m, 6H).
EXAMPLE 35 (4) 4-(2,4-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1870] 1893
[1871] TLC: Rf 0.48 (methylene chloride:methanol=95:5);
[1872] NMR (DMSO-d6): &dgr; 5 9.04 (t, J=5 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.90-7.70 (m, 5H), 7.62 (t, J=7.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.47 (dd , J=8.4, 2.4 Hz, 1H), 6.27 (d, J=8.5 Hz, 1H), 4.47 (dd, J=15, 5 Hz, 1H), 4.29 (dd, J=15, 5Hz, 1H), 4.08 (dd, J=15, 8.5 Hz, 1H), 3.97 (d, J=15 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H).
EXAMPLE 35 (5) 4-(1-Benzylpiperidin-4-yl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1873] 1894
[1874] Free Compound:
[1875] TLC: Rf 0.30 (methylene chloride:methanol=9:1);
[1876] NMR (CDCl3+CD3OD). &dgr; 8.00-7.50 (m, 8H), 7.45-7.20 (m, 1H), 6.25 (dd, J=7.5, 2.5 Hz, 1H), 4.10-3.90 (m, 1H), 3.8 0 (dd, J=15, 2.5 Hz, H), 3.70-3.60 (m, H), 3.55 (s, 2H), 3.10-2.90 (m H, ), 2.30-1.95 (m, 4H), 1.90-1.70 (m, 2H).
[1877] Hydrochloride:
[1878] TLC: Rf 0.40 (methanol:ethyl acetate=1:10);
[1879] NMR (CD3OD): &dgr; 8.04-7.43 (m, 13H), 6.15 (dd, J=8.2 Hz, 2.6 Hz, 1H), 4.35 (s, 2H), 4.34-4.06 (m,1H), 3.94 (dd, J=15.2 Hz, 8.2 Hz,1H), 3.83 (dd, J=15.2 Hz, 2.6 Hz,1H), 3.74-3.08 (m, 4H), 2.56-1.56 (m, 4H).
[1880] Methanesulfonic Acid Salt:
[1881] TLC: Rf 0.40 (methanol:ethyl acetate=1:10);
[1882] NMR (CD3OD): &dgr; 8.06-7.44 (m, 13H), 6.14 (dd, J=8.2 Hz, 2.6 Hz, 1H), 4.34 (s, 2H), 4.32-4.12 (m,1H), 4.01-3.77 (m, 2H), 3.68-3.08 (m, 4H), 2.69 (s, 3H), 2.54-1.74 (m, 4H).
EXAMPLE 35 (6) 4-(Pyridin-4-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1883] 1895
[1884] TLC: Rf 0.35 (chloroform:methanol=9:1);
[1885] NMR (DMSO-d6). &dgr; 9.45 (t. J=7 Hz, 1H), 8.50 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.90 (t, J=8 Hz,1H), 7.80-7.55 (m, 5H), 7.45 (d, J=8 Hz, 2H), 6.30 (dd, J=1 Hz and 7 Hz, 1H), 4.55 (m, 2H), 4.10 (dd, J=7 Hz and 15 Hz, 1H), 4.00 (dd, J=1 Hz and 15 Hz, 1H).
EXAMPLE 35 (7) 4-(2-t-Butoxycarbonylethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1886] 1896
[1887] TLC: Rf 0.37 (ethyl acetate:hexane=3:2);
[1888] NMR (DMSO-d6): &dgr; 8.90 (t, J=7 Hz, 1H), 8.00-7.55 (m, 8H), 6.25 (dd, J=1 Hz and 7Hz, 1H), 4.10 (dd, J=7Hz and 15Hz, 1H), 3.95 (dd, J=1 Hz and 15 Hz, 1H), 3.45 (m, 2H), 2.60 (t, J=7 Hz, 2H).
EXAMPLE 35 (8) 4-(Thiophen-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1889] 1897
[1890] TLC: Rf 0.67 (chloroform:methanol=4:1);
[1891] NMR (DMSO-d6): &dgr; 9.40 (t, J=7 Hz, 1H), 8.00-7.60 (m, 8H), 7.40 (d, J=6 Hz, 1H), 7.10 (d, J=4 Hz, 1H), 7.00 (dd, J=4 Hz and6 Hz, 1H), 6.30 (dd, J=1 Hz and7 Hz, 1H), 4.75 (dd, J=7 Hz and 16 Hz, 1H), 4.55 (dd, J=7 Hz and 16 Hz, 1H),4.10 (dd, J=7 Hz and 12 Hz, 1H), 4.00 (dd, J=1 Hz and 12 Hz, 1H).
EXAMPLE 35 (9) 4-Benzylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1892] 1898
[1893] TLC: Rf 0.58 (methylene chloride:methanol=10:1);
[1894] NMR (CDCl3+DMSO-d6): &dgr; 8.74 (t, J=5.7 Hz,1H), 8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.93-7.80 (m, 3H), 7.78-7.68 (m, 2H), 7.59 (t, J=7.8 Hz, 2H), 7.50 (d, J=6.9 Hz, 2H), 7.39-7.20 (m, 3H), 6.36 (d, J=7.8 Hz, 1H), 4.71 (dd, J=14.9, 5.7 Hz, 1H), 4.62 (dd, J 14.9, 5.7 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.69 (dd, J=15.0, 7.8 Hz, 1H).
EXAMPLE 35 (10) 4-(Pyridin-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1895] 1899
[1896] TLC: Rf 0.56 (methylene chloride:methanol=10:1);
[1897] NMR (DMSO-d6): &dgr; 9.42 (t, J=6.3 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.95-7.82 (m, 1H), 7.80-7.70 (m, 4H). 7.62 (t, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 1H), 7.30-7.24 (m, 1H), 6.30 (d, J=8.7 Hz, 1H), 4.65 (dd, J=16.0,4.8 Hz, 1H), 4.54 (dd, J=16.0, 4.8 Hz, 1H), 4.10 (dd, J=15.6,4.8 Hz, 1H), 4.00 (d, J=15.6, 9.3 Hz, 1H).
EXAMPLE 35 (11) 4-(2-(Piperidin-1-yl) ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1898] 1900
[1899] Free Compound:
[1900] TLC: Rf 0.10 (methylene chloride:methanol=10:1);
[1901] NMR (CDCl3): &dgr; 7.90-7.78 (m, 4H), 7.75-7.64 (m, 2H), 7.62-7.51 (m, 2H), 7.42 (bs, 1H), 6.29 (d, J=8.1 Hz, 1H), 3.84 (dd, J=15.0, 1.5 Hz, 1H), 3.75-3.60 (m, 2H), 3.58-3.45 (m, 1H), 2.77-2.60 (m , 2H), 2.55-2.40 (m, 4H), 1.80-1.40 (m, 6H).
[1902] Hydrochloride:
[1903] TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[1904] NMR (DMSO-d6): &dgr; 10.25 (br. s, 1H), 9.32 (t, J=5.4 Hz, 1H),8.10 (dd, J=7, 1.4 Hz, 1H), 8.00-7.80 (m, 2H),7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H),6.30 (d, J=8 Hz, 1H), 4.14 (dd, J=15, 8 Hz, 1H ), 3.97 (d, J=15 Hz, 1H), 3.90-3.70 (m, 2H),3.70-3.50 (m, 2H), 3.50-3.10 (m, 3H), 3.10-2.80(m, 2H), 2.00-1.60 (m, 4H), 1.60-1.20 (m, 1H).
[1905] Methanesulfonic Acid Salt:
[1906] TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[1907] NMR (DMSO-d6): &dgr; 9.13 (t, J=5 Hz, 1H), 9.00 (br. s, 1H), 8.05 (dd, J=7, 1.4 Hz, 1H), 8.00-7.80 (m, 2H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 6.28 (d, J=8.2 Hz, 1H), 4.12 (dd, J=16, 8.2 Hz, 1H), 3.94 (d, J=16 Hz, 1H), 3.90-3.50 (m, 5H), 3.50-3.20 (m, 2H), 3.15-2.90 (m, 2H), 2.00-1.60 (m, 4H), 1.60-1.30 (m, 1H).
EXAMPLE 35 (12a) 4-((1S)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1908] 1901
[1909] TLC: Rf 0.34 (hexane:ethyl acetate=1:1);
[1910] NMR (CDCl3): &dgr; 7.99 (dd, J=7.5, 0.9 Hz, 1H), 7.87-7.84 (m, 3H), 7.75 (t, J=7.5 Hz, 1H), 7.72-7.67 (m, 1H), 7.60-7.55 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 6.25 (d, J=8.7 Hz, 1H), 4.67 (dd, J=8.8, 3.9 Hz, 1H), 3.80 (d-like, J=15.0 Hz, 1H), 3.65 (dd, J=15.0, 8.7 Hz, 1H), 2.47-2.41 (m, 1H), 1.54 (s, 9H), 1.12 (d, J=7.0 Hz, 3H), 1.06 (d, J=7.0 Hz, 3H).
[1911] (The determination of the absolute configuration of the carbon atom to which phenylsulfonyl is bonded is not performed, but this compound is a single isolated one.)
EXAMPLE 35 (12b) 4-((1S)-1-t-Butoxycarbonyl-2-methypropyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1912] 1902
[1913] TLC: Rf 0.34 (hexane:ethyl acetate=1:1);
[1914] NMR (CDCl3): &dgr; 7.98 (d, J=7.8 Hz, 0.5H), 7.91-7.80 (m, 3.5H), 7.76-7.67 (m, 2H), 7.60-7.55 (m, 2H), 6.92 (d, J=8.1 Hz, 0.5H), 6.84 (d, J=8.7 Hz, 0.5H), 6.25 (dd, J=9.3, 1.5 Hz, 0.5H), 6.18 (dd, J=9.3, 1.5 Hz, 0.5H), 4.66 (dd, J=8.7, 3.9 Hz, 0.5H), 4.62 (dd, J=8.1, 5.3 Hz, 0.5H), 3.87 (dd, J=15.0, 1.5 Hz, 0.5H), 3.80 (dd, J=15.0, 1.5 Hz, 0.5H), 3.67 (dd, J=15.0, 9.3 Hz, O.SH), 2.41-2.36 (m, 0.5H), 2.33-2.24 (m, 0.5H), 1.54 (s, 4.5H), 1.46 (s, 4.5H), 1.11 (d, J=6.9 Hz, 1.5H), 1.07 (d, J=6.9 Hz, 1.5H), 1.06 (d, J=6.9 Hz, 1.5H), 1.05 (d, J=6.9 Hz, 1.5H).
EXAMPLE 35 (13) 4-(2-Fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1915] 1903
[1916] TLC: Rf 0.60 (chloroform:methanol=9:1);
[1917] NMR (DMSO-d6): &dgr; 9.35 (t, J=7Hz, 1H), 8.05 (d, J=8Hz, 1H), 7.95 (d, J=8Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.80-7.50 (m, 6H), 7.40-7.10 (m, 3H), 6.25 (d, J=10 Hz, 1H), 4.60 (dd, J=16 Hz and 7Hz, 1H),4.45 (dd, J=16 Hz and 7Hz, 1H),4.10 (dd, J=16Hz and 10 Hz, 1H), 4.00 (d, J=16 Hz, 1H).
EXAMPLE 35 (14) 4-(3-Fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1918] 1904
[1919] TLC: Rf 0.60 (chloroform:methanol=9:1);
[1920] NMR (DMSO-d6): &dgr; 9.40 (t, J=7 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.45-7.20 (m, 3H), 7.05 (m, 1H), 6.25 (d, J=10 Hz, 1H), 4.55 (d, J=7 Hz, 2H), 4.10 (dd, J=16 Hz and 10 Hz, 1H), 3.97 (dd, J=16 Hz, 1H).
EXAMPLE 35 (15) 4-(3-Methylphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1921] 1905
[1922] TLC: Rf 0.69 (chloroform:methanol=9:1);
[1923] NMR (DMSO-d6): &dgr; 9.31 (t, J=6.0 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.30-7.15 (m, 3H), 7.15-7.00 (m, 1H), 6.31 (dd, J=8.6 Hz and 2.0 Hz, 1H), 4.48 (m, 2H), 4.10 (dd, J=15 Hz and 8.6 Hz, 1H), 3.98 (dd, J=15 Hz and 2.0 Hz, 1H), 2.27 (s, 3H).
EXAMPLE 35 (16) 4-(2-Methoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1924] 1906
[1925] TLC: Rf 0.70 (chloroform:methanol=9:1);
[1926] NMR (DMSO-d6): &dgr; 9.15 (t-like, J=6 Hz, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.95 (d, J 7.5 Hz,1H), 7.85 (t, J=7.5 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.50-7-35 (m, 1H), 7.35-7.20 (m, 1H), 7.10-6.80 (m, 2H), 6.28 (d, J=8 Hz, 1H), 4.57 (dd, J=16 Hz and 6 Hz, 1H), 4.35 (dd, J=16 Hz and 6 Hz, 1H), 4.10 (dd, J=15.5 Hz and 8 Hz, 1H), 4.00 (d, J=15.5 Hz, 1H), 3.85 (s, 3H).
EXAMPLE 35 (17) 4-(2,3-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1927] 1907
[1928] TLC: Rf 0.52 (chloroform:methanol=9:1);
[1929] NMR (DMSO-d6): &dgr; 9.22 (t, J=5.5 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.85 (t, J=7.0 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.15-6.90 (m, 3H), 6.29 (dd, J=8.5 Hz and 2.0 Hz, 1H), 4.62 (dd, J=15.0 Hz and 5.5 Hz, 1H), 4.38 (dd, J=15.0 Hz and 5.5 Hz, 1H), 4.11 (dd, J=15.5 Hz and 8.5 Hz, 1H), 3.99 (dd, J=15.5 Hz and 2.0 Hz, 1H), 3.82 (s, 6H).
EXAMPLE 35 (18) 4-(3,4-Dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1930] 1908
[1931] TLC: Rf 0.48 (chloroform:methanol=9:1);
[1932] NMR (DMSO-d6): &dgr; 9.27 (t, J=6.0 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.44 (s, 1H), 7.00-6.85 (m, 2H), 6.31 (dd, J=8.6 Hz and 1.4 Hz, 1H), 4.45 (m, 2H), 4.11 (dd, J=15.0 Hz and 8.6 Hz, 1H), 3.99 (dd, J=15.0 Hz and 1.4 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H).
EXAMPLE 35(19) 4-(2,5-Difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1933] 1909
[1934] TLC: Rf 0.59 (chloroform:methanol=9:1);
[1935] NMR (DMSO-d6): &dgr; 9.41 (t, J=5.8Hz, 1H), 8.09 (dd, J=7.6Hz and 1.5 Hz, 1H), 7.98 (dd, J=7.6 Hz and 1.5 Hz, 1H), 7.87 (t, J=7.6 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.57 (m, 2H), 7.50-7.35 (m, 1H), 7.35-7.07 (m, 2H), 6.26 (dd, J=15 Hz and 8.4 Hz,1H), 4.54 (d, J=5.8 Hz, 2H), 4.10 (dd, J=15 Hz and 8.4 Hz, 1H), 3.97 (dd, J=15 Hz and 2.0 Hz,1H).
EXAMPLE 35 (20) 4-(3,4,5-Trimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1—dioxidebenzo[b]thiophene[1936] 1910
[1937] TLC: Rf 0.58 (chloroform:methanol=9:1);
[1938] NMR (DMSO-d6): &dgr; 9.31 (m, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H),7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 6.79 (s, 2H), 6.32 (d, J=8.4 Hz, 1H), 4.61 (dd, J=15.2 Hz and 6.6 Hz, 1H), 4.37 (dd, J=15.2 Hz and 4.6 Hz, 1H), 4.12 (dd, J=15 Hz and 8.4 Hz, 1H), 3.99(d, J=15 Hz, 1H), 3.73 (s, 6H), 3.61 (s, 3H).
EXAMPLE 35 (21) 4-(Benzimidazol-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1939] 1911
[1940] TLC: Rf 0.27 (chloroform:methanol=9:1);
[1941] NMR (DMSO-d6): &dgr; 12.23 (broad-s, 1H), 9.48 (m, 1H), 8.17 (d, J=7 Hz, 1H), 8.00-7.80 (m, 2H), 7.80-7.70 (m, 3H), 7.70-7.45 (m, 4H), 7.20-7.10 (m, 2H), 6.29 (d, J=8 Hz, 1H), 4.89 (dd, J=16 Hz and 6 Hz, 1H), 4.51 (dd, J=16 Hz and 5 Hz, 1H), 4.13 (dd, J=15 Hz and 8 Hz, 1H), 3.99 (d, J=15 Hz, 1H).
EXAMPLE 35 (22) 4-(3,5-Difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1942] 1912
[1943] TLC: Rf 0.63 (chloroform:methanol=9:1);
[1944] NMR (DMSO-d6): &dgr; 9.44 (t, J=5.6 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H), 7.98 (d, J=7.4 Hz,1H), 7.88 (t, J=7.4 Hz,1H), 7.80-7.70 (m, 3H), 7.70-7.55 (m, 2H), 7.30-7.00 (m, 3H), 6.29 (dd, J=8.5 Hz and 2 Hz, 1H), 4.55 (m, 2H), 4.11 (dd, J=15 Hz and 8.5 Hz, 1H), 3.98 (dd, J=15 Hz and 2 Hz,1H).
EXAMPLE 35 (23) 4-(N-Benzyl-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1945] 1913
[1946] NMR (CDCl3): &dgr; 8.00-7.25 (m, 13H), 6.00-5.90 (m, 1H), 5.19 (d, J=15 Hz) and 5.03 (d, J=18 Hz, total 1H), 4.49 (d, J=15 Hz) and 4.40 (d, J=18 Hz, total 1H), 3.75 (dd, J=2 Hz and 15 Hz, 1H), 3.63 (dd, J=8.5 Hz and 15 Hz, 1H), 3.18 and 3.12 (each s, total 3H).
EXAMPLE 35 (24) 4-(4-Nitrophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1947] 1914
[1948] TLC: Rf 0.50 (chloroform:methanol=9:1);
[1949] NMR (DMSO-d6): &dgr; 9.52 (m, 1H), 8.30-7.55 (m, 13H), 6.27 (d, J=6.4 Hz, 1H), 4.65 (m, 2H), 4.10 (dd, J=15.5 Hz and 6.4 Hz, 1H), 3.97 (d, J=15.5 Hz, 1H).
EXAMPLE 35 (25) 5-(2-Hydroxyethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1950] 1915
[1951] TLC: Rf 0.39 (ethyl acetate:methanol=95:5);
[1952] NMR (DMSO-d6): &dgr; 8.79 (t, J=5.7 Hz, 1H), 8.18 (brs,1H), 8.14 (d, J=8.1 Hz,1H), 7.91 (d, J=8.1 Hz,1H), 7.82-7.75 (m, 3H), 7.68-7.58 (m, 2H), 5.83 (dd, J=9.4 Hz, 8.0 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 4.03 (dd, J=15.0 Hz, 9.6 Hz, 1H), 3.84 (dd, J=15.0 Hz, 3.0 Hz, 1H), 3.54 (q, J=5.7 Hz, 2H), 3.36 (q, J=5.7 Hz, 2H).
EXAMPLE 35 (26) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1953] 1916
[1954] Free Compound:
[1955] TLC: Rf 0.32 (ethyl acetate:methanol=9:1);
[1956] NMR (CDCl3): &dgr; 8.59-8.56 (m, 2H), 8.04 (d, J=8.5 Hz, 1H), 7.74-7.68 (m, 3H), 7.58-7.53 (m, 1H), 7.47-7.31 (m, 5H), 5.16 (d, J=8.5 Hz, 1H), 4.68 (dd, J=15.0, 6.0 Hz, 1H), 4.59 (dd, J=15.0, 6.0 Hz, 1H), 4.11 (d, J=15.0 Hz, 1H), 3.77 (dd, J=15.0, 8.5 Hz, 1H), 3.67 (s, 3H).
[1957] Hydrochloride:
[1958] TLC: Rf 0.32 (ethyl acetate:methanol=9:1);
[1959] NMR (DMSO-d6): &dgr; 9.37 (t, J=5.5 Hz, 1H), 8.90 (s, 1H), 8.84 (d, J=5.5 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.02 (dd, J=8.0, 5.5 Hz, 1H), 7.85-7.75 (m, 4H), 7.67-7.56 (m, 3H), 5.70 (d, J=9.0 Hz, 1H), 4.72-4.60 (m, 2H), 4.15 (d, J=15.0 Hz, 1H), 4.02 (dd, J=15.0, 9.0 Hz, 1H), 3.56 (s, 3H).
EXAMPLE 35 (27) 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1960] 1917
[1961] Free Compound:
[1962] TLC: Rf 0.24 (ethyl acetate:methanol:triethylamine=8:1:1);
[1963] NMR (CDCl3): &dgr; 8.00 (d, J=8.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.67-7.61 (m, 1H), 7.51-7.41 (m, 3H), 7.32 (bt, J=5.0 Hz, 1H), 5.23 (t, J=9.0 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 3.81 (dd, J=15.0, 9.0 Hz, 1H), 3.77 (s, 3H), 3.64-3.42 (m, 2H), 2.51 (t, J=6.0 Hz, 1H), 2.28 (s, 6H).
[1964] Hydrochloride:
[1965] TLC: Rf 0.24 (ethyl acetate:methanol:triethylamine=8:1:1);
[1966] NMR (DMSO-d6): &dgr; 10.47 (br, 1H), 8.90 (t, J=5.5 Hz, 1H), 7.86-7.76 (m, 4H), 7.69-7.64 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 5.69 (d, J=8.5 Hz, 1H), 4.13 (d, J=15.0 Hz, 1H), 4.00 (d, J=15.0, 8.5 Hz, 1H), 3.65-3.60 (m, 2H), 3.63 (s, 3H), 3.25 (t, J=6.0 Hz, 2H), 2.82 (s, 6H).
EXAMPLE 35 (28) 5-Dimethylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1967] 1918
[1968] TLC: Rf 0.35 (ethyl acetate);
[1969] NMR (DMSO-d6): &dgr; 7.83 (d, J=8.0 Hz, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.63 (dd, J=8.0 Hz, 7.5 Hz, 2H), 7.49 (d, J=8.0 Hz,1H), 7.46 (d, J=7.5 Hz,1H), 5.63 (d, J=8.5 Hz, 1H), 4.13 (d, J=14.5 Hz, 1H), 4.02 (dd, J=14.5 Hz, 8.5 Hz, 1H), 3.59 (s, 3H), 3.01 (s, 3H), 2.78 (s, 3H).
EXAMPLE 35 (29) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1970] 1919
[1971] TLC: Rf 0.21 (ethyl acetate:hexane=2:1);
[1972] NMR (DMSO-d6): &dgr; 7.87-7.70 (m, 3H), 7.70-7.60 (m, 2H), 7.60-7.53 (m, 2H),5.67 (d, J=8.7 Hz, 1H), 4.26 (d, J=15.0 Hz, 1H), 4.05 (dd, J=15.0, 8.7 Hz, 1H), 3.70-3.54 (m, 2H), 3.48 (s, 3H), 3.20-3.15 (m, 2H),1.85-1.40 (m, 8H).
EXAMPLE 35 (30) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1973] 1920
[1974] TLC: Rf 0.54 (ethyl acetate:hexane=2:1);
[1975] NMR (DMSO-d6): &dgr; 8.13 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.83-7.70 (m, 2H), 7.70-7.56 (m, 2H), 7.66 (t, J=7.8 Hz, 2H), 7.31 (d, J=7.5 Hz,1H), 7.25 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 5.72 (d, J=8.7 Hz, 1H), 4.39-3.97 (m, 2H), 3.76 (dd, J=18.6, 8.7 Hz, 1H), 3.70-3.50 (m, 1H), 3.57 (s, 3H), 3.21-3.08 (m, 2H).
EXAMPLE 35 (31) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1976] 1921
[1977] TLC: Rf 0.78 (methylene chloride:methanol=10:1);
[1978] NMR (CDCl3+DMSO-d6): &dgr; 7.94-7.86 (m, 1H), 7.77-7.66 (m, 2H), 7.64-7.50 (m, 4H), 7.44-7.16 (m, 2H), 7.10699 (m, 2H),5.38-5.27 (m, 1H), 4.26-4.00 (m, 2H), 3.95 and 3.78 (each s, total 3H), 3.90-3.65 (m, 2H),3.50-2.80 (m, 6H).
EXAMPLE 35 (32) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1979] 1922
[1980] TLC: Rf 0.51 (methylene chloride:methanol=10:1);
[1981] NMR (CDCl3): &dgr; 7.93-7.86 (m, 1H), 7.74-7.43 (m, 7H), 7.40-7.30 (m, 3H), 5.31-5.20 (m, 1H), 4.24-3.64 (m, 7H), 3.34-3.10 (m, 2H), 3.06-2.90 (m, 2H), 2.70-2.30 (m, 6H).
EXAMPLE 35 (33) 4-(Pyridin-3-ylcarbonyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1982] 1923
[1983] Free Compound:
[1984] TLC: Rf 0.38 (ethyl acetate:methanol=9:1);
[1985] NMR (DMSO-d6): &dgr; 9.31 (t, J=6.0 Hz, 1H), 9.05 (d, J=1.5 Hz, 1H), 8.72 (dd, J 5.0, 1.5 Hz, 1H), 8.23 (dt, J=8.0, 1.5 Hz. 1H); 7.87-7.63 (m, 8H), 7.52 (dd, J=8.0, 5.0 Hz, 1H), 6.05 (d, J=8.5 Hz, 1H), 5.01 (dd, J=16.0, 6.0 Hz, 1H), 4.78 (dd, J=16.0, 6.0 Hz, 1H), 4.02 (dd, J=15.3, 8.5 Hz, 1H), 3.86 (d, J=15.3 Hz, 1H).
[1986] Hydrochloride:
[1987] TLC: Rf 0.38 (ethyl acetate:methanol=9:1);
[1988] NMR (DMSO-d6): &dgr; 9.63-9.59 (m, 1H), 9.20 (s, 1H), 8.86 (d, J=5.0 Hz, 1H), 8.57-8.54 (m, 1H), 7.87-7.63 (m, 9H), 6.11 (d, J=8.5 Hz, 1H), 5.02 (dd, J=15.8, 5.7 Hz, 1H), -4.80 (dd, J=15.8, 5.7 Hz, 1H), 4.00 (dd, J=15.5, 8.5 Hz, 1H), 3.86 (d, J=15.5 Hz, 1H).
EXAMPLE 35 (34) 4-(3-Pyrrol-1-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1989] 1924
[1990] TLC: Rf 0.20 (ethyl acetate:hexane=1:1);
[1991] NMR (CDCl3): &dgr; 7.75-7.35 (m, 6H), 7.24 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.68 (t, J=2 Hz, 2H), 6.15 (t, J=2 Hz, 2H), 5.21 (d, J=9 Hz, 1H), 4.53-4.00 (m, 2H), 4.10 (d, J=15 Hz, 1H), 4.00-3.65 (m, 2H), 3.73 (dd, J=9, 15 Hz, 1H), 2.19 (quint, J=5 Hz, 2H).
EXAMPLE 35 (35) 4-(Quinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1992] 1925
[1993] Free Compound:
[1994] TLC: Rf 0.21 (benzene:ethyl acetate=2:1);
[1995] NMR (CDCl3): &dgr; 8.42 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 2H), 7.90-7.20 (m, 11H), 5.80 (d, J=8 Hz, 1H), 5.31 (d, J=13 Hz, 1H), 5.09 (d, J=13 Hz, 1H), 4.24 (d, J=15 Hz, 1H), 4.02 (dd, J=8, 15 Hz, 1H). hydrochloride:
[1996] TLC: Rf 0.30 (hexane:ethyl acetate=1:2);
[1997] NMR (DMSO-d6): &dgr; 8.64 (d, J=8.5 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.92 (t-like, J=8.5 Hz, 1H), 7.81-7.65 (m, 5H), 7.48-7.31 (m, 5H), 5.91 (d, J=9.0 Hz, 1H), 5.42 (d, J=13.5 Hz, 1H), 5.21 (d, J=13.5 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 4.02 (dd, J=9.0 Hz, 1H).
EXAMPLE 35 (36) 4-(2-(Pyrrol-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[1998] 1926
[1999] TLC: Rf 0.36 (hexane:ethyl acetate=1:2);
[2000] NMR (CDCl3+CD3OD): &dgr; 7.85-7.58 (m, 3H), 7.58-7.42 (m, 3H), 7.28 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.74 (t, J=2 Hz, 2H), 6.18 (t, J=2 Hz, 2H), 5.16 (d, J=9 Hz, 1H), 4.30-4.05 (m, 5H), 3.73 (dd, J=9,15 Hz, 1H).
EXAMPLE 35 (37) 4-(2-(4-Methylthiazol-5-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2001] 1927
[2002] TLC: Rf 0.25 (ethyl acetate);
[2003] NMR (CD3OD): &dgr; 9.88 (s, 1H), 7.80-7.40 (m, 6H), 7.26 (d, J=8 Hz, 1H), 7.25 (d, J=8Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.42-4.18 (m, 2H), 4.08 (d, J=15 Hz, 1H), 3.92 (dd, J=9,15 Hz, 1H), 3. 55-3.15 (m, 2H), 2.60 (s, 3H).
EXAMPLE 35 (38) 4-(3-(Pyridin-4-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2004] 1928
Free Compound:[2005] TLC: Rf 0.26 (ethyl acetate:methanol=10:1);
[2006] NMR (CDCl3): &dgr; 8.53 (dd, J=1, 5 Hz, 2H), 7.78-7.35 (m. 6H), 7.25 (d, J=7 Hz, 1H), 7.17 (d, J=6 Hz, 2H), 6.95 (d, J=8 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.14 (d, J=15 Hz, IH), 4.05-3.82 (m , 2H), 3.74 (dd, J=9, 15 Hz, 1H), 2.87 (t, J=6 Hz, 2H), 2.10 (quint, J=6 Hz, 2H).
[2007] Hydrochloride:
[2008] TLC: Rf 0.39 (ethyl acetate:methanol:ammonia water=100:10:1);
[2009] NMR (DMSO-d6): &dgr; 8.83 (d, J=6 Hz, 2H), 7.90 (d, J=5 Hz, 2H), 7.85-7.52 (m, 6H), 7.34 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 5.64 (d, J=9 Hz, 1H), 4.18 (d, J=15 Hz, 1H), 4.00 (dd, J=9,15 Hz, 1H), 3.10-2.80 (m, 2H), 2.10-1.60 (m, 2H).
EXAMPLE 35 (39) 4-(1-t-Butoxycarbonylpiperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2010] 1929
[2011] TLC: Rf 0.23 (hexane:ethyl acetate=1:1);
[2012] NMR (CD3OD): &dgr; 7.95-7.45 (m, 6H), 7.40-7.05 (m, 2H), 5.53 (d, J=9 Hz, 1H), 4.15 (d, J=15 Hz, 1H), 3.92 (dd, J=9,15 Hz, 1H), 4.05-3.55 (m, 4H), 3.20-2.40 (m, 2H), 2.00-1.20 (m, 5H), 1.47 and 1.44 (each s, 9H).
EXAMPLE 35 (40) 4-(2-(Pyrrolidin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2013] 1930
Free Compound:[2014] TLC: Rf 0.17 (chloroform:methanol=10:1);
[2015] NMR (CDCl3): &dgr; 7.85-7.68 (m, 2H), 7.68-7.35 (m, 4H), 7.28 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.23 (d, J=15 Hz, 1H), 4.15-3.95 (m, 1H), 3.95-3.70 (m, 1H), 3.74 (dd, J=9, 15 Hz,1H), 2.78 (t, J=6 Hz, 2H), 2.70-2.45 (m, 4H), 1.95-1.60 (m, 4H).
[2016] Hydrochloride:
[2017] TLC: Rf 0.36 (ethyl acetate:acetic acid:water=3:1:1);
[2018] NMR (CDCl3+CD3OD): &dgr; 7.98-7.82 (m,2H), 7.80-7.45 (m, 4H), 7.34 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 6.20-6.05 (m, 1H), 4.75-4.50 (m, 1H), 4.50-4.25 (m, 1H), 4.10-3.85 (m, 2H), 3.85-3.45 (m, 4H), 3.30-2.90 (m, 2H), 2.40-2.00 (m, 4H).
EXAMPLE 35 (41) 4-(2-(Piperidin-1-yl) ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2019] 1931
[2020] Free Compound:
[2021] TLC: Rf 0.24 (chloroform:methanol=10:1);
[2022] NMR (CDCl3): &dgr; 7.85-7.67 (m, 2H), 7.67-7.36 (m, 4H), 7.27 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 5.29 (d, J=9 Hz, 1H), 4.25 (d, J=15 Hz, 1H), 4.18-3.92 (m, 1H), 3.92-3.65 (m, 1H), 3.74 (dd, J=9, 15 Hz, 1H), 2.62 (t, J=6 Hz, 2H), 2.46 (t, J=6 Hz, 4H), 1.90-1.35 (m, 6H).
[2023] Hydrochloride:
[2024] TLC: Rf 0.40 (ethyl acetate:acetic acid:water=3:1:1);
[2025] NMR (CDCl3+CD3OD): &dgr; 7.95-7.75 (m, 2H), 7.75-7.45 (m, 4H), 7.32 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 6.05-5.85 (m, 1H), 4.75-4.38 (m,2H), 3.95-3.42 (m, 6H), 3.15-2.85 (m, 2H), 2.35-1.35 (m, 6H).
EXAMPLE 35 (42) 4-(2-(2-Acetyloxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2026] 1932
[2027] TLC: Rf 0.17 (ethyl acetate:hexane=2:1);
[2028] NMR (CDCl3): &dgr; 7.82-7.70 (m, 2H), 7.65-7.35 (m, 4H), 7.27 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.32-4.05 (m, 4H), 4.05-3.88 (m, 1H), 3.84-3.75 (m, 5H), 2.05 (s, 3H).
EXAMPLE 35 (43) 4-(2-(4-Benzylpiperazin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2029] 1933
[2030] Free Compound:
[2031] TLC: Rf 0.42 (chloroform:methanol=5:1);
[2032] NMR (CDCl3): &dgr; 7.80-7.68 (m, 2H), 7.68-7.37 (m, 4H), 7.37-7.18 (m, 6H), 6.96 (d, J=8 Hz, 1H), 5.27 (d, J=9 Hz, 1H), 4.22 (d, J=15 Hz, 1H), 4.15-3.94 (m, 1H), 3.94-3.70 (m, 1H), 3.72 (dd , J=9, 15 Hz, 1H), 3.52 (s, 2H), 2.68 (t, J=6 Hz, 2H), 2.63-2.35 (m, 8H).
[2033] 2hydrochloride:
[2034] TLC: Rf 0.28 (ethyl acetate:acetic acid:water=3:1:1);
[2035] NMR (CD3OD): &dgr; 7.907-7.22 (m, 13H), 6.13-6.00 (m, 1H), 4.68-4.35 (m, 2H), 4.46 (S, 2H), 4.10-3.40 (m, 12H).
EXAMPLE 35 (44) 4-Diethylcarbamoylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2036] 1934
[2037] TLC: Rf 0.40 (ethyl acetate);
[2038] NMR (CDCl3): &dgr; 7.83-7.77 (m, 2H), 7.68-7.59 (m, 1H), 7.56-7.45 (m, 3H), 7.32 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 5.44 (d, J=8.8Hz, 1H), 4.59 (d, J=14.5 Hz, 1H), 4.51 (d, J=14.5 Hz, 1H), 4.15 (d, J=15.0 Hz, 1H), 3.74 (dd, J=15.0, 8.8 Hz, 1H), 3.39 (q, J=7.0 Hz, 2H), 3.30 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H).
EXAMPLE 35 (45) 4-Cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2039] 1935
[2040] TLC: Rf 0.27 (hexane:ethyl acetate=1:2);
[2041] NMR (DMSO-d6): &dgr; 7.82-7.72 (m, 4H), 7.68-7.60 (m, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 5.60 (dd, J=9.0, 1.2 Hz, 1H), 5.04 (d, J=16.0 Hz, 1H), 4.90 (d, J=16.0 Hz, 1H), 4.20 (dd, J=15.2, 1.2 Hz, 1H), 4.00 (dd, J=15.2, 9.0 Hz, 1H).
EXAMPLE 35 (46) 5-(Pyridin-3-yloxy) methyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2042] 1936
[2043] Free Compound:
[2044] TLC: Rf 0.27 (ethyl acetate);
[2045] NMR (CDCl3): &dgr; 8.37-8.36 (m, 1H), 8.31-8.29 (m, 1H), 7.76-7.71 (m, 3H), 7.66-7.61 (m, 1H), 7.49-7.43 (m, 3H), 7.27-7.25 (m, 2H), 5.25 (dd, J=9.5,1.0 Hz, 1H), 5.16 (d, J=12.5 Hz, 1H), 5.12 (d, J=12.5 Hz, 1H), 4.15 (dd, J=15.0,1.0 Hz, 1H), 3.90 (s, 3H), 3.81 (dd, J=15.0, 9.5 Hz, 1H)
[2046] Hydrochloride:
[2047] TLC: Rf 0.27 (ethyl acetate);
[2048] NMR (DMSO-d6): &dgr; 8.76 (d, J=2.5 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.15 (dd, J=8.5, 2.5 Hz, 1H), 7.93-7.74 (m, 5H), 7.65-7.60 (m, 3H), 5.78 (d, J=8.5 Hz, 1H), 5.35 (s, 2H), 4.17 (d, J=15.0 Hz, 1H), 4.06 (dd, J=15.0, 8.5 Hz, 1H), 3.69 (s, 3H).
EXAMPLE 35 (47) 5-(2-(t-Butoxycarbonyl amino)ethyl)oxy-4-nitro-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2049] 1937
[2050] TLC: Rf 0.34 (hexane:ethyl acetate=1:2);
[2051] NMR (CDCl3): &dgr; 7.86-7.70 (m, 4H), 7.63-7.54 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 5.69 (dd, J=9.0, 1.8 Hz, 1H), 5.07 (br, 1H), 4.38-4.22 (m, 2H), 3.90 (dd, J=15.0, 1.8 Hz, 1H), 3.75 (dd, J=15.0, 9.0 Hz, 1H), 3.68-3.52 (m, 2H), 1.46 (s, 9H).
EXAMPLE 35 (48) 5-((2E)-3-Ethoxycarbonyl-2-propenyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2052] 1938
[2053] TLC: Rf 0.41 (hexane:ethyl acetate=1:1);
[2054] NMR (CDCl3): &dgr; 5 7.72-7.65 (m, 3H), 7.62-7.46 (m, 4H), 7.15 (dd, J=8.7,2.1 Hz,1H), 7.08 (dt, J=15.6, 4.2 Hz, 1H), 6.20 (dt, J=15.6, 2.1 Hz, 1H), 5.01 (dd, J=8.7, 4.8 Hz, 1H), 4.87-4.81 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.77 (dd, J=14.7,4.8 Hz, 1H), 3.70 (dd, J=14.7, 8.7 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H).
EXAMPLE 35 (49) 4-(2,4-Dimethoxyphenylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2055] 1939
[2056] Free Compound:
[2057] TLC: Rf 0.35 (ethyl acetate);
[2058] NMR (CDCl3): &dgr; 7.69 (dd, J=6.9, 1.5 Hz, 1H), 7.64-7.50 (m, 5H), 7.46-7.41 (m, 2H), 7.01 (d, J=8.0 Hz, 1H), 6.45 (d, J=2.5 Hz,1H), 6.43 (dd, J=8.0,2.5 Hz,1H), 6.05 (dd, J=9.3, 1.2 Hz, 1H), 4.51 (d, J=14.1 Hz, 1H), 3.91 (d, J=14.1 Hz, 1H), 3.85 (dd, J=15.0, 1.2 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.73 (d, J=13.0 Hz, 1H), 3.66 (d, J=13.0 Hz, 1H), 3.65 (dd, J=15.0, 9.3 Hz, 1H).
[2059] Hydrochloride:
[2060] TLC: Rf 0.35 (ethyl acetate);
[2061] NMR (DMSO-d6): &dgr; 9.40 (br, 2H), 8.20-8.11 (m, 1H), 7.86-7.59 (m, 7H), 7.42 (d, J 8.4 Hz, 1H), 6.61-6.56 (m, 2H), 6.09 (dd, J=6.8, 3.0 Hz, 1H), 4.65 (d, J=13.8 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.22-4.06 (m, 2H), 3.88-3.85 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H).
EXAMPLE 35 (50) 4-(Pyridin-3-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride[2062] 1940
[2063] TLC: Rf 0.44 (chloroform:methanol=9:1);
[2064] NMR (CD3OD): &dgr; 9.21 (s, 1H), 8.95 (d, J=5.6 Hz, 1H), 8.92-8.84 (m, 1H), 8.22 (dd, J=6.6, 2.2 Hz, 1H), 8.16 (dd, J=8.0, 5.6 Hz, 1H), 7.93-7.74 (m, 5H), 7.68-7.58 (m, 2H), 6.20 (dd, J=8.6, 1.6 Hz, 1H), 4.96 (d, J=13.2 Hz, 1H), 4.83-4.70 (m, 3H), 3.92 (dd, J=15.4, 8.6 Hz, 1H), 3.77 (dd, J=15.4, 1.6 Hz, 1H).
EXAMPLE 35 (51) 4-(2-Dimethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene-2hydrochloride[2065] 1941
[2066] TLC: Rf 0.51 (chloroform:methanol:triethylamine=9:1:1);
[2067] NMR (DMSO-d6): &dgr; 10.85-10.50 (br, 1H), 10.10-9.75 (br, 1H), 9.72-9.40 (br, 1H), 8.22 (dd, J=5.4, 3.0 Hz, 1H), 7.90-7.85 (m, 2H), 7.82-7.75 (m, 3H), 7.67-7.59 (m, 2H), 6.47 (t like, J=1.5 Hz, 1H), 4.72 (brd, J=12.0 Hz, 1H), 4.51 (brd, J=12.0 Hz, 1H), 3.91-3.84 (m, 2H), 3.70-3.30 (m, 4H), 2.85 (s, 6H).
EXAMPLE 35 (52) 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dlhydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2068] 1942
[2069] TLC: Rf 0.53 (chloroform:methanol=9:1);
[2070] NMR (DMSO-d6): &dgr; 10.15-9.90 (br, 1H), 8.24 (d, J=6.6 Hz, 1H), 7.95-7.72 (m, 5H), 7.69-7.58 (m, 2H), 6.16 (d, J=8.7 Hz, 1H), 5.80-5.10 (br, 2H), 5.11 (brd, J=13.8 Hz, 1H), 4.70 (brd, J=13.8 Hz, 1H), 4.02 (dd, J=15.0, 8.7 Hz, 1H), 3.94-3.70 (m, 4H), 3.82 (d, J=15.0 Hz, 1H), 3.47-3.18 (m, 3H), 3.12-2.92 (m, 1H).
EXAMPLE 35 (53) 4-(2-(2-Hydroxyethoxy)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2071] 1943
[2072] TLC: Rf 0.46 (methylene chloride:methanol=9:1);
[2073] NMR (DMSO-d6): &dgr; 9.40-9.10 (br, 2H), 8.16 (dd, J=6.3, 2.4 Hz, 1H), 7.91-7.75 (m, 5H), 7.68-7.59 (m, 2H), 6.29 (dd, J=7.5, 2.4 Hz, 1H), 4.90-4.30 (br, 1H), 4.75-4.63 (m, 1H), 4.50-4.35 (m, 1H), 3.90 (dd, J=15 .6, 7.5 Hz, 1H), 3.84 (dd, J=15.6, 2.4 Hz, 1H), 3.74 (t, J=5.1 Hz, 2H), 3.58-3.47 (m, 4H), 3.28-3 15 (m, 2H).
EXAMPLE 35 (54) 4-(4-Benzylpiperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2074] 1944
[2075] Free Compound:
[2076] TLC: Rf 0.29 (chloroform:methanol=19:1);
[2077] NMR (CDCl3): &dgr; 7.68-7.57 (m, 4H), 7.56-7.50 (m, 2H), 7.50-7.42 (m, 2H), 7.36-7.20 (m, 5H), 6.33 (d, J=9.0 Hz, 1H), 4.69 (d, J=14.1 Hz, 1H), 3.90 (d, J=15.0 Hz, 1H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.51 (s, 2H), 3.41 (d, J=14.1 Hz,1H), 2.70-2.25 (m, 8H).
[2078] 2hydrochloride:
[2079] TLC: Rf 0.29 (chloroform:methanol=19:1); NMR (DMSO-d6): &dgr; 8.30-7.95 (br, 1H), 7.93-7.72 (m, 5H), 7.70-7.55 (m, 4H), 7.50-7.40 (m, 3H), 6.65-6.20 (br, 1H), 5.40-4.20 (br, 4H), 4.50-4.10 (br, 2H), 3.98 (dd, J=15.6, 9.0 Hz, 1H), 3.84 (d, J=15.6 Hz, 1H), 3.70-2.80 (m, 6H).
EXAMPLE 35 (55) 4-(4-(Pyridin-2-yl)piperazi n-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2080] 1945
[2081] Free Compound:
[2082] TLC: Rf 0.43 (chloroform:methanol 19:1);
[2083] NMR (CDCl3): &dgr; 8.23-8.16 (m, 1H), 7.71-7.52 (m, 6H), 7.52-7.42 (m, 3H), 6.68-6.62 (m, 2H), 6.30 (d, J=9.0 Hz, 1H), 4.76 (d, J=14.1 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 3.62-3. 45 (m, 4H), 3.49 (d, J=14.1 Hz, 1H), 2.73-2.61 (m, 2H), 2.58-2.44 (m, 2H). 3hydrochloride:
[2084] TLC: Rf 0.43 (chloroform:methanol=19:1);
[2085] NMR (DMSO-d6): &dgr; 12.05-11.70 (br, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.15-8.09 (m, 1H), 7.96-7.84 (m, 3H), 7.83-7.75 (m, 3H), 7.68-7.58 (m, 2H), 7.24 (d, J=8.7 Hz,1H), 6.93 (t, J=6.3 Hz, 1H), 6.46 (d, J=8.7 Hz,1H), 4.87 (d, J=13.8 Hz, 1H), 4.62 (d, J=13.8 Hz, 1H), 4.55-4.30 (m, 2H), 4.00 (dd, J=15.0, 8.7 Hz, 1H), 3.83 (d, J=15.0 Hz, 1H), 3.72-3.50 (m, 2H), 3.50-3.15 (m, 4H).
EXAMPLE 35 (56) 4-(4-Ethoxycarbonylpiperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2086] 1946
[2087] Free Compound:
[2088] TLC: Rf 0.45 (chloroform:methanol 19:1);
[2089] NMR (CDCl3): &dgr; 7.69-7.52 (m, 6H), 7.51-7.41 (m, 2H), 6.16 (d, J=9.0 Hz, 1H), 4.71 (d, J=14.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.91 (d, J=15.0 Hz, 1H), 3.74 (dd, J=15.0, 9.0 Hz, 1H), 3.54-3.39 (m, 5H), 2.55-2.46 (m, 2H), 2.41-2.29 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
[2090] Hydrochloride:
[2091] TLC: Rf 0.45 (chloroform:methanol=19:1);
[2092] NMR (DMSO-d6): &dgr; 11.60-11.30 (br, 1H), 8.40-8.20 (br, 1H), 8.00-7.74 (m, 5H), 7.68-7.58 (m, 2H), 6.31 (brd, J=8.1 Hz, 1H), 4.98-4.70 (m, 1H), 4.70-4.52 (m, 1H), 4.20-3.89 (m, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.82 (d, J=15.3 Hz, 1H), 3.77-3.60 (m, 1H), 3.52-2.90 (m, 6H), 1.18 (t, J=7.2 Hz, 3H).
EXAMPLE 35 (57) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2093] 1947
[2094] Free Compound:
[2095] TLC: Rf 0.31 (chloroform:methanol=9:1);
[2096] NMR (CDCl3): &dgr; 7.70-7.50 (m, 6H), 7.50-7.41 (m, 2H), 6.29 (d, J=9.0 Hz, 1H), 4.72 (d, J=14.1 Hz, 1H), 3.91 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 3.63 (t, J=5.1 Hz, 2H), 3.43 (d, J=14.1 Hz, 1H), 2.80-2.30 (m, 10H).
[2097] 2hydrochloride:
[2098] TLC. Rf 0.31 (chloroform:methanol=9:1);
[2099] NMR (DMSO-d6): &dgr; 11.50-10.60 (br, 1H), 8.30-8.00 (br, 1H), 7.88-7.73 (m, 5H), 7.67-7.58 (m, 2H), 6.60-6.30 (br, 1H), 5.80-4.92 (br, 2H), 4.92-4.10 (br, 1H), 3.99 (dd, J=15.0, 8.7 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.81-3.74 (m, 2H), 3.73-2.80 (m, 10H).
EXAMPLE 35 (58) 4-(4-(Pyridin-4-yl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2100] 1948
[2101] free compound:
[2102] TLC: Rf 0.36 (chloroform:methanol=9:1);
[2103] NMR (DMSO-d6): &dgr; 8.14 (d, J=6.6 Hz, 2H), 7.88-7.81 (m, 1H), 7.81-7.74 (m, 3H), 7.74-7.68 (m, 2H), 7.67-7.59 (m, 2H), 6.78 (d, J=6.6 Hz, 2H), 6.21 (d, J=9.0 Hz, 1H), 4.16 (d, J=14.4 Hz, 1H), 4.05 (dd, J=15.0, 9.0 Hz, 1H), 3.86 (d, J=15.0 Hz, 1H), 3.57 (d, J=14.4 Hz, 1H), 3.42-3.18 (m, 4H), 2.43 (t, J=4.8 Hz, 4H). 3hydrochloride:
[2104] TLC: Rf 0.36 (chloroform:methanol=9:1);
[2105] NMR (DMSO-d6): &dgr; 14.20-13.80 (br, 1H), 12.30-11.90 (br, 1H), 8.46-8.20 (br, 1H), 8.35 (d, J=6.9 Hz, 2H), 7.98-7.82 (m, 2H), 7.82-7.74 (m, 3H), 7.67-7.57 (m, 2H), 7.25 (d, J=6.9 Hz, 2H), 6.48 (brd, J=8.7 Hz,1H), 5.05-4.75 (m, 1H), 4.75-4.52 (m,1H), 4.52-4.15 (m, 2H), 3.98 (dd, J=15.3, 8.7 Hz, 1H), 3.95-3.55 (m, 6H), 3.84 (d, J=15.3 Hz, 1H).
EXAMPLE 35 (59) 4-Benzylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2106] 1949
[2107] Free Compound:
[2108] TLC: Rf 0.46 (ethyl acetate);
[2109] NMR (CDCl3): &dgr; 7.74 (dd, J=7.2, 1.5 Hz, 1H), 7.65-7.51 (m, 5H), 7.45-7.40 (m, 2H), 7.36-7.25 (m, 5H), 5.84 (dd, J=9.3, 1.0 Hz, 1H), 4.49 (d, J=14.1 Hz, 1H), 3.98 (d, J 14.1 Hz, 1H), 3.85 (d, J=12.7 Hz, 1H), 3.84 (dd, J=15.0, 1.0 Hz, 1H), 3.77 (d, J=12.7, 1H), 3.65 (dd, J=15.0, 9.3 Hz, 1H).
[2110] Hydrochloride:
[2111] TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5);
[2112] NMR (DMSO-d6): &dgr; 9.87 (brs, 1H), 9.57 (brs, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.90-7.75 (m, 3H), 7.75-7.57 (m, 6H), 7.50-7.41 (m, 3H), 6.33-6.25 (m, 1H), 4.67 (d, J=13.5 Hz, 1H), 4.40 (d, J=13.5 Hz, 1H), 4.30 (s, 2H), 3.93-3.80 (m, 2H).
EXAMPLE 35 (60) 4-(1-benzylpiperidin-4-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2113] 1950
[2114] Free Compound:
[2115] TLC: Rf 0.30 (ethyl acetate:methanol=2:1);
[2116] NMR (CDCl3): &dgr; 7.70 (dd, J=7.3, 1.3 Hz, 1H), 7.65-7.41 (m, 7H), 7.32-7.24 (m, 5H), 6.09 (dd, J=9.3, 1.0 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 3.98 (d, J=14.0 Hz, 1H), 3.87 (dd, J=15.0, 1.0 Hz, 1H), 3.72 (dd, J=15.0, 9.3 Hz, 1H), 3.50 (s, 2H), 2.90-2.81 (m, 2H), 2.58-2.51 (m, 1H), 2.09-1.96 (m, 3H), 1.83-1.79 (m, 1H), 1.52-1.38 (m, 2H).
[2117] 2hydrochloride:
[2118] TLC: Rf 0.30 (ethyl acetate:methanol=2:1);
[2119] NMR (CD3OD): &dgr; 8.16-8.12 (m, 1H), 7.91-7.74 (m, 5H), 7.65-7.49 (m, 7H), 6.06 (dd, J=8.4, 1.8 Hz, 1H), 4.84-4.68 (m, 2H), 4.36 (br, 2H), 3.90 (dd, J=15.4, 8.4 Hz, 1H), 3.77 (dd, J=15.4, 1.8 Hz, 1H), 3.80-3.60 (m, 3H), 3.30-3.15 (m, 2H), 2.58-2.43 (m, 2H), 2.35-2.13 (m, 2H).
EXAMPLE 35 (61) 4-(Morpholin-4-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2120] 1951
[2121] Free Compound:
[2122] TLC: Rf 0.34 (hexane:ethyl acetate=1:2);
[2123] NMR (CDCl3): &dgr; 7.68-7.51 (m, 6H), 7.48-7.42 (m, 2H), 6.21 (dd, J=9.3, 0.9 Hz, 1H), 4.68 (d, J=14.3 Hz, 1H), 3.91 (dd, J=15.0, 0.9 Hz, 1H), 3.74 (dd, J=15.0, 9.3 Hz, 1H), 3.74-3.64 (m, 4H), 3.45 (d, J=14.3 Hz, 1H), 2.58-2.52 (m, 2H), 2.40-2.33 (m, 2H).
[2124] Hydrochloride:
[2125] TLC: Rf 0.34 (hexane:ethyl acetate=1:2);
[2126] NMR (DMSO-d6): &dgr; 11.48 (br, 1H), 8.31 (d, J=7.2 Hz, 1H), 7.94-7.79 (m, 5H), 7.68-7.62 (m, 2H), 6.44 (d, J=8.1 Hz, 1H), 4.85-4.79 (m, 1H), 4.62-4.57 (m, 1H), 4.05-3.81 (m, 6H), 3.50-3.13 (m, 4H).
EXAMPLE 35 (62) 4-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2127] 1952
[2128] TLC: Rf 0.18 (methylene chloride);
[2129] NMR (CDCl3): &dgr; 8.24 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.86 (dd, J=7.8 Hz, 1.5 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.71-7.64 (m, 3H), 7.56-7.47 (m, 2H), 6.19 (dd, J=9.3 Hz, 1.5 Hz, 1H), 4.53-4.40 (m, 2H), 3.94 (dd, J=15.0 Hz, 1.5 Hz, 1H), 3.77 (dd, J=15.0 Hz, 9.3 Hz, 1H), 1.47 (t, J=7.2 Hz, 3H).
EXAMPLE 35 (63) 4-Benzyloxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2130] 1953
[2131] TLC: Rf 0.37 (chloroform:ethyl acetate=19:1);
[2132] NMR (CDCl3): &dgr; 8.26 (dd, J=7.5, 1.2 Hz, 1H), 7.85 (dd, J=7.8, 1.2 Hz, 1H), 7.78-7.70 (m, 1H), 7.69-7.60 (m, 3H), 7.55-7.47 (m, 4H), 7.47-7.35 (m, 3H), 6.13 (dd, J=9.3, 1.2 Hz, 1H), 5.45 (d, J=12.3 Hz, 1H), 5.40 (d, J=12.3 Hz, 1H), 3.91 (dd, J=15.0, 1.2 Hz, 1H), 3.73 (dd, J=15.0, 9.3 Hz, 1H).
EXAMPLE 35 (64) 4-(Pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2133] 1954
[2134] TLC: Rf 0.55 (chloroform:methanol=9:1);
[2135] NMR (DMSO-d6): &dgr; 9.11 (s, 1H), 8.86 (d, J=5.4 Hz, 1H), 8.57 (d, J=5.4 Hz, 1H), 7.99-7.84 (m, 4H), 7.73-7.64 (m, 1H), 7.53-7.43 (m, 2H), 7.42-7.35 (m, 2H), 5.99 (dd, J=7.2, 3.0 Hz, 1H), 4.07 (dd, J=15.3, 7.2 Hz, 1H), 4.01 (dd, J=15.3, 3.0 Hz, 1H).
EXAMPLE 35 (65) 6-(Pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2136] 1955
[2137] TLC: Rf 0 60 (chloroform:methanol 9:1);
[2138] NMR (DMSO-d6): &dgr; 9.29 (d, J=2.1 Hz, 1H), 8.85 (d, J=5.1 Hz, 1H), 8.76 (d, J=7.8 Hz, 1H), 8.37 (s, 1H), 8.29 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (dd, J=8.4, 5.1 Hz, 1H), 7.89-7.75 (m, 4H), 7.71-7.60 (m, 2H), 5.93 (dd, J=9.3, 3.0 Hz, 1H), 4.06 (dd, J=15.0, 9.3 Hz, 1H), 3.85 (dd, J=15.0, 3.0 Hz, 1H).
EXAMPLE 35 (66) 4-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2139] 1956
[2140] TLC: Rf 0.22 (ethyl acetate:hexane=1:1);
[2141] NMR (CDCl3): &dgr; 8.23 (d, J=6.0 Hz, 1H), 7.73-7.67 (m, 2H), 7.67-7.54 (m, 3H), 7.48-7.40 (m, 2H), 6.36 (dd, J=9.0 Hz, 1.8 Hz, 1H), 4.26 (d, J=7.5 Hz, 1H), 4.22 (d, J=7.5 Hz, 1H), 3.89 (dd, J=15.0 Hz, 1.8 Hz, 1H), 3.78 (dd, J=15.0 Hz, 9.0 Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H).
EXAMPLE 35 (67) 6-Bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2142] 1957
[2143] TLC: Rf 0.24 (methylene chloride);
[2144] NMR (DMSO-d6): &dgr; 8.13 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.5, 2.0 Hz, 1H), 7.83-7.76 (m, 3H), 7.67-7.60 (m, 3H), 5.79 (dd, J=9.5, 3.0 Hz, 1H), 4.05 (dd, J=15.5, 9.5 Hz, 1H), 3.85 (dd, J=15.5, 3.0 Hz, 1H).
EXAMPLE 35 (68) 6-Amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2145] 1958
[2146] TLC: Rf 0.34 (hexane:ethyl acetate=1:2);
[2147] NMR (DMSO-d6): &dgr; 7.79-7.71 (m, 3H), 7.64-7.56 (m, 2H), 7.28 (d, J=8.5 Hz, 1H), 6.89 (dd, J=8.5, 2.2 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 6.00 (s, 2H), 5.47 (dd, J=9.2,3.0 Hz, 1H), 3.89 (dd, J=15.2, 9.2 Hz, 1H), 3.64 (dd, J=15.2, 3.0 Hz, 1H).
EXAMPLES 36˜36 (3)[2148] By the same procedure as described in Example 28 using carboxylic acid corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine corresponding to (pyridin-3-ylmethyl)amine, the following compounds of the present invention were obtained.
EXAMPLE 36 5-Methylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2149] 1959
[2150] TLC: Rf 0.38 (methanol:ethyl acetate=5:95);
[2151] NMR(DMSO-d6): &dgr; 8.40 (d, J=4.8 Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 3.89 (s, 3H), 2.78 (d, J=4.8 Hz, 3H).
EXAMPLE 36 (1) 4-Dimethylcarbamoyl-1,1-dioxidebenzo[b]thiophene[2152] 1960
[2153] TLC: Rf 0.34 (methanol:ethyl acetate=5:95);
[2154] NMR(CDCl3): &dgr; 7.76 (dd, J=7.0 Hz, 1.4 Hz, 1H), 7.58 (t, J=7.0 Hz, 1H), 7.51 (dd, J=7.0 Hz, 1.4 Hz, 1H), 7.33 (d, J=6.8 Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 3.17 (s, 3H), 3.00 (s, 3H).
EXAMPLE 36 (2) 4-Carbamoyl-1,1-dioxidebenzo[b]thiophene[2155] 1961
[2156] TLC: Rf 0.50 (methanol:ethyl acetate=5:95);
[2157] NMR(DMSO-d6): &dgr; 8.22 (brs, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (brs, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H).
EXAMPLE 36 (3) 4-(Furan-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2158] 1962
[2159] TLC: Rf 0.36 (ethyl acetate:hexane 1;1); NMR (CDCl3+DMSO-d6): &dgr; 7.96 (dd, J=7.2, 0.9 Hz, 1H), 7.81-7.76 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 7.51 (t, J=5.7 Hz, 1H), 7.40-7.38 (m, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.37-6.30 (m, 2H), 4.62 (d, J=5.7 Hz, 2H).
EXAMPLES 37˜37 (6)[2160] By the same procedure as described in Example 18 using an alcohol derivative corresponding to the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using an alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and an alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained.
EXAMPLE 37 4-(2-(Pyridin-4-yl)ethyl) oxy-1,1-dioxidebenzo[b]thiophene[2161] 1963
[2162] TLC: Rf 0.23 (hexane:ethyl acetate=1:3);
[2163] NMR (CDCl3): &dgr; 8.56 (d, J=6.0 Hz, 2H), 7.46 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (d, J=6.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 6.60 (d, J=7.2 Hz, 1H), 4.33 (t, J=6.5 Hz, 2H), 3.14 (t, J=6.5 Hz, 2H).
EXAMPLE 37 (1) 4-(2-(Pyridin-3-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[2164] 1964
[2165] TLC: Rf 0.38 (ethyl acetate);
[2166] NMR(CDCl3): &dgr; 8.56 (d, J=1.8 Hz, 1H), 8.52 (dd, J=4.8, 1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.28 (dd, J=7.0 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.60 (d, J=7.0 Hz, 1H), 4.30 (t, J=6.4 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H).
EXAMPLE 37(2) 4-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2167] 1965
[2168] TLC: Rf 0.38 (hexane:ethyl acetate=1:1);
[2169] NMR (CDCl3): &dgr; 7.53 (d, J=7.2 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.65 (d, J=7.2 Hz, 1H), 4.72 (s, 2H), 4.27 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).
EXAMPLE 37 (3) 6-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2170] 1966
[2171] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[2172] NMR (CDCl3): “ 7.28 (d, J=8.4 Hz, 1H), 7.24 (d, J=2.6 Hz,1H), 7.17 (d, J=7.0 Hz, 1H), 7.05 (dd, J=8.4,2.6 Hz, 1H), 6.63 (d, J=7.0 Hz, 1H), 4.68 (s, 2H), 4.29 (q, J=7.0 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H).
EXAMPLE 37 (4) 6-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene[2173] 1967
[2174] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[2175] NMR (CDCl3): &dgr; 7.36 (d, J=8.4Hz,1H), 7.34 (dd, J=2.6,0.8Hz, 1H), 7.20 (dd, J=7.0, 0.8 Hz, 1H), 7.14 (dd, J=8.4, 2.6 Hz, 1H), 6.69 (d, J=7.0 Hz,1H), 4.84 (s, 2H).
EXAMPLE 37 (5) 5-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2176] 1968
[2177] TLC: Rf 0.31 (ethyl acetate:hexane=1:1);
[2178] NMR (CDCl3): &dgr; 7.64 (d, J=8.2 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 6.98-6.86 (m,2H), 6.74 (d, J=6.8 Hz, 1H), 4.69 (s, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
EXAMPLE 37 (6) 7-Ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2179] 1969
[2180] TLC: Rf 0.28 (ethyl acetate:hexane=1:1);
[2181] NMR (CDCl3): &dgr; 7.46 (dd, J=8.6 Hz, 7.0 Hz, 1H), 7.14 (d, J=7.0 Hz, 1H), 6.96 (d, J=7.0 Hz,1H), 6.89 (d, J=8.6 Hz,1H), 6.68 (d, J=7.0 Hz,1H), 4.84 (s, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H).
EXAMPLES 38˜38 (3)[2182] By the same procedure as described in Example 32 using a carboxylic acid derivative corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and a halogenated compound corresponding to bromoethane, the following compounds of the present invention having the following physical data were obtained.
EXAMPLE 38 5-Benzyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2183] 1970
[2184] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[2185] NMR (CDCl3): &dgr; 7.98 (d, J=8.0 Hz, 1H), 7.51-7.36 (m, 7H), 6.73 (d, J=7.0 Hz, 1H), 5.38 (s, 2H), 3.87 (s, 3H).
EXAMPLE 38 (1) 5-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene[2186] 1971
[2187] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[2188] NMR (CDCl3): &dgr; 8.22 (dd, J=8.0, 1.0 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.80 (d, J=7.0 Hz, 1H), 4.43 (q , J=7.0 Hz,1H), 1.42 (t, J=7.0 Hz,, 3H).
EXAMPLE 38 (2) 7-Methoxycarbonyl-1,1-dioxidebenzo[b]thiophene[2189] 1972
[2190] TLC: Rf 0.15 (hexane:ethyl acetate=2:1);
[2191] NMR (CDCl3): &dgr; 8.11 (d, J=8 Hz, 1H), 7.66 (t, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.20 (d, J=7 Hz, 1H), 6.77 (d, J=7 Hz, 1H), 4.05 (s, 3H).
EXAMPLE 38 (3) 7-Ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene[2192] 1973
[2193] TLC: Rf 0.39 (ethyl acetate:hexane=1:1);
[2194] NMR (CDCl3): &dgr; 8.13 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.52 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 6.76 (d, J=6.8 Hz, 1H), 4.53 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 1H).
EXAMPLE 39 5-t-Butoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2195] 1974
[2196] A suspension of 5-carboxy-4-methoxy-1,1-dioxidebenzo[b]thiophene (934 mg) in benzene (15 ml) was refluxed. Thereto was added dimethylformamidedi-t-butylacetal (4.02 g) dropwise. The mixture was refluxed for 1 hour. To the reaction mixture water was added. The mixture was extracted by benzene. The extract was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane=1:0) to give the compound of the present invention (942 mg) having the following physical data.
[2197] TLC: Rf 0.25 (ethyl acetate:hexane=1:4);
[2198] NMR (CDCl3): &dgr; 7.87 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 3.95 (s, 3H), 1.62 (s, 9H).
EXAMPLE 40 5-((E)-2-(Ethoxycarbonyl)ethenyl)-4-methoxybenzo[b]thiophene[2199] 1975
[2200] To a suspension of 62.5% sodium hydride (920 mg) in anhydrous tetrahydrofuran (40 ml), was added a solution of triethylphosphonoacetate (5.83 g) in anhydrous tetrahydrofuran (20 ml) dropwise. The mixture was stirred for 15 minutes. To the reaction mixture, was added a solution of 5-formyl-4-methoxybenzo[b]thiophene (3.84 g) in anhydrous tetrahydrofuran (20 ml) dropwise. The mixture was stirred at room temperature for 1 hour. To the reaction mixture, was added acetic acid (1.5 ml). The mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the compound of the present invention (5.17 g) having the following physical data.
[2201] TLC: Rf 0.37 (hexane:ethyl acetate=5:1);
[2202] NMR (CDCl3): &dgr; 8.13 (d, J=16.2 Hz, 1H), 7.62-7.41 (m, 4H), 6.53 (d, J=16.2 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 4.00 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).
EXAMPLE 41 5-(2-(Ethoxycarbonyl)ethyl)-4-methoxybenzo[b]thiophene[2203] 1976
[2204] To a solution of the compound prepared in Example 40 (5.16 g) in ethanol (100 ml), 10% palladium carbon (200 mg) was added. Under an atmosphere of hydrogen the mixture was stirred at room temperature. The reaction mixture was filtrated through celite, and the filtrate was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the compound of the present invention (3.23 g) having the following physical data.
[2205] TLC: Rf 0.40 (hexane:ethyl acetate=5:1);
[2206] NMR (CDCl3): &dgr; 6 7.56 (d, J=8.1 Hz, 1H), 7.41 (q, J=5.4 Hz, 2H), 7.20 (d, J=8.1 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.97 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
EXAMPLE 42 5-(2-(Ethoxycarbonyl)ethyl)-4-methoxy-1,1-dioxidebenzo[b]thiophene[2207] 1977
[2208] By the same procedure as described in 3 using the compound prepared in Example 41 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE® as an oxidizer).
[2209] TLC: Rf 0.25 (hexane:ethyl acetate=2:1);
[2210] NMR (CDCl3): &dgr; 7.45-7.36 (m, 3H), 6.70 (d, J=6.8 Hz, 1H), 4.15 (q, J=7.4 Hz, 2H), 3.92 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.4 Hz, 3H).
EXAMPLE 43 5-(4.4-Dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene[2211] 1978
[2212] Using the compound which was obtained with using 5-carboxy-1,1-dioxidebenzo[b]thiophene and (2-hydroxy-1,1-dimethylethyl)amine instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene and (pyridin-3-ylmethyl)amine respectively, by the same procedure as described in Example 28, by the same procedure as described in Example 34, the compound of the present invention having the following physical data was obtained.
[2213] TLC: Rf 0.39 (ethyl acetate:hexane=1:1);
[2214] NMR (CDCl3): &dgr; 8.08 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.98 (d, J=1.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.23 (d, J=7.0 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 4.16 (s, 2H), 1.40 (s, 6H).
EXAMPLES 44˜44 (24)[2215] By the same procedure as described in Example 1 using the compounds prepared in Examples 36˜36 (2), Examples 37˜37 (6), Examples 38˜38 (3), Example 39, Example 42, Example 36 (3), Example 43 instead of 1,1-dioxidebenzo[b]thiophene or a corresponding derivative and thiol derivatives corresponding to thiophenol, the following compounds of the present invention were obtained.
EXAMPLE 44 5-Methylcarbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2216] 1979
[2217] TLC: Rf 0.58 (methanol:ethyl acetate 5:95);
[2218] NMR (CDCl3): &dgr; 8.10 (d, J=5.6 Hz, 1H), 7.56 (d, J=5.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.43-7.35 (m, 3H), 7.17 (brs, 1H), 5.07 (dd, J=4.6 Hz, 1.4 Hz, 1H), 4.04 (s, 3H), 3.72 (dd, J=9.4 Hz, 4.6 Hz, 1H), 3.63 (dd, J=9.4 Hz, 1.4 Hz, 1H), 3.07 (d, J=4.8 Hz, 3H).
EXAMPLE 44 (1) 4-Dimethylcarbamoyl-3-phenylthio-2,3-di hydro-1,1-dioxidebenzo[b]thiophene[2219] 1980
[2220] TLC: Rf 0.52 (methanol:ethyl acetate=5:95);
[2221] NMR (CDCl3): &dgr; 7.78 (dd, J=7.5 Hz, 1.8 Hz, 1H), 7.63-7.51 (m, 4H), 7.43-7.34 (m, 3H), 5.41 (dd, J=7.8 Hz, 1.8 Hz, 1H), 3.74 (dd, J=14.1 Hz, 7.8 Hz, 1H), 3.61 (dd, J=14.1 Hz, 1.8 Hz, 1H), 3.17 (s, 3H), 3.00 (s, 3H).
EXAMPLE 44 (2) 4-Carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2222] 1981
[2223] TLC: Rf 0.49 (methanol:ethyl acetate=5:95);
[2224] NMR (DMSO-d6): &dgr; 8.19 (brs, 1H), 7.96-7.64 (m, 4H), 7.52-7.30 (m, 5H), 5.87 (d, J=7.4 Hz, 1H), 4.10 (dd, J=14.6 Hz, 7.4 Hz, 1H), 3.61 (d, J=14.6 Hz, 1H).
EXAMPLE 44 (3) 4-(2-(Pyridin-4-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-11-dioxidebenzo[b]thiophene[2225] 1982
[2226] TLC: Rf 0.44 (ethyl acetate:methanol=10:1);
[2227] NMR (CDCl3): &dgr; 8.50 (d, J=6 Hz, 2H), 7.60-7.13 (m, 9H), 7.07 (d, J=8 Hz, 1H), 4.93 (dd, J=2, 7 Hz, 1H), 4.50-4.15 (m, 2H), 3.80-3.50 (m, 2H), 3.15 (t, J=7 Hz, 2H).
EXAMPLE 44 (4) 4-(2-(Pyridin-3-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2228] 1983
[2229] TLC: Rf 0.38 (ethyl acetate);
[2230] NMR (CDCl3): &dgr; 8.57 (d, J=1.8 Hz, 1H), 8.48 (dd, J=5.0 Hz, 1.8 Hz, 1H), 7.63 (m, 1H), 7.54-7.32 (m, 7H), 7.19 (dd, J=7.8 Hz, 4.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 4.97 (dd, J=6.2 Hz, 1.8 Hz, 1H), 4.32 (m, 2H), 3.67 (dd, J=14.2 Hz, 6.2 Hz, 1H), 3.58 (dd, J=14.2 Hz, 1.8 Hz, 1H), 3.16 (t, J=7.2 Hz, 2H).
EXAMPLE 44 (5) 4-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2231] 1984
[2232] TLC: Rf 0.45 (hexane:ethyl acetate=1:1);
[2233] NMR (CDCl3): &dgr; 7.57-7.53 (m, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.38-7.33 (m, 4H), 6.96 (d, J=8.1 Hz, 1H), 5.16 (dd, J=7.0, 1.8 Hz, 1H), 4.71 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.72 (dd, J=14.0, 7.0 Hz, 1H), 3.62 (dd, J=14.0, 1.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).
EXAMPLE 44 (6) 6-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2234] 1985
[2235] TLC: Rf 0.54 (hexane:ethyl acetate=1:1);
[2236] NMR (CDCl3): &dgr; 7.62 (d, J=8.7 Hz, 1H), 7.43-7.40 (m, 2H), 7.35-7.33 (m, 3H), 7.25 (dd, J=8.7, 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 4.91 (t, J=6.8 Hz, 1H), 4.66 (s, 2K), 4.28 (q, J=7.2 Hz, 2H), 3.81 (dd, J=13.7, 6.8 Hz, 1H), 3.52 (dd, J=13.7, 6.8 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H).
EXAMPLE 44 (7) 6-Cyanomethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2237] 1986
[2238] TLC: Rf 0.54 (hexane:ethyl acetate=2:1);
[2239] NMR (CDCl3): &dgr; 7.69 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.38-7.34 (m, 3H), 7.28 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 4.93 (t, J=6.9 Hz, 1H), 4.83 (s, 2H), 3.83 (dd, J=13.7, 6.9 Hz 1H) 3.54 (dd, J=13.7, 6.9 Hz, 1H).
EXAMPLE 44 (8) 5-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2240] 1987
[2241] TLC: Rf 0.45 (ethyl acetate:hexane=1:1);
[2242] NMR (CDCl3): &dgr; 7.64 (d, J=8.6 Hz, 1H), 7.48-7.30 (m, 5H), 7.15 (d, J=2.2 Hz, 1H), 7.06 (dd, J=8.6 Hz, 2.2 Hz, 1H), 4.90 (t, J=7.0Hz, 1H), 4.69 (s, 2H), 4.29 (q, J=7.4Hz, 2H), 3.79 (dd, J=13.6 Hz, 7.0 Hz, 1H), 3.50 (dd, J=13.6 Hz, 7.0 Hz, 1H), 1.32 (t, J=7.4 Hz, 3H).
EXAMPLE 44 (9) 7-Ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2243] 1988
[2244] TLC: Rf 0.43 (ethyl acetate:hexane=1:1);
[2245] NMR (CDCl3): &dgr; 7.55 (t, J=8.4 Hz, 1H), 7.46-7.27 (m, 6H), 6.82 (d, J=8.4 Hz, 1H), 4.91 (dd, J=7.6 Hz, 6.6 Hz, 1H), 4.80 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.80 (dd, J=13.6 Hz, 7.6 Hz, 1H) 3.54 (dd, J=13.6 Hz, 6.6 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H).
EXAMPLE 44 (10) 5-Benzyloxycarbonyl-4-methoxy-3-phenylethio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2246] 1989
[2247] TLC: Rf 0.55 (hexane:ethyl acetate=1:1);
[2248] NMR (CDCl3): &dgr; 7.99 (d, J=8.0 Hz, 1H), 7.54-7.34 (m, 1H), 5.40 (s, 2H), 5.08 (dd, J=6.0, 2.5 Hz, 1H), 3.97 (s, 3H), 3.69 (dd, J=14.0, 6.0 Hz, 1H), 3.60 (dd, J=14.0, 2.5 Hz, 1H).
EXAMPLE 44 (1 1) 5-Ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2249] 1990
[2250] TLC: Rf 0.55 (hexane:ethyl acetate=1:1);
[2251] NMR (CDCl3): &dgr; 8.36 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.47-7.33 (m, 5H), 4.97 (t, J=7.0 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.84 (dd, J=13.7, 7.0 Hz, 1H), 3.54 (dd, J=13.7, 7.0 Hz, 1H), 1.43 (t, J=7.0 Hz, 3H).
EXAMPLE 44 (12) 7-Methoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2252] 1991
[2253] TLC: Rf 0.39 (ethyl acetate:hexane=1:1);
[2254] NMR (CDCl3): &dgr; 8.12 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.48-7.33 (m, 5H), 4.92 (dd, J=7.6 Hz, 6.8 Hz, 1H), 4.01 (s, 3H), 3.86 (dd, J=13.6 Hz, 7.6 Hz, 1H), 3.56 (dd, J=1 3.6 Hz, 6.8 Hz, 1H).
EXAMPLE 44 (13) 7-Ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2255] 1992
[2256] TLC: Rf 0.60 (ethyl acetate:hexane=1:1);
[2257] NMR (CDCl3): &dgr; 8.13 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.46-7.38 (m, 2H), 7.38-7.30 (m, 3H), 4.92 (dd, J=7.8 Hz, 6.9 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.84 (dd, J=13.5 Hz, 7.8 Hz, 1H), 3.55 (dd, J=13.5 Hz, 6.9 Hz, 1H), 1.44 (t, J=7.2 Hz, 3H).
EXAMPLE 44 (14) 5-t-Butoxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2258] 1993
[2259] TLC: Rf 0.22 (ethyl acetate:hexane 1:4);
[2260] NMR (CDCl3): &dgr; 7.88 (d, J=8.0 Hz,1H), 7.58-7.49 (m, 2H), 7.46 (d, J=8.0 Hz,1H), 7.43-7.34 (m, 3H), 5.10 (dd, J=6.0 Hz, 2.8 Hz, 1H), 4.08 (s, 3H), 3.70 (dd, J=13.8 Hz, 6.0 Hz, 1H), 3.61 (dd, J=13.8 Hz, 2.8 Hz, 1H), 1.63 (s, 9H).
EXAMPLE 44 (15) 5-(2-(Ethoxycarbonyl)ethyl)4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2261] 1994
[2262] TLC: Rf 0.25 (hexane:ethyl acetate=2:1);
[2263] NMR (CDCl3): &dgr; 7.55-7.50 (m, 2H), 7.44 (s, 2H), 7.43-7.30 (m, 3H), 5.08 (dd, J=6.9, 2.1 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.05 (s, 3H), 3.68 (dd, J=15.2, 7.2 Hz, 1H), 3.60 (dd, J=15.2, 2.1 Hz, 1H), 3.18-3.00 (m, 2H), 2.66 (t, J=7.8 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).
EXAMPLE 44 (16) 4-(Furan-2-ylmethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2264] 1995
[2265] TLC: Rf 0.37 (ethyl acetate:benzene=1:2);
[2266] NMR (DMSO-d6): &dgr; 9.24 (t, J=5.6 Hz, 1H), 7.93-7.82 (m, 2H), 7.77-7.66 (m, 1H), 7.55-7.51 (m, 1H), 7.47-7.31 (m, 5H), 6.37-6.29 (m, 2H), 5.75 (d, J=7.6 Hz, 1H), 4.46 (d, J=5.6 Hz, 2H), 4.12 (dd, J=14.2 Hz, 7.6 Hz, 1H), 3.62 (d, J=14.2 Hz, 1H).
EXAMPLE 44 (17) 5-(4,4-Dimethyl-4,5-dihydroxazol-2-yl)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2267] 1996
[2268] TLC: Rf 0.50 (ethyl acetate:hexane=1:1);
[2269] NMR (CDCl3): &dgr; 8.32 (brs, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.50-7.30 (m, 5H), 4.96 (dd, J=7.2 Hz, 6.6 Hz, 1H), 4.18 (s, 2H), 3.82 (dd, J=13.8 Hz, 7.2 Hz, 1H), 3.54 (dd, J=13.8 Hz, 6.6 Hz, 1H), 1.42 (s, 6H).
EXAMPLE 44 (18) 3-Benzylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2270] 1997
[2271] TLC: Rf 0.52 (hexane:ethyl acetate 1:1);
[2272] NMR (CDCl3): &dgr; 3.42 (dd, J=13.8Hz, 6.3Hz, 1H), 3.69 (dd, J=13.8Hz, 7.8Hz, 1H), 3.78 (d, J=13.7Hz, 1H), 3.86 (d, J=13.7Hz, 1H), 4.53 (t-like, J=7.1Hz, 1H), 7.27-7.33 (m, 5H), 7.46-7.56 (m,1H), 7.59-7.62 (m, 2H), 7.71 (d, J=7.6Hz, 1H).
EXAMPLE 44 (19) 3-(3,4-Dichlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2273] 1998
[2274] TLC: Rf 0.57 (hexane:ethyl acetate=1:1);
[2275] NMR (CDCl3): &dgr; 3.48 (dd, J=13.6Hz, 5.8Hz, 1H), 3.83 (dd, J=13.6Hz, 7.6Hz, 1H), 4.97 (t-like, J=6.8Hz, 1H), 7.23 (dd, J=8.3Hz, 2.2Hz, 1H), 7.41 (d, J=8.3Hz, 1H), 7.51 (d, J=2.2Hz, 1H), 7.54-7.62 (m, 1H), 7.66-7.69 (m, 2H), 7.74 (d, J=76Hz, 1H).
EXAMPLE 44 (20) 3-(4-Nitrophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2276] 1999
[2277] TLC: Rf 0.15 (methylene chloride); NMR (CDCl3): &dgr; 3.55 (dd, J=13.8Hz, 6.0Hz, 1H), 3.97 (dd, J=13.8Hz, 7.5Hz, 1H), 5.20 (t-like, J=6.8Hz, 1H), 7.47 (d, J=8.7Hz, 2H), 7.55-7.64 (m, 1H), 7.68-7.70 (m, 2H), 7.79 (d, J=7.6Hz,1H), 8.19 (d, J=8.7Hz, 2H).
EXAMPLE 44 (21) 5-Hydroxymethyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2278] 2000
[2279] TLC: Rf 0.64 (ethyl acetate);
[2280] NMR (CDCl3): &dgr; 7.68 (d, J=7.8 Hz, 1H), 7.55-7.47 (m, 3H), 7.39-7.35 (m, 3H), 5.08 (dd, J=6.6, 2.5 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 4.06 (s, 3H), 3.69 (dd, J=13.9, 6.6 Hz, 1H), 3.58 (dd, J=13.9, 2.5 Hz, 1H), 2.15 (t, J=6.0 Hz, 1H).
EXAMPLE 44 (22) 4-Hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2281] 2001
[2282] TLC: Rf 0.22 (chloroform:ethyl acetate=4:1);
[2283] NMR (CDCl3): &dgr; 7.77-7.66 (m, 2H), 7.61 (d, J=7.4 Hz, 1H), 7.57-7.44 (m, 2H), 7.43-7.32 (m, 3H), 5.20 (dd, J=6.8, 2.0 Hz, 1H), 5.03 (s, 2H), 3.72 (dd, J=14.0, 6.8 Hz, 1H), 3.62 (dd, J=14.0, 2.0 Hz, 1H), 2.45-2.15 (br,1H).
EXAMPLE 44 (23) 6-Fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2284] 2002
[2285] TLC: Rf 0.62 (ethyl acetate:hexane=1:4);
[2286] NMR (CDCl3): &dgr; 7.70 (ddd, J=7.6Hz, 4.4Hz, 0.4Hz,1H), 7.47-7.29 (m, 7H),4.93 (t, J=7.0 Hz, 1H), 3.84 (dd, J=13.8 Hz, 7.0 Hz, 1H), 3.55 (dd, J=13.8 Hz, 7.0 Hz, 1H).
EXAMPLE 44 (24) 4-Fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2287] 2003
[2288] TLC: Rf 0.55 (ethyl acetate:hexane=1:4);
[2289] NMR (CDCl3): &dgr; 7.64-7.45 (m, 4H), 7.42-7.27 (m, 4H), 5.06 (dd, J=7.4 Hz, 2.8 Hz, 1H), 3.77 (dd, J=14.2 Hz, 7.4 Hz, 1H), 3.63 (dd, J=14.2 Hz, 2.8 Hz, 1H).
EXAMPLES 45˜45 (22)[2290] Using the compounds prepared in Examples 44˜44 (15) and Examples 44 (18)˜44 (24) instead of the compound prepared in Example 1 by the same procedure as described in Example 3, or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@ as an oxidizer, and if necessary, by converting into a corresponding salt by known methods, the following compounds of the present invention were obtained.
EXAMPLE 45 5-Methylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2291] 2004
[2292] TLC: Rf 0.33 (methanol:ethyl acetate=5:95); NMR (DMSO-d6): &dgr; 8.47 (q-like, J=3.4 Hz, 1H), 7.87-7.73 (m, 3H), 7.69-7.60 (m, 3H), 7.50 (d, J=5.4 Hz, 1H), 5.65 (d, J=6.0 Hz, 1H), 4.13 (d, J=10.2 Hz, 1H), 3.98 (dd, J=10.2 Hz, 6.0 Hz, 1H), 3.59 (s, 3H), 2.77 (d, J=3.4 Hz, 3H).
EXAMPLE 45 (1) 4-Dimethylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2293] 2005
[2294] TLC: Rf 0.55 (methanol:ethyl acetate=5:95);
[2295] NMR (DMSO-d6): &dgr; 7.93-7.73 (m, 6H), 7.70-7.62 (m, 2H), 5.86 (d, J=9.3 Hz, 1H), 4.12 (dd, J=15.3 Hz, 9.3 Hz, 1H), 3.91 (d, J=15.3 Hz, 1H), 3.07 (s, 3H), 3.03 (s, 3H).
EXAMPLE 45 (2) 4-Carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2296] 2006
[2297] TLC: Rf 0.43 (methanol:ethyl acetate=5:95);
[2298] NMR (DMSO-d6): &dgr; 8.30 (brs, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.86-7.72 (m, 5H), 7.68 (brs, 1H), 7.63 (t, J=7.8 Hz, 1H), 6.37 (d, J=9.3 Hz, 1H), 4.08 (dd, J=15.3 Hz, 9.3 Hz, 1H), 3.95 (d, J=15.3 Hz, 1H).
EXAMPLE 45 (3) 4-(2-Pyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2299] 2007
[2300] Free Compound:
[2301] TLC: Rf 0.25 (ethyl acetate:methanol=10:1);
[2302] NMR (CDCl3): &dgr; 8.58 (d, J=6 Hz, 2H), 7.80-7.35 (m, 6H), 7.35-7.14 (m, 3H), 6.98 (d, J=8 Hz, 1H), 5.12 (d, J=9 Hz, 1H), 4.30-4.05 (m, 3H), 3.70 (dd, J=9, 15 Hz, 1H), 3.25-2.90 (m, 2H).
[2303] Hydrochloride:
[2304] TLC: Rf 0.25 (ethyl acetate:methanol=10:1);
[2305] NMR (DMSO-d6): &dgr; 8.83 (d, J=6.6 Hz, 2H), 7.96 (d, J=6.6 Hz, 2H), 7.78-7.58 (m, 6H), 7.35-7.30 (m, 2H), 5.40 (d, J=8.5 Hz, 1H), 4.36-4.28 (m, 1H), 4.19-4.12 (m, 1H), 4.11 (d, J=15.0 Hz, 1H),3.98 (dd, J=15.0, 8.5 Hz, 1H), 3.24-3.15 (m, 1H), 3.11-3.01 (m, 1H).
[2306] Methanesulfonic Acid Salt:
[2307] TLC: Rf 0.25 (ethyl acetate:methanol=10:1);
[2308] NMR (DMSO-d6): &dgr; 8.85 (d, J=6.6 Hz, 2H), 7.98 (d, J=6.6 Hz, 2H), 7.78-7.58 (m, 6H), 7.35-7.30 (m, 2H), 5.39 (d, J=8.5 Hz, 1H), 4.36-4.29 (m, 1H), 4.19-4.13 (m, 1H), 4.11 (d, J=15.0 Hz, 1H), 3.97 (dd, J=15.0, 8.5 Hz,1H), 3.25-3.17 (m, 1H), 3.11-3.02 (m, 1H).
EXAMPLE 45 (4) 4-(2-(Pyridin-3-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1,-dioxidebenzo[b]thiophene.[2309] 2008
[2310] Free Compound:
[2311] TLC: Rf 013 (ethyl acetate);
[2312] NMR (DMSO-d6): &dgr; 8.46 (d, J=1.8 Hz, 1H), 8.43 (dd, J=4.8 Hz, 1.8 Hz, 1H), 7.86-7.54 (m, 6H), 7.42-7.30 (m, 4H), 5.43 (d, J=7.4Hz, 1H), 4.26-3.82, (m, 4H), 2.75 (t, J=6.6 Hz, 2H).
[2313] Hydrochloride:
[2314] TLC: Rf 0.13 (ethyl acetate);
[2315] NMR (DMSO-d6): &dgr; 8.88 (s, 1H), 8.80 (d, J=5.7 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.78-7.54 (m, 6H), 7.30 (d, J=7.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 5.47 (d, J=7.8 Hz, 1H), 4.34-4.20 (m, 1H), 4.16-3.91 (m, 3H), 3.19-2.94 (m, 2H).
EXAMPLE 45 (5) 4-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2316] 2009
[2317] TLC: Rf 0.17 (hexane:ethyl acetate=1:1);
[2318] NMR (CDCl3): &dgr; 7.82-7.78 (m, 2H), 7.68-7.60 (m, 1H), 7.58-7.44 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.38 (d, J=8.5 Hz, 1H), 4.45 (d, J=16.2 Hz, 1H), 4.30 (d, J=16.2 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.24 (d, J=15.0 Hz, 1H), 3.76 (dd, J=15.0, 8.5 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H).
EXAMPLE 45 (6) 6-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2319] 2010
[2320] TLC: Rf 0.31 (hexane:ethyl acetate=1:1);
[2321] NMR (CDCl3): &dgr; 7.90 (d, J=8.8 Hz, 1H), 7.71-7.62 (m, 3H), 7.55-7.46 (m, 2H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 5.00 (dd, J=7.8, 5.4 Hz, 1H), 4.67 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.80 (dd, J=15.0, 5.4 Hz, 1H), 3.72 (dd, J=15.0, 7.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).
EXAMPLE 45 (7) 6-Cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2322] 2011
[2323] TLC: Rf 0.32 (hexane:ethyl acetate=2:1);
[2324] NMR (DMSO-d6): &dgr; 7.81-7.75 (m, 3H), 7.68-7.60 (m, 3H), 7.53 (d, J=2.5 Hz, 1H), 7.48 (dd, J=8.5, 2.5 Hz, 1H), 5.73 (dd, J=9.5, 3.0 Hz, 1H), 5.33 (s, 2H), 4.03 (dd, J=15.0, 9.5 Hz, 1H), 3.81 (dd, J=15.0, 3.0 Hz, 1H).
EXAMPLE 45 (8) 5-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2325] 2012
[2326] TLC: Rf 0.35 (ethyl acetate:hexane=1:1);
[2327] NMR (CDCl3): &dgr; 7.73-7.61 (m, 3H), 7.58-7.45 (m,3H), 7.44 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.8 Hz, 2.2 Hz, 1H), 5.00 (t, J=7.0 Hz, 1H), 4.78 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.81-3.65 (m, 2H), 1.35 (t, J=7.2 Hz, 3H).
EXAMPLE 45 (9) 7-Ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2328] 2013
[2329] TLC: Rf 0.17 (ethyl acetate:hexane=1:1);
[2330] NMR (CDCl3): &dgr; 7.72-7.47 (m, 7H), 6.91 (d, J=6.9 Hz, 1H), 5.03 (dd, J=8.7 Hz, 5.4 Hz, 1H), 4.76 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.79 (dd, J=14.7 Hz, 5.4 Hz, 1H), 3.73 (dd, J=14.7 Hz, 8 .7 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H).
EXAMPLE 45 (10) 5-Benzyloxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2331] 2014
[2332] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[2333] NMR (CDCl3): &dgr; 7.90 (d, J=8.0 Hz, 1H), 7.76-7.71 (m, 2H), 7.63-7.55 (m, 1H), 7.47-7.36 (m, 8H), 5.37 (s, 2H), 5.24 (dd, J=9.0, 1.0Hz, 1H), 4.16 (dd, J=15.0, 1.0 Hz, 1H), 3.74 (s, 3H), 3.73 (dd, J=15.0, 9.0 Hz, 1H).
EXAMPLE 45 (11) 5-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2334] 2015
[2335] TLC: Rf 0.34 (hexane:ethyl acetate=1:1);
[2336] NMR (DMSO-d6): &dgr; 8.23 (d-like, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85-7.78 (m, 3H), 7.69-7.61 (m, 2H), 5.91 (dd, J=9.3, 3.2 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 4.10 (dd, J=15.3, 9.3 Hz, 1H), 3.91 (dd, J=15.3, 3.2 Hz; 1H); 1.35 (t, J=7.0 Hz, 3H).
EXAMPLE 45 (12) 7-Methoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2337] 2016
[2338] TLC: Rf 0.16 (ethyl acetate:hexane=1:1);
[2339] NMR (CDCl3): &dgr; 8.23 (d, J=8.1 Hz, 2H), 7.81 (t, J=8.1 Hz, 1H), 7.72-7.64 (m, 3H), 7.55-7.47 (m, 2H), 5.07 (dd, J=9.3 Hz, 4.8 Hz, 1H), 3.97 (s, 3H), 3.84 (dd, J=14.7 (t, 4.8 Hz, 1H), 3.75 (dd, J=14.7 Hz, 9.3 Hz, 1H).
EXAMPLE 45 (13) 7-Ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2340] 2017
[2341] TLC: Rf 0.22 (ethyl acetate:hexane=1:1);
[2342] NMR (CDCl3): &dgr; 8.25 (d, J=7.8 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.73-7.65 (m, 3H), 7.56-7.48 (m, 2H), 5.06 (dd, J=9.3 Hz, 4.8 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.83 (dd, J=14.7 Hz, 4.8 Hz, 1H), 3.73 (dd, J=14.7 Hz, 9.3 Hz, 1H), 1.40 (t, J=7.2 Hz, 3H).
EXAMPLE 45 (14) 5-t-Butoxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2343] 2018
[2344] TLC: Rf 0.37 (ethyl acetate:hexane 1:1);
[2345] NMR (CDCl3): &dgr; 7.80 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 5.27 (dd, J=9.3 Hz, 1.2 Hz, 1H), 4.14 (dd, J=15.0 Hz, 1.2 Hz, 1H), 3.86 (s, 3H), 3.74 (dd, J=15.0 Hz, 9.3 Hz, 1H), 1.61 (s, 9H).
EXAMPLE 45 (15) 5-(2-Ethoxycarbonylethyl)-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2346] 2019
[2347] TLC: Rf 0.28 (ethyl acetate:hexane=1:1);
[2348] NMR (CDCl3): &dgr; 7.77-7.70 (m, 2H), 7.61 (t, J=7.5 Hz, 1H), 7.50-7.35 (m, 4H), 5.19 (dd, J=9.3, 1.8 Hz, 1H), 4.23 (dd, J=15.0, 1.8 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.81 (dd, J=15.0, 9.3 Hz, 1H), 3.80 (s, 3H), 3.00-2.87 (m, 2H), 2.65-2.40 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
EXAMPLE 45 (16) 3-Benzylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2349] 2020
[2350] TLC: Rf 0.39 (hexane:ethyl acetate=1:1);
[2351] NMR (CDCl3): &dgr; 3.89 (dd, J=15.0 Hz, 9.3 Hz, 1H), 3.98 (d, J=14.0 Hz, 1H), 4.03 (dd, J=15.0 Hz, 3.6 Hz, 1H), 4.31 (d, J=14.0 Hz, 1H), 4.91 (dd, J=9.3, Hz, 3.6 Hz, 1H), 7.21-7.35 (m, 5H), 7.62-7.71 (m, 2H), 7.80-7.90 (m, 2H).
EXAMPLE 45 (17) 3-(3,4-Dichlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2352] 2021
[2353] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[2354] NMR (DMSO-d6): &dgr; 7.98 (d, J=2.1 Hz, 1H), 7.75-7.89 (m, 5H), 7.63 (dd, J=8.4, 2.1 Hz, 1H), 5.91 (dd, J=8.0, 4.4 Hz, 1H), 4.04 (dd, J=15.4, 8.0 Hz, 1H), 3.95 (dd, J=15.4, 4.4 Hz,1H).
EXAMPLE 45 (18) 3-(4-Nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2355] 2022
[2356] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);
[2357] NMR (DMSO-d6): &dgr; 8.41 (d, J=8.8 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.76-7.85 (m, 4H), 5.97 (dd, J=9.0, 3.2 Hz, 1H), 4.04 (dd, J=15.4, 9.0 Hz, 1H), 3.90 (dd, J=15.4, 3.2 Hz,1H).
EXAMPLE 45 (19) 5-Hydroxymethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2358] 2023
[2359] TLC: Rf 0.51 (ethyl acetate);
[2360] NMR (DMSO-d6): &dgr; 7.80-7.72 (m, 4H), 7.64-7.51 (m, 3H), 5.66 (dd, J=8.5, 1.5 Hz, 1H), 5.43 (t, J=5.5 Hz, 1H), 4.52 (d, J=5.5 Hz, 1H), 4.13 (dd, J=15.0,8.5Hz, 1H), 4.00 (dd, J=15.0, 1.5 Hz, 1H), 3.58 (s, 3H).
EXAMPLE 45 (20) 4-Hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2361] 2024
[2362] TLC: Rf 0.54 (chloroform:methanol=9:1);
[2363] NMR (CDCl3): &dgr; 7.84 (d, J=7.5 Hz, 1H), 7.72-7.63 (m, 2H), 7.62-7.53 (m, 3H), 7.51-7.44 (m, 2H), 5.53 (d, J=9.3 Hz, 1H), 5.08 (d, J=13.5 Hz, 1H), 5.01 (d, J=13.5 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H), 3.75 (dd, J=15.0, 9.3 Hz, 1H), 3.00-1.80 (br, 1H).
EXAMPLE 45 (21) 6-Fluoro-3-phenylsuifonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2364] 2025
[2365] TLC: Rf 0.40 (ethyl acetate:hexane=1:1);
[2366] NMR (DMSO-d6): &dgr; 7.85-7.58 (m, 8H), 5.77 (dd, J=9.6 Hz, 2.7 Hz,1H), 4.07 (dd, J=15.6 Hz, 9.6 Hz, 1H), 3.87 (dd, J=15.6 Hz, 2.7 Hz, 1H).
EXAMPLE 45 (22) 4-Fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2367] 2026
[2368] TLC: Rf 0.29 (ethyl acetate:hexane=1:1);
[2369] NMR (DMSO-d6): &dgr; 7.83-7.57 (m, 8H), 5.81 (dd, J=9.0 Hz, 1.5 Hz, 1H), 4.09 (dd, J=15.6 Hz, 1.5 Hz, 1H), 3.99 (dd, J=15.6 Hz, 9.0 Hz, 1H).
EXAMPLE 46 5-Methoxycarbonyl-4-ethoxybenzo[b]thiophene[2370] 2027
[2371] By the same procedure as described in Example 18 using 5-methoxycarbonyl-4-hydroxybenzo[b]thiophene instead of the compound prepared in Example 9 (12) and ethyl iodide instead of 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained.
[2372] TLC: Rf 0.44 (hexane:ethyl acetate=4:1); NMR (CDCl3): &dgr; 7.82 (d, J=8 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.43 (d, J=6 Hz, 1H), 4.21 (q, J=7 Hz, 2H), 3.95 (s, 3H), 1.49 (t, J=7 Hz, 3H).
EXAMPLE 47 5-Carboxy-4-ethoxybenzo[b]thiophene[2373] 2028
[2374] To the compound prepared in Example 46 (1.11 g), were added methanol (10 ml) and a 2N aqueous solution of sodium hydroxide (5.0 ml). The mixture was refluxed for 30 minutes. The reaction mixture was concentrated. The residue was acidified by addition of 1 N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (1.02 g) having the following physical data.
[2375] TLC: Rf 0.06 (hexane:ethyl acetate 4:1);
[2376] NMR (CDCl3): &dgr; 8.09 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.52 (d, J=6 Hz, 1H), 7.49 (d, J=6 Hz, 1H), 4.44 (q, J=7 Hz, 2H), 1.58 (t, J=7 Hz, 3H).
EXAMPLE 48 5-Benzyloxycarbonyl-4-ethoxybenzo[b]thiophene[2377] 2029
[2378] By the same procedure as described in Example 32 using the compound prepared in Example 47 instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and benzyl bromide, the compound having the following physical data was obtained.
[2379] TLC: Rf 0.46 (hexane:ethyl acetate=4:1);
[2380] NMR (CDCl3): &dgr; 7.85 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.56-7.26 (m, 7H), 5.40 (s, 2H), 4.15 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H).
EXAMPLE 49 5-Benzyloxycarbonyl-4-ethoxy-1,1-dioxidebenzo[b]thiophene[2381] 2030
[2382] By the same procedure as described in 3 using the compound prepared in Example 48 instead of the compound prepared in Example 1, the compound having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE™ as an oxidizer).
[2383] TLC: Rf 0.10 (hexane:ethyl acetate=4:1);
[2384] NMR (CDCl3): &dgr; 7.99 (d, J=8 Hz, 1H), 7.60-7.30 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, 2H) 4.03 (q, J=7 Hz, 2H), 131 (t, J=7 Hz, 3H.
EXAMPLES 50˜50 (2)[2385] By the same procedure as described in Example 46→Example 47→Example 48→Example 49 using a corresponding halide compound instead of ethyl iodide, the following compounds of the present invention were obtained.
EXAMPLE 50 5-Benzyloxycarbonyl-4-hexyloxy-1,1-dioxidebenzo[b]thiophene[2386] 2031
[2387] TLC: Rf 0.22 (hexane:ethyl acetate=4:1); (s, 2H), 3.93 (t, J=7 Hz, 2H), 7.55-7.30 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, 2H), 3.93 (t, J=7 Hz, 2H), 1.80-1.45 (m, 2H), 1.45-1.10 (m, 6H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 50 (1) 5-Benzyloxycarbonyl-4-butoxy-1,1-dioxidebenzo[b]thiophene[2388] 2032
[2389] TLC: Rf 0.24 (hexane:ethyl acetate=4:1);
[2390] NMR (CDCl3): &dgr; 7.98 (d, J=8 Hz, 1H), 7.58-7.38 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.33 (s, 2H), 3.94 (t, J=7 Hz, 2H), 1.78-1.50 (m, 2H), 1.50-1.20 (m, 2H), 0.92 (t, J=7 Hz, 3H).
EXAMPLE 50 (2) 5-Benzyloxycarbonyl-4-octyloxy-1,1-dioxidebenzo[b]thiophene[2391] 2033
[2392] TLC: Rf 0.33 (hexane:ethyl acetate=4:1);
[2393] NMR (CDCl3): &dgr; 7.97 (d, J=8 Hz, 1H), 7.60-7.25 (m, 7H), 6.72 (d, J=7 Hz, 1H), 5.38 (s, 2H), 3.92 (t, J=7 Hz, 2H), 1.82-1.45 (m, 2H), 1.45-1.05 (m, 10H), 0.89 (t, J=7 Hz, 3H).
EXAMPLES 51˜51 (3)[2394] By the same procedure as described in Example 27 using the compounds prepared in Example 49 and Examples 50˜50 (2) instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained.
EXAMPLE 51 5-Benzyloxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2395] 2034
[2396] TLC: Rf 0.41 (chloroform hexane:methanol=5:5:1);
[2397] NMR (CDCl3): &dgr; 7.90 (d, J=8 Hz, 1H), 7.78-7.66 (m, 2H), 7.64-7.30 (m, 9H), 5.34 (s, 2H), 5.17 (d, J=9 Hz, 1H), 4.30 (dd, J=1, 15 Hz, 1H), 4.10-3.60 (m, 3H), 1.13 (t, J=7 Hz, 3H).
EXAMPLE 51 (1) 5-benzyloxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2398] 2035
[2399] TLC: Rf 0.45 (chloroform:hexane:methanol=5:5:1);
[2400] NMR (CDCl3): &dgr; 7.88 (d, J=8 Hz, 1H), 7.78-7.64 (m, 2H), 7.60-7.28 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.00-3.46 (m, 3H), 1.75-1.05 (m, 8H), 0.91 (t, J=7 Hz, 3H).
EXAMPLE 51 (2) 5-Benzyloxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2401] 2036
[2402] TLC: Rf 0.43 (chloroform:hexane:methanol=5:5:1);
[2403] NMR (CDCl3): &dgr; 7.88 (d, J=8 Hz, 1H), 7.78-7.64 (m, 2H), 7.60-7.28 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.02-3.48 (m, 3H), 1.70-1.10 (m, 4H), 0.87 (t, J=7 Hz, 3H).
EXAMPLE 51 (3) 5-Benzyloxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2404] 2037
[2405] TLC: Rf 0.47 (chloroform:hexane:methanol=5:5:1);
[2406] NMR (CDCl3): &dgr; 7.88 (d, J=8 Hz, 1H), 7.76-7.64 (m, 2H), 7.60-7.26 (m, 9H), 5.34 (s, 2H), 5.15 (d, J=9 Hz, 1H), 4.32 (dd, J=1, 15 Hz, 1H), 4.00-3.46 (m, 3H), 1.75-1.05 (m, 12H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 52 5-Carboxy-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2407] 2038
[2408] To a solution of the compound prepared in Example 51 (670 mg) in ethyl acetate (50 ml). Thereto was added 10% palladium carbon (220 mg). Under an atmosphere of hydrogen the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite. The filtrate was washed by ethyl acetate and concentrated. The residue was dissolved in ethyl acetate under heating and was recrystallized by addition of hexane (5 ml). The crystal was separated by filtration and dried to give the compound of the present invention (471 mg) having the following physical data.
[2409] TLC: Rf 0.21 (chloroform:acetic acid=10:1);
[2410] NMR (CDCl3+acetone-d6): &dgr; 8.02 (d, J=8 Hz, 1H), 7.86-7.72 (m, 2H), 7.72-7.58 (m, 1H), 7.58-7.32 (m, 3H), 5.33 (d, J=9 Hz, 1H), 4.30 (d, J=15 Hz, 1H), 4.24-4.06 (m, 1H), 4.20 (bs, 1H), 4.02-3. 74 (m, 2H), 1.25 (t, J=7 Hz, 3H).
EXAMPLES 52 (1)˜52 (3)[2411] By the same procedure as described in Example 52 using the compounds prepared in Examples 51 (1)˜51 (3) instead of Example 51, the following compounds were obtained.
EXAMPLE 52 (1) 5-Carboxy-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2412] 2039
[2413] TLC: Rf 0.38 (chloroform:acetic acid=10:1);
[2414] NMR (CDCl3+acetone-d6): &dgr; 8.00 (d, J=8 Hz, 1H), 7.88-7.72 (m, 2H), 7.72-7.56 (m, 1H), 7.56-7.34 (m, 3H), 5.32 (d, J=9 Hz,1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.20 (brs, H), 4.14 (dt, J=7, 9 Hz, 1H), 4.02-3.66 (m, 2H), 1.80-1.45 (m, 2H), 1.45-1.12 (m, 6H), 0.91 (t, J=7 Hz, 3H).
EXAMPLE 52 (2) 5-Carboxy-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2415] 2040
[2416] TLC: Rf 0.34 (chloroform:acetic acid=10:1);
[2417] NMR (CDCl3+acetone-d6): &dgr; 8.00 (d, J=8 Hz, 1H), 7.86-7.72 (m, 2H), 7.72-7.56 (m, 1H), 7.56-7.34 (m, 3H), 5.32 (d, J=9 Hz,1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.20 (brs, 1H), 4.15 (dt, J=7,9 Hz, 1H), 4.00-3.66 (m, 2H), 1.74-1.48 (m, 2H), 1.48-1.20 (m, 2H), 0.92 (t, J=7 Hz, 3H).
EXAMPLE 52 (3) 5-Carboxy-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2418] 2041
[2419] TLC: Rf 0.40 (chloroform:acetic acid 10:1);
[2420] NMR (CDCl3+acetone-d6): &dgr; 8.00 (d, J=8 Hz, 1H), 7.84-7.72 (m, 2H), 7.72-7.57 (m, 1H), 7.57-7.34 (m, 3H), 5.33 (d, J=9 Hz, 1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.13 (dt, J=7, 9 Hz, 1H), 4.10 (brs,1 H ), 4.00-3.66 (m, 2H), 1.74-1.43 (m, 2H), 1.43-1.05 (m, 10H), 0.90 (t, J=7 Hz, 3H).
EXAMPLES 53˜53 (3)[2421] By the same procedure as described in Example 32 using the compounds prepared in Examples 52˜52 (3) instead of 4-hydroxy 1,1-dioxidebenzo[b]thiophene and corresponding alcohol derivatives instead of 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained.
EXAMPLE 53 5-Methoxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2422] 2042
[2423] TLC: Rf 0.35 (chloroform:hexane:methanol=5:5:1);
[2424] NMR (CDCl3): &dgr; 6 7.91 (d, J=8 Hz, 1H), 7.84-7.72 (m, 2H), 7.72-7.57 (m, 1H), 7.57-7.32 (m, 3H), 5.21 (d, J=9 Hz,1H), 4.28 (dd, J=1,15 Hz,1H), 4.20-4.00 (m, 1H), 3.93 (s, 3H), 3.95-3.68 (m, 2H), 1.26 (t, J=7 Hz, 3H).
EXAMPLE 53 (1) 5-Methoxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2425] 2043
[2426] TLC: Rf 0.42 (chloroform:hexane:methanol=5:5:1);
[2427] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.82-7.69 (m, 2H), 7.69-7.55 (m, 1H), 7.55-7.30 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.30 (d, J=15 Hz, 1H), 4.08 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.95-3.55 (m, 2H), 1.80-1.46 (m, 2H), 1.46-1.15 (m, 6H), 0.92 (t, J=7 Hz, 3H).
EXAMPLE 53 (2) 5-Methoxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2428] 2044
[2429] TLC: Rf 0.37 (chloroform:hexane:methanol=5:5:1);
[2430] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.82-7.68 (m, 2H), 7.68-7.55 (m, 1H), 7.55-7.34 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.31 (dd, J=1, 15 Hz, 1H), 4.05 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.88-3.60 (m, 2H), 1.80-1.50 (m, 2H), 1.50-1.18 (m, 2H), 0.94 (t, J=7 Hz, 3H).
EXAMPLE 53 (3) 5-Methoxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2431] 2045
[2432] TLC: Rf 0.44 (chloroform:hexane:methanol=5:5:1);
[2433] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.80-7.69 (m, 2H), 7.69-7.55 (m, 1H), 7.55-7.34 (m, 3H), 5.19 (d, J=9 Hz, 1H), 4.30 (dd, J=1,15 Hz, 1H), 4.06 (dt, J=7, 9 Hz, 1H), 3.93 (s, 3H), 3.90-3.58 (m, 2H), 1.80-1.45 (m, 2H), 1.45-1.10 (m, 10H), 0.90 (t, J=7 Hz, 3H).
EXAMPLES 54˜54 (19)[2434] By the same procedure as described in Example 28 using the compounds prepared in Examples 52˜52 (3) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivatives corresponding to (pyridin-3-ylmethyl)amine, the following compounds of the present invention were obtained.
EXAMPLE 54 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2435] 2046
[2436] TLC: Rf 0.73 (chloroform:methanol=5:1);
[2437] NMR (CDCl3): &dgr; 7.90 (d, J=8 Hz, 1H), 7.78-7.15 (m, 10H), 5.33 and 5.19 (each d, J=9 Hz, total 1H), 4.40-3.50 (m, 6H), 3.40-2.25 (m, 10H), 1.30-1.10 (m, 3H).
EXAMPLE 54 (1) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2438] 2047
[2439] TLC: Rf 0.75 (chloroform:methanol=5:1);
[2440] NMR (CDCl3): &dgr; 7.90 (d, J=8 Hz, 1H), 7.80-6.85 (m, 10H), 5.33 and 5.21 (each d, J=9 Hz, total 1H), 4.45-3.55 (m, 6H), 3.50-2.80 (m, 6H), 1.25 (t, J=7 Hz, 3H).
EXAMPLE 54 (2) 5-(2-Dimethylaminoethyl)carbamoyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2441] 2048
[2442] TLC: Rf 0.34 (chloroform:methanol 5:1);
[2443] NMR (CDCl3): &dgr; 8.24 and 8.11 (each d, J=8 Hz, total 1H), 8.00-7.15 (m, 7H), 5.15 (d, J=9 Hz, 1H), 4.50-3.30 (m, 6H), 2.54 (t, J=7 Hz, 2H), 2.32 (s, 6H), 1.45-1.20 (m, 3H).
EXAMPLE 54 (3) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2444] 2049
[2445] TLC: Rf 0.19 (ethyl acetate:hexane=2:1);
[2446] NMR (CDCl3): &dgr; 7.87 (d, J=8 Hz, 1H), 7.80-7.20 (m, 6H), 5.32 and 5.20 (each d, J=9 Hz, total 1H), 4.40-2.90 (m, 8H), 2.10-1.00 (m, 11H).
EXAMPLE 54 (4) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2447] 2050
[2448] TLC: Rf 0.40 (ethyl acetate:hexane=2:1);
[2449] NMR (CDCl3): &dgr; 8.29 (d, J=8 Hz, 1H), 8.05-6.90 (m, 10H), 5.38-5.10 (m, 1H), 4.50-3.40 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.40-1.00 (m, 3H).
EXAMPLE 54 (5) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2450] 2051
[2451] TLC: Rf 0.57 (chloroform:methanol=10:1);
[2452] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.76-7.20 (m, 10H), 5.30 and 5.17 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.20-3.50 (m, 5H), 3.50-2.80 (m, 4H), 280-2.20 (m, 6H), 1.90-1.05 (m, 8H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 54 (6) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene[2453] 2052
[2454] TLC: Rf 0.66 (chloroform:methanol 10:1);
[2455] NMR (DMSO-d6): &dgr; 8.31 (s, 1H), 8.00-6.95 (m, 10H), 5.66 (d, J=9 Hz, 1H), 4.32 (d, J=15 Hz, 1H), 4.22-2.70 (m, 11H), 1.60-1.02 (m, 8H), 0.87 (t, J=7 Hz, 3H).
EXAMPLE 54 (7) 5-(2-Dimethylaminoethyl)carbamoyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2456] 2053
[2457] TLC: Rf 0.23 (chloroform:methanol=10:1);
[2458] NMR (CDCl3): &dgr; 8.21 and 8.07 (each d, J=8 Hz, total 1H), 7.90-7.10 (m, 7H), 5.13 (d, J=9 Hz,1H), 4.32 (d, J=15 Hz, 1H), 4.25-3.35 (m, 5H), 2.56 and 2.57 (each t, J=6 Hz, total 2H), 2.33 (s, 6H), 2.05-1.10 (m, 8H), 0.92 (t, J=7 Hz, 3H).
EXAMPLE 54 (8) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2459] 2054
[2460] TLC: Rf 0.23 (hexane:ethyl acetate 1:1);
[2461] NMR (CDCl3): &dgr; 7.86 (d, J=8 Hz, 1lH), 7.78-7.20 (m, 6H), 5.30 and 5.18 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.35-3.00 (m, 7H), 2.10-1.10 (m, 16H), 0.91 (t, J=7 Hz, 3H).
EXAMPLE 54 (9) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2462] 2055
[2463] TLC: Rf 0.39 (hexane:ethyl acetate=1:1);
[2464] NMR (CDCl3) &dgr; 8.29 (d, J=8 Hz, 1H), 8.10-6.80 (m, lIOH), 5.40-5.05 (m, 1H), 4.50-3.35 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.90-0.95 (m, 8H), 0.95-0.75 (m, 3H).
EXAMPLE 54 (10) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2465] 2056
[2466] TLC: Rf 0.56 (chloroform:methanol=10:1);
[2467] NMR (CDCl3): &dgr;7.88 (d, J=8 Hz, 1H), 7.80-7.00 (m, 10H), 5.30 and 5.18 (each d, J=9 Hz, total 1H), 4.40-3.45 (m, 6H), 3.45-2.80 (m, 4H), 2.80-2.15 (m, 6H), 2.00-1.10 (m, 4H), 0.97 and 0.91 (each t, J=7 Hz, total 3H).
EXAMPLE 54 (11) 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2468] 2057
[2469] TLC: Rf 0.65 (chloroform:methanol=10:1);
[2470] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.80-7.17 (m, 8H), 7.17-6.85 (m, 2H), 5.31 and 5.19 (each d, J=9 Hz, total 1H), 4.40-3.55 (m, 6H), 3.55-2.70 (m, 6H), 2.00-1.15 (m, 4H), 0.99 and 0.94 (each t, J=7 Hz, total 3H).
EXAMPLE 54 (12) 5-(2-Dimethylamino ethyl)carbamoyl-4-butoxy-3-phenyl sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2471] 2058
[2472] TLC: Rf 0.21 (chloroform:methanol=10:1);
[2473] NMR (CDCl3): &dgr; 8.08 (d, J=8 Hz, 1H), 7.85-7.35 (m, 6H), 7.25 (broad peak, 1H), 5.13 (d, J=9 Hz, 1H), 4.32 (d, J=15 Hz, 1H), 4.05-3.66 (m, 3H), 3.66-3.35 (m, 2H), 2.52 (t, J=7 Hz, 2H), 2.3 1 (s, 6H), 1.90-1.15 (m, 4H), 0.96 (t, J=7 Hz, 3H).
EXAMPLE 54 (13) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2474] 2059
[2475] TLC: Rf 0.19 (ethyl acetate:hexane=1:1);
[2476] NMR (CDCl3). &dgr; 7.85 (d, J=8 Hz, 1H), 7.76-7.20 (m, 6H), 5.29 and 5.18 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.25-3.60 (m, 4H), 3.60-3.00 (m, 3H), 2.10-1.10 (m, 12H), 0.96 and 0.92 (each t, J=7 Hz, total 3H).
EXAMPLE 54 (14) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2477] 2060
[2478] TLC: Rf 0.31 (ethyl acetate:hexane=1:1);
[2479] NMR (CDCl3): &dgr; 8.29 (d, J=8 Hz, 1H), 8.05-7.42 (m, 6H), 7.42-6.95 (m, 4H), 5.36-5.06 (m, 1H), 4.50-3.40 (m, 6H), 3.16 (t, J=7 Hz), 1.90-1.05 (m, 4H), 0.81 (t, J=7 Hz, 3H).
EXAMPLE 54 (15) 5-(4-(2-(2-Trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2480] 2061
[2481] TLC: Rf 0.66 (chloroform:methanol=10:1);
[2482] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.80-7.20 (m, 10H), 5.30 and 5.17 (each d, J=9 Hz, total 1H), 4.25 (d, J=15 Hz, 1H), 4.30-3.55 (m, 5H), 3.55-2.80 (m, 4H), 2.80-2.25 (m, 6H), 1.90-1.05 (m, 12H), 0.88 (t, J=7 Hz, 3H).
EXAMPLE 54 (16)[2483] 5-(4-(2-Chlorophenyl)piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2062
[2484] TLC: Rf 0.74 (chloroform:methanol 10:1);
[2485] NMR (CDCl3): &dgr; 7.89 (d, J=8 Hz, 1H), 7.82-6.85 (m, 10H), 5.31 and 5.19 (each d, J=9 Hz, total 1H), 4.38-2.70 (m, 12H), 1.90-1.05 (m, 12H), 0.89 (t, J=7 Hz, 3H).
EXAMPLE 54 (17) 5-(2-Dimethylaminoethyl)carbamoyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2486] 2063
[2487] TLC: Rf 0.34 (chloroform:methanol=10:1);
[2488] NMR (CDCl3): &dgr; 7.99 (d, J=8 Hz, 1H), 7.92-7.10 (m, 7H), 5.30-5.00 (m, 1H), 4.40-3.45 (m, 6H), 2.70 (t, J=6 Hz, 2H), 2.46 (s, 6H), 1.95-1.05 (m, 12H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 54 (18) 5-(2,3,4,5,6,7-Hexahydro-1H-azepin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2489] 2064
[2490] TLC: Rf 0.26 (hexane:ethyl acetate 1:1);
[2491] NMR (CDCl3): &dgr; 7.85 (d, J=8 Hz, 1H), 7.88-7.15 (m, 6H), 5.29 and 5.18 (each d, J=9 Hz, total 1H), 4.40-3.00 (m, 8H), 2.10-1.05 (m, 20H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 54 (19) 5-(2,3-Dihydroindol-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2492] 2065
[2493] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[2494] NMR (CDCl3): &dgr; 8.29 (d, J=8 Hz, 1H), 8.10-6.80 (m, 10H), 5.40-5.05 (m, 1H), 4.60-3.40 (m, 6H), 3.16 (t, J=8 Hz, 2H), 1.90-1.00 (m, 12H), 0.85 (t, J=7 Hz, 3H).
EXAMPLE 55 5-Hydroxy-4-formylbenzo[b]thiophene[2495] 2066
[2496] To a solution of 5-hydroxybenzo[b]thiophene (3.0 g) in methylene chloride (60 ml), were added at 0° C. dichloromethyl methyl ether (4.52 ml) and titanium tetrachloride (5.48 ml) dropwise. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto ice-water. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (methylene chloride) to give the compound of the present invention (1.50 g) having the following physical data.
[2497] TLC: Rf 0.69 (hexane:ethyl acetate=2:1);
[2498] NMR (CDCl3): &dgr; 11.97 (s, 1H), 10.55 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H).
EXAMPLE 56 5-Benzyloxy-4-formylbenzo[b]thiophene[2499] 2067
[2500] By the same procedure as described in Example 18 using the compound prepared in Example 55 instead of the compound prepared in Example 9 (12) and benzylbromide instead of 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained.
[2501] TLC: Rf 0.65 (hexane:ethyl acetate=2:1);
[2502] NMR (CDCl3): &dgr; 10.81 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.55-7.30 (m, 5H), 7.15 (d, J=8.8 Hz, 1H), 5.28 (s, 2H).
EXAMPLE 57 5-Benzyloxy-4-hydroxymethylbenzo[b]thiophene[2503] 2068
[2504] To a solution of the compound prepared in Example 56 (1.24 g) in methylene chloride (9.0 ml), were added sodium borohydride (246 mg) and methanol, (3.0 ml). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto 1 N hydrochloric acid and was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with chromatography on silica gel (hexane:ethyl acetate=4:1) to give the compound of the present invention (1.25 g) having the following physical data.
[2505] TLC: Rf 0.40 (hexane:ethyl acetate=2:1);
[2506] NMR (CDCl3): &dgr; 7.76 (d, J=8.8 Hz, 1H), 7.54-7.28 (m, 7H), 7.12 (d, J=8.8 Hz, 1H), 5.20 (s, 2H), 5.04 (br-s, 2H), 2.30-2.12 (br, 1H).
EXAMPLE 58 5-Benzyloxy-4-hydroxymethyl-1,1-dioxidebenzo[b]thiophene[2507] 2069
[2508] By the same procedure as described in Example 3 using the compound prepared in Example 57 instead of the compound prepared in Example 1, the compound having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer.).
[2509] TLC: Rf 0.43 (hexane:ethyl acetate=1:1);
[2510] NMR (CDCl3): &dgr; 7.61 (d, J=7.0 Hz,1H), 7.56 (d, J=7.0 Hz, 1H), 7.48-7.34 (m, 5H), 7.02 (d, J=8.4 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 5.18 (s, 2H), 4.84 (brs, 2H), 2.26-2.10 (br, 1H).
EXAMPLE 59 5-Benzyloxy-4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2511] 2070
[2512] By the same procedure as described in Example 1 using the compound prepared in Example 58 instead of 1,1-dioxidebenzo[b]thiophene, and thiophenol, the compound of the present invention having the following physical data was obtained.
[2513] TLC: Rf 0.60 (chloroform:ethyl acetate=19:1);
[2514] NMR (CDCl3): &dgr; 7.67 (d, J=8.4 Hz, 1H), 7.57-7.48 (m, 2H), 7.46-7.32 (m, 8H), 7.15, (d, J=8.4 Hz, 1H), 5.24 (s, 2H), 5.19 (dd, J=6.6, 1.8 Hz, 1H), 4.99 (d, J=6.0 Hz, 2H), 3.71 (dd, J=14.0, 6.6 Hz, 1H), 3.59 (dd, J=14.0, 1.8 Hz, 1H), 2.59 (t, J=6.0 Hz,1H).
EXAMPLE 60 5-Benzyloxy-4-bromomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenz[b]thiophene[2515] 2071
[2516] To a solution of the compound prepared in Example 59 (1.45 g) in methylene chloride (15 ml), was added triphenylphosphine (1.38 g) and carbon tetrabromide (1.74 g). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention having the following physical data.
[2517] TLC: Rf 0.76 (hexane:ethyl acetate=1:1); NMR (CDCl3): &dgr; 7.66 (d, J=8.8 Hz, 1H), 7.60-7.51 (m, 2H), 7.50-7.30 (m, 8H), 7.12 (d, J=8.8 Hz, 1H), 5.27 (s, 2H), 5.15 (dd, J=6.8, 1.6 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.94 (d, J=10 Hz, 1H), 3.74 (dd, J=13.8, 6.8 Hz, 1H), 3.60 (dd, J=13.8,1.6 Hz, 1H).
EXAMPLE 61 5-Benzyloxy-4-aminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2518] 2072
[2519] To a solution of 28% aqueous ammonia solution (6.75 ml) in tetrahydrofuran (30 ml), were added a solution of the compound prepared in Example 60 (1.60 g) in tetrahydrofuran (30 ml) and potassium carbonate (700 mg) successively. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=20:1) to give the compound of the present invention (747 mg) having the following physical data.
[2520] TLC: Rf 0.05 (hexane:ethyl acetate=1:1);
[2521] NMR (CDCl3): &dgr; 7.63 (d, J=8.5 Hz, 1H), 7.58-7.48 (m, 2H), 7.46-7.28 (m, 8H), 7.14 (d, J=8.5 Hz, 1H), 5.23 (s, 2H), 5.13 (dd, J=6.4, 1.6 Hz, 1H), 4.12 (d, J=13.6 Hz, 1H), 4.02 (d, J=13.6 Hz, 1H), 3.70 (dd, J=14.0, 6.0 Hz, 1H), 3.59 (dd, J=14.0, 1.6 Hz, 1H).
EXAMPLE 62 5-Benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2522] 2073
[2523] To the solution of the compound prepared in Example 61 (735 mg) in tetrahydrofuran (12 ml) and water (3.0 ml), were added sodium bicarbonate (165 mg) and di-t-butyldicarbonate (430 mg) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water and was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the compound of the present invention (867 mg) having the following physical data.
[2524] TLC: Rf 0.73 (hexane:ethyl acetate=1:1);
[2525] NMR (CDCl3): &dgr; 7.70-7.56 (m, 3H), 7.48-7.30 (m, 8H), 7.12 (d, J=8.8 Hz, 1H), 5.66 (br-d, J=5.8 Hz, 1H), 5.22 (s, 2H), 5.20-4.88 (m, 2H), 4.25-4.10 (m, 1H), 3.71 (dd, J=14.0, 6.8 Hz, 1H), 3.56 (d, J=14.0 Hz, 1H), 1.41 (s, 9H).
EXAMPLE 63 5-Benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2526] 2074
[2527] By the same procedure as described in Example 3 using the compound prepared in Example 62 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer.).
[2528] TLC: Rf 0.31 (hexane:ethyl acetate=2:1);
[2529] NMR (CDCl3): &dgr; 7.83-7.76 (m, 2H), 7.71-7.64 (m, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.56-7.38 (m, 7H), 7.19 (d, J=8.7 Hz, 1H), 6.05 (brd, J=6.9 Hz, 1H), 5.27-5.15 (m, 1H), 5.25 (s, 2H), 5.10-4.95 (m, 1H), 4.27-4.16 (m, 1H), 3.81 (dd, J=15.3, 2.1 Hz, 1H), 3.74 (dd, J=15.3, 8.1, 1H), 1.37 (s, 9H).
EXAMPLE 64 5-Benzyloxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[2530] 2075
[2531] By the same procedure as described in Example 7 using the compound prepared in Example 63 instead of the compound prepared in Example 6 (8), the compound of the present invention having the following physical data was obtained.
[2532] TLC: Rf 0.43 (chloroform:methanol=9:1);
[2533] NMR (DMSO-d6): &dgr; 8.18 (brs, 3H), 7.86 (d, J=9.0 Hz, 1H), 7.83-7.75 (m, 3H), 7.67-7.48 (m, 5H), 7.47-7.33 (m, 3H), 6.37 (dd, J=6.0, 3.9 Hz, 1H), 5.41 (d, J=12.3 Hz, 1H), 5.33 (d, J=12.3 Hz, 1H), 4.44 (d, J=13.8 Hz, 1H), 4.24 (d, J=13.8 Hz, 1H), 3.90-3.76 (m, 2H).
EXAMPLE 65 5- Hydroxy-4-t-butoxycarbonylaminoethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2534] 2076
[2535] By the same procedure as described in Example 52 using the compound prepared in Example 63 instead of the compound prepared in Example 51, the compound of the present invention having the following physical data was obtained.
[2536] TLC: Rf 0.22 (hexane:ethyl acetate=1:1);
[2537] NMR (CDCl3): &dgr; 10.75 (s, 1H), 7.75-7.58 (m, 3H), 7.56-7.41 (m, 3H), 7.18 (d, J=8.6 Hz, 1H), 6.35-6.50 (m, 1H), 5.24-5.15 (m, 1H), 4.76-4.60 (m, 1H), 4.34 (dd, J=16.0, 5.4 Hz,1H), 3.86-3.66 (m, 2H), 1.37 (s, 9H).
EXAMPLES 66˜66 (1)[2538] By the same procedure as described in Example 29 using the compound prepared in Example 65 instead of 4-hydroxy-1,1-dioxidebenzo[b)thiophene and alcohol derivatives corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained.
EXAMPLE 66 5-Methoxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2539] 2077
[2540] TLC: Rf 0.28 (hexane:ethyl acetate=1:1);
[2541] NMR (CDCl3): &dgr; 7.86-7.75 (m, 2H), 7.74-7.47 (m, 4H), 7.14 (d, J=8.8 Hz, 1H), 6.10-6.00 (m, 1H), 5.32-5.18 (m, 1H), 5.10-4.92 (m, 1H), 4.25-4.10 (m, 1H), 4.00 (s, 3H), 3.85-3.65 (m, 2H), 1.38 (s, 9H).
EXAMPLE 66 (1) 5-(3-Phenylpropyl) oxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2542] 2078
[2543] TLC: Rf 0.51 (hexane:ethyl acetate=1:1);
[2544] NMR (CDCl3): &dgr; 7.87-7.73 (m, 2H), 7.73-7.40 (m, 6H), 7.40-7.16 (m, 3H), 7.07 (d, J=8.8 Hz, 1H), 6.55-6.30 (br, 1H), 6.07-5.95 (m, 1H), 5.26-5.12 (m, 1H), 5.10-4.90 (m, 1H), 4.20-4.05 (m, 2H), 3.86-3.64 (m, 2H), 2.86 (t, J=7.0 Hz, 2H), 2.33-2.15 (m, 2H), 1.38 (s, 9H).
EXAMPLES 67˜67(1)[2545] By the same procedure as described in Example 7 using the compounds prepared in Examples 66˜66 (1) instead of the compound prepared in Example 6 (8), the following compounds of the present invention were obtained.
EXAMPLE 67 5-Methoxy-4-aminomethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2546] 2079
[2547] TLC: Rf 0.19 (chloroform:methanol=4:1);
[2548] NMR (DMSO-d6): &dgr; 8.19 (brs, 3H), 7.89-7.76 (m, 4H), 7.68-7.60 (m, 2H), 7.47 (d, J=8.7 Hz, 1H), 6.39 (t, J=5.4 Hz, 1H), 4.47-4.28 (br, 1H), 4.25-4.08 (br, 1H), 3.98 (s, 3H), 3.82 (d, J=5.4 Hz, 2H).
EXAMPLE 67 (1) 5-(3-Phenylpropyl)oxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thibphene.hydrochloride[2549] 2080
[2550] TLC: Rf 0.43 (chloroform:methanol=9:1);
[2551] NMR (DMSO-d6): &dgr; 8.14 (brs, 3H), 7.86-7.76 (m, 4H), 7.68-7.61 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.34-7.27 (m, 4H), 7.25-7.15 (m, 1H), 6.45-6.34 (m, 1H), 4.47-4.13 (m, 4H), 3.89-3.75 (m, 2H), 2.86-2.73 (m, 2H), 2.22-2.08 (m, 2H).
EXAMPLE 68 5-Benzyloxy-4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2552] 2081
[2553] By the same procedure as described in Example 3 using the compound prepared in Example 59 instead of the compound prepared in Example 1 the compound of the present invention having the following physical data was obtained (with the proviso that 3-chloroperbenzoic acid was used instead of OXONE@ as an oxidizer).
[2554] TLC: Rf 0.25 (hexane:ethyl acetate=1:1); NMR (CDCl3): &dgr; 7.72-7.58 (m, 3H), 7.56-7.30 (m, 8H), 7.20 (d, J=8.8 Hz, 1H), 5.53 (dd, J=8.4,1.8Hz, 1H), 5.33 (d, J=11.8 Hz, 1H), 5.25 (d, J=11.8 Hz, 1H), 5.10-5.01 (m, 2H), 3.87 (dd, J=15.4,1.8 Hz, 1H), 3.75 (dd, J=15.4,1.8 Hz, 1H), 3.40-3.28 (m, 1H).
EXAMPLE 69 5-Benzyoxy-4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2555] 2082
[2556] To a solution of the compound prepared in Example 68 (444 mg) in methylene chloride (10 ml) were added pyridinium dichromate (564 mg) and magnesium sulfate (500 mg). The mixture was stirred at room temperature for 6 hours. The undissolved ingredients were filtered off. The filtrate was poured onto 1 N hydrochloric acid and was extracted by methylene chloride. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was washed by methanol and was dried. The obtained solid was dissolved in dimethylformamide (16 ml) and water (4.0 ml). Thereto, were added 2-methyl-2-butene (0.48 ml), sodium phosphate bishydrate (120 mg) and sodium hypochloric acid (358 mg). The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto 0.5 N hydrochloric acid and was extracted by ethyl acetate. The extract was concentrated. The residue was washed by ether to give the compound of the present invention (305 mg) having the following physical data.
[2557] TLC: Rf 0.17 (chloroform:methanol=9:1);
[2558] NMR (DMSO-d6): &dgr; 13.52 (s, 1H), 7.92-7.68 (m, 4H), 7.67-7.30 (m, 8H), 5.88 (d, J 9.0 Hz, 1H), 5.37 (s, 2H), 4.09 (dd, J=15.0, 9.0 Hz, 1H), 3.88 (d, J=15.0 Hz, 1H).
EXAMPLE 70 5-Benzyloxy-4-(pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2559] 2083
[2560] By the same procedure as described in Example 28 using the compound prepared in Example 69 instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and (pyridin-3-ylmethyl)amine, the compound of the present invention having the following physical data was obtained.
[2561] TLC: Rf 0.53 (chloroform:methanol=9:1);
[2562] NMR (DMSO-d6): &dgr; 9.05 (t, J=6.0 Hz, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz,1H), 7.85 (d, J=8.7 Hz, 1H), 7.80-7.72 (m, 3H), 7.65-7.55 (m, 4H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 3H), 7.15 (dd, J=8.1, 4.8 Hz, 1H), 5.96 (d, J=9.0 Hz, 1H), 5.29 (s, 2H), 4.63 (dd, J=15.0, 6.0 Hz,1H), 4.35 (dd, J=15.0, 6.0 Hz, 1H), 4.06 (dd, J=15.0,9.0 Hz, 1H), 3.87 (d, J=15.0 Hz, 1H).
EXAMPLE 71 5-Hydroxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2563] 2084
[2564] By the same procedure as described in Example 52 using the compound prepared in Example 70 instead of the compound prepared in Example 51, the compound of the present invention having the following physical data was obtained.
[2565] TLC: Rf 0.29 (chloroform:methanol=9:1);
[2566] NMR (DMSO-d6): &dgr; 11.70 (br, 1H), 9.10-8.90 (br, 1H), 8.66 (d, 1H), 8.44 (dd, 1H), 7.88-7.81 (m, 1H), 7.78-7.68 (m, 3H), 7.67-7.54 (m, 3H), 7.34 (dd, J=7.5, 4.8 Hz, 1H), 7.23 (d, J=8.7 Hz,1H), 6.14 (d, J=9.0 Hz, 1H), 4.67 (dd, J=15.3, 6.3 Hz, 1H), 4.39 (dd, J=15.3, 5.4 Hz, 1H), 4.02 (dd, J=15.0, 9.0 Hz, 1H), 3.84 (d, J=15.0 Hz, 1H).
EXAMPLES 72˜72 (31)[2567] By the same procedure as described in Example 28 using carboxylic acids corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and amine derivatives corresponding to (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salts by known methods, the following compounds of the present invention were obtained.
EXAMPLE 72 4-(1,1-Dimethyl-2-hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2568] 2085
[2569] TLC: Rf 0.64 (ethyl acetate);
[2570] NMR (DMSO-d6): &dgr; 8.05 (brs, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.63 (t, J=7.4 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 4.87 (t, J=5.8 Hz, 1H), 3.54 (d, J=5.8 Hz, 2H), 1.29 (s, 6H).
EXAMPLE 72 (1) 4-(2-Hydroxyethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2571] 2086
[2572] TLC: Rf 0.30 (ethyl acetate);
[2573] NMR (DMSO-d6): &dgr; 8.72 (t, J=5.6 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.88-7.80 (m, 2H), 7.66 (t, J=7.4 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 4.77 (t, J=5.6 Hz, 1H), 3.53 (q, J=5.6 Hz, 2H), 3.33 (q, J=5.6 Hz, 2H).
EXAMPLE 72 (2) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2574] 2087
[2575] TLC: Rf 0.45 (ethyl acetate:methanol=9:1);
[2576] NMR (CDCl3): &dgr; 7.76 (d, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.47 (dd, J=7.5, 1.2 Hz, 1H), 7.32 (dd, J=7.2, 1.2 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 4.26-4.19 (m, 1H), 4.03-3.96 (m,1H), 3.88-3.78 (m, 2H), 3.35 (br, 2H), 2.72-2.67 (m, 2H), 2.67-2.60 (m, 2H), 2.50-2.42 (m, 2H).
EXAMPLE 72 (3) 4-(N-Methyl-N-methoxycarbamoyl)-1,1-dioxidebenzo[b]thiophene[2577] 2088
[2578] TLC: Rf 0.22 (hexane:ethyl acetate=1:1);
[2579] NMR (CDCl3) &dgr; 7.78 (dt, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=7.8, 1.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.41 (dd, J=7.0, 1.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 3.49 (s, 3H), 3.40 (s, 3H).
EXAMPLE 72 (4) 4-(4-(Thiazol-2-ylsulfamoyl)phenyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2580] 2089
[2581] TLC: Rf 0.20 (chloroform:methanol 9:1);
[2582] NMR (CDCl3+DMSO-d6): &dgr; 10.71 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.90-7.67 (m, 6H), 7.67 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.94 (d, J=5 Hz, 1H), 6.52 (d, J=5 Hz, 1H), 5.30 (broad peak, 1H).
EXAMPLE 72 (5) 4-((1 R)-1-t-Butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2583] 2090
[2584] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[2585] NMR (CDCl3): &dgr; 7.95 (dd, J=7.2, 1.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.76 (dd, J=7.8, 1.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 4.64 (dd, J=8.4, 4.5 Hz, 1H), 2.36-2.25 (m, 1H), 1.51 (s, 9H), 1.02 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H).
EXAMPLE 72 (6) 6-(1-Benzylpiperidin-4-yl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2586] 2091
[2587] TLC: Rf 0.44 (ethyl acetate:methanol 4:1);
[2588] NMR (CDCl3): &dgr; 7.66 (s, 1H), 7.54 (s, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.40-7.20 (m, 5H), 6.73 (d, J=7.0 Hz, 1H), 6.40-6.20 (m, 1H), 4.10-3.90 (m, 1H), 3.97 (s, 3H), 3.53 (s, 2H), 3.00-2.80 (m, 2H), 2.30-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.70-1.50 (m, 2H).
EXAMPLE 72 (7) 6-(2-Diethylaminoethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2589] 2092
[2590] TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=14:4:1);
[2591] NMR (CDCl3): &dgr; 7.71 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=6.9 Hz, 1H), 7.10-7.00 (m,1H), 6.71 (d, J=6.9 Hz, 1H), 3.98 (s, 3H), 3.52 (q, J=5.5 Hz, 2H), 2.53 (t, J=5.5 Hz, 2H), 2.28 (s, 6H).
EXAMPLE 72 (8) 6-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2592] 2093
[2593] TLC: Rf 0.49 (ethyl acetate:methanol=4:1);
[2594] NMR (DMSO-d6): &dgr; 9.36 (t, J=6.0 Hz, 1H), 8.58 (s, 1H), 8.48 (d, J=4.5 Hz, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=7.8Hz, 1H), 7.64 (d, J=7.0Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 7.36 (dd, J=7.8, 4.5 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H), 3.99 (s, 3H).
EXAMPLE 72 (9) 5-(6-Dimethylaminohexyl)oxycarbonyl-1,1-dioxidebenzo[b]thiophene -hydrochloride[2595] 2094
[2596] TLC: Rf 0.16 (chloroform:methanol=9:1);
[2597] NMR (CDCl3): &dgr; 12.60-12.30 (br, 1H), 7.96 (d, J=7.4 Hz, 1H), 7.54-7.43 (m, 2H), 6.76 (d, J=7.2 Hz, 1H), 4.35 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 3.06-2.90 (m, 2H), 2.81 (s, 3H), 2.79 (s, 3H), 2.03-1.73 (m, 4H ), 1.57-1.35 (m, 4H).
EXAMPLE 72 (11) 4-(4-t-Butoxycarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2598] 2095
[2599] TLC: Rf 0.65 (methylene chloride:methanol 10:1);
[2600] NMR (CDCl3): &dgr; 7.78 (dd, J=7.2, 1.2 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.48 (dd, J=7.2, 1.2 Hz, 1H), 7.32 (d, J=6.9 Hz, 1H), 6.80 (d, J=6.9 Hz, 1H), 3.85-3.70 (m, 2H), 3.65-3.45 (m, 2H), 3.45-3.24 (m, 4H), 1.47 (s, 9H).
EXAMPLE 72 (11) 4-(Piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride[2601] 2096
[2602] TLC: Rf 0.13 (methylene chloride:methanol=10:1);
[2603] NMR (DMSO-d6): &dgr; 9.35 (bs, 2H), 7.96 (d, J=6.9 Hz, 1H), 7.80-7.73 (m, 2H), 7.60 (d, J=7.2 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 4.00-3.80 (m, 2H), 3.60-3.40 (m, 2H), 3.30-3.15 (m, 2H), 3.15-3.00 (m, 2H).
EXAMPLE 72 (12) 4-(4-(4-Methoxyphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2604] 2097
[2605] TLC: Rf 0.50 (methylene chloride:methanol=10:1);
[2606] NMR (DMSO-d6): &dgr; 7.97 (t, J=4.2 Hz, 1H), 7.71 (d, J=4.2 Hz, 2H), 7.58-7.43 (m, 2H), 7.54 (d, J=4.2 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 4.65-4.50 (m, 1H), 4.30-4.20 (m, 2H), 3.78 (s, 3H), 3.70-3.00 (m, 8H).
EXAMPLE 72 (13) 4-(4-(4-Phenylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2607] 2098
[2608] TLC: Rf 0.33 (ethyl acetate);
[2609] NMR (DMSO-d6): &dgr; 8.00-7.92 (m, 1H), 7.80-7.64 (m, 8H), 7.60-7.35 (m, 5H), 4.65-4.50 (m, 1H), 4.48-4.30 (m, 2H), 3.70-3.00 (m, 8H).
EXAMPLE 72 (14) 4-(4-(Naphthalen-1-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2610] 2099
[2611] TLC: Rf 0.70 (ethyl acetate);
[2612] NMR (DMSO-d6): &dgr; 8.42-7.30 (m, 1H), 8.13-7.77 (m, 4H), 7.76-7.40 (m, 7H), 4.93-4.76 (m, 2H), 4.66-4.53 (m, 1H), 3.64-3.00 (m, 8H).
EXAMPLE 72 (15) 4-(4-(4-Ethylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2613] 2100
[2614] TLC: Rf 0.40 (ethyl acetate);
[2615] NMR (DMSO-d6): &dgr; 7.98 (t, J=4.2 Hz, 1H), 7.71 (d, J=4.2 Hz, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 4.66-4.45 (m, 1H), 4.33-4.20 (m, 2H), 3.66-3.00 (m, 8H), 2.63 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
EXAMPLE 72 (16) 4-(4-(Naphthalen-2-ylcarbonylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride[2616] 2101
[2617] TLC: Rf 0.40 (ethyl acetate);
[2618] NMR (DMSO-d6): &dgr; 8.72 (s, 1H), 8.20-7.93 (m, 5H), 7.80-7.64 (m, 4H), 7.60 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 5.30-5.10 (m, 2H), 4.60-4.40 (m, 1H), 3.80-3.10 (m, 8H).
EXAMPLE 72 (17)[2619] 4-(4-(Pyridin-2-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.2hydrochloride 2102
[2620] TLC: Rf 0.46 (methylene chloride:methanol=10:1);
[2621] NMR (DMSO-d6): &dgr; 8.69 (d, J=5.1 Hz, 1H), 8.00-7.90 (m, 2H), 7.75-7.64 (m, 3H), 7.60-7.46 (m, 3H), 4.50 (s, 2H), 4.09-3.90 (m, 2H),3.67-3.59 (m, 2H), 3.48-3.35 (m, 2H), 3.33-3.20 (m, 2H).
EXAMPLE 72 (18) 4-(4-(Pyridin-3-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.2hydrochloride[2622] 2103
[2623] TLC: Rf 0.46 (methylene chloride:methanol=10:1);
[2624] NMR (DMSO-d6): &dgr; 8.90 (s, 1H), 8.80-8.73 (m, 1H), 8.36-8.30 (m, 1H), 7.98-7.92 (m, 1H), 7.80-7.66 (m, 3H), 7.57 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 4.50-3.00 (m, 10H).
EXAMPLE 72 (19) 4-(4-benzoylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2625] 2104
[2626] TLC: Rf 0.52 (methylene chloride:methanol=10:1);
[2627] NMR (CDCl3): &dgr; 7.79 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.53-7.36 (m, 6H), 7.34 (d, J=6.0 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.00-3.25 (m, 8H).
EXAMPLE 72 (20) 4-(4-(Furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2628] 2105
[2629] TLC: Rf 0.46 (methylene chloride:methanol=10:1);
[2630] NMR (CDCl3): &dgr; 7.80 (d, J=6.9 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.35 (d, J=6.9 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.81 (d, J=6.9 Hz, 1H), 6.52 (d, J=3.6 Hz, 1H), 4.06-3.36 (m, 8H).
EXAMPLE 72 (21) 4-(4-Benzylcarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2631] 2106
[2632] TLC: Rf 0.47 (methylene chloride:methanol=10:1);
[2633] NMR (CDCl3): &dgr; 7.77 (d, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.48-7.14 (m, 6H), 7.28 (d, J=7.2 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 3.86-3.00 (m, 10H).
EXAMPLE 72 (22) 4-(2-(pyrrolidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2634] 2107
[2635] TLC: Rf 0.26 (ethyl acetate:acetic acid:water=3:1:1);
[2636] NMR (CDCl3): &dgr; 8.00 (dd, J=7.5 Hz and 1 Hz, 1H), 7.79 (dt, J=7.5 Hz and 1 Hz, 1H), 7.72 (dd, J=7.5 Hz and 1 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 6.90 (broad s, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.55 (m, 2H ), 2.73 (t, J=6 Hz, 2H), 2.57 (m, 4H), 1.80 (m, 4H).
EXAMPLE 72 (23) 4-(3-(Pyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2637] 2108
[2638] TLC: Rf 0.19 (ethyl acetate acetic acid:water 3:1:1);
[2639] NMR (CDCl3): &dgr; 9.30 (broad s, 1H), 8.17 (d, J=7.5 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 3.58 (m, 2H), 2.76 (t, J=6 Hz, 2H), 2.5 9 (m, 4H), 2.00-1.70 (m, 6H).
EXAMPLE 72 (24) 4-(4-(2-Methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2640] 2109
[2641] TLC: Rf 0.64 (ethyl acetate:hexane=2:1);
[2642] NMR (DMSO-d6): &dgr; 7.97-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.57 (d, J=7.2 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.20-7.10 (m, 2H), 7.06-6.93 (m, 2H), 3.90-3.78 (m, 2H), 3.45-3.34 (m, 2H), 3.00-2.90 (m, 2H), 2.85-2.74 (m, 2H), 2.27 (s, 3H).
EXAMPLE 72 (25) 4-(4-(3-Methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2643] 2110
[2644] TLC: Rf 0.48 (ethyl acetate:hexane=2:1);
[2645] NMR (DMSO-d6): &dgr; 8.00-7.92 (m, 1H), 7.74-7.66 (m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.90-6.80 (m, 2H), 6.71 (d, J=7.8 Hz, 1H), 3.90-3.80(m, 2H), 3. 46-3.36 (m, 2H), 3.36-3.24 (m, 2H), 3.18-3.08 (m, 2H), 2.56 (s, 3H).
EXAMPLE 72 (26) 4-(4-(2-Fluorophenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2646] 2111
[2647] TLC: Rf 0.59 (ethyl acetate:hexane=2:1);
[2648] NMR (DMSO-d6): &dgr; 8.00-7.90 (m, 1H), 7.74-7.66 (m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.20-6.96 (m, 4H), 3.90-3.80 (m, 2H), 3.46-3.36 (m, 2H), 3.18-3.06 (m, 2H), 3.02-2.90 (m, 2H).
EXAMPLE 72 (27) 4-(4-(4-Fluorophenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2649] 2112
[2650] TLC: Rf 0.40 (ethyl acetate:hexane=2:1);
[2651] NMR (DMSO-d6): &dgr; 8.00-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.54 (d, J=6.9 Hz, 1H), 7.49 (d, J=6.9 Hz, 1H), 7.14-6.97 (m, 4H), 3.89-3.78 (m, 2H), 3.45-3.34 (m, 2H), 3.30-3.19 (m, 2H), 3.13-3.00 (m, 2H).
EXAMPLE 72 (28) 4-(4-(4-Methoxyphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2652] 2113
[2653] TLC: Rf 0.22 (ethyl acetate:hexane=2:1);
[2654] NMR (DMSO-d6): &dgr; 8.00-7.92 (m, 1H), 7.77-7.66 (m, 2H), 7.58 (d, J=6.9 Hz, 1H), 7.50 (d, J=6.9 Hz, 1H), 7.13-7.08 (m, 2H), 6.96-6.86 (m, 2H), 4.10-3.70 (m, 2H), 3.72 (s, 3H), 3.54-3.40 (m, 2H), 3.38-3.22 (m, 2H), 3.20-3.06 (m, 2H).
EXAMPLE 72 (29) 4-(4-(3-Trifluoromethylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene.hydrochloride[2655] 2114
[2656] TLC: Rf 0.47 (ethyl acetate:hexane=2:1);
[2657] NMR (DMSO-d6): &dgr; 7.98-7.93 (m, 1H), 7.74-7.67 (m, 2H), 7.56 (d, J=6.9 Hz, 1H), 7.49 (d, J=6.9 Hz, 1H), 7.48-7.40 (m, 1H), 7.27-7.16 (m, 2H), 7.14-7.07 (m, 1H), 3.88-3.67 (m, 2H), 3.46-3.34 (m, 4H), 3.27-3.18 (m, 2H).
EXAMPLE 72 (30) 4-((3R)-1-Benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2658] 2115
[2659] TLC: Rf 0.45 (chloroform:methanol=9:1);
[2660] NMR (CDCl3): &dgr; 7.92 (dd, J=1.0 Hz and 7.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.0 Hz and 7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.40-7.20 (m, 5H), 6.75 (d, J=7.0 Hz, 1H), 6.70 (m, 1H), 4.65 (m, 1H), 3.66 (s, 2H), 3.05-2.95 (m, 1H), 2.78 (dd, J=1.0 Hz and 10 Hz, 1H), 2.60 (dd, J=6.0 Hz and 10 Hz, 1H), 2.50-2.20 (m, 2H), 1.85-1.70 (m, 1H).
EXAMPLE 72 (31) 4-((3S)-1-Benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2661] 2116
[2662] TLC: Rf 0.45 (chloroform:methanol=9:1);
[2663] NMR (CDCl3): &dgr; 7.92 (dd, J=1.0 Hz and 7.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.0 Hz and 7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.40-7.20 (m, 5H), 6.75 (d, J=7.0 Hz, 1H), 6.70 (m, 1H), 4.65 (m, 1H), 3.66 (s, 2H), 3.05-2.95 (m, 1H), 2.78 (dd, J=1.0 Hz and 10 Hz, 1H), 2.60 (dd, J=6.0 Hz and 10 Hz, 1H), 2.50-2.20 (m, 2H), 1.85-1.70 (m, 1H).
EXAMPLES 73˜73 (29)[2664] By the same procedure as described in Example 18 using an alcohol derivative corresponding to the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, or by the same procedure as described in Example 29 using an alcohol derivative corresponding to 4-hydroxy-1,1-dioxidebenzo[b]thiophene and an alcohol derivative corresponding to 1-(3-hydroxypropyl)pyrrole, the following compounds of the present invention were obtained, with the proviso that when the compounds of the following Examples 73 (26)˜73 (29) were prepared by the same procedure as described in Example 18, an aqueous solution of sodium hydroxide was used instead of potassium carbonate.
EXAMPLE 73 5-Acetylmethyloxy-1,1-dioxidebenzo[b]thiophene[2665] 2117
[2666] TLC: Rf 0.25 (ethyl acetate:hexane:methylene chloride=1:1:1);
[2667] NMR (CDCl3): &dgr; 7.65 (d, J=8.2Hz, 1H), 7.15 (d, J=6.8Hz, 1H),6.92 (dd, J=8.2Hz, 2.2 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 4.64 (s, 2H), 2.30 (s, 3H).
EXAMPLE 73 (1) 5-Cyanomethyloxy-1,1-dioxidebenzo[b]thiophene[2668] 2118
[2669] TLC: Rf 0.36 (hexane:ethyl acetate=1:1);
[2670] NMR (CDCl3): &dgr; 7.72 (d, J=8.4 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 4.86 (s, 2H).
EXAMPLE 73 (2) 5-t-Butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2671] 2119
[2672] TLC: Rf 0.54 (hexane:ethyl acetate=1:1);
[2673] NMR (CDCl3): &dgr; 7.63, (d, J=8.4 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.73 (d, J=6.9 Hz, 1H), 4.58 (s, 2H), 1.49 (s, 9H).
EXAMPLE 73 (3) 5-(3-(Ethoxycarbonyl)propyloxy-1,1-dioxidebenzo[b]thiophene[2674] 2120
[2675] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[2676] NMR (CDCl3): &dgr; 7.61 (d, J=8.7 Hz, 1H), 7.12 (d, J=6.9 Hz, 1H), 6.94 (dd, J=8.7, 2. 0 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.71 (d, J=6.9 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 4.08 (t, J=6.6 Hz, 1H), 2.51 (t, J=6.6 Hz, 1H), 2.13 (quint, J=6.6 Hz, 1H), 1.26 (t, J 7.2 Hz, 3H).
EXAMPLE 73 (4) 5-(4-(Ethoxycarbonyl)butyl)oxy-1,1-dioxidebenzo[b]thiophene[2677] 2121
[2678] TLC: Rf 0.48 (hexane:ethyl acetate=1:1);
[2679] NMR (CDCl3): &dgr; 7.61 (dd, J=8.4, 0.9 Hz, 1H), 7.12 (dd, J=6.9, 0.9 Hz, 1H), 6.93 (dd, J=8.4,2.4Hz, 1H), 6.84 (d, J=2.4Hz, 1H), 6.71 (d, J=6.9Hz, 1H), 4.13 (q, J=7.0Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 2.39 (t, J=7.0 Hz, 2H), 1.88-1.80 (m, 4H), 1.26 (t, J=7.0 Hz, 3H).
EXAMPLE 73 (5) 4-(Pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2680] 2122
[2681] TLC: Rf 0.42 (ethyl acetate:methanol=9:1);
[2682] NMR (CDCl3): &dgr; 5.19 (s, 2H), 6.63 (d, J=7.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.0 Hz, 5.0 Hz, 1H), 7.45 (dd, J=7.0 Hz, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.75 (dt, J=8.0 Hz, 2.0 Hz, 1H), 8.64 (dd, J=5.0 Hz, 2.0 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H).
EXAMPLE 73 (6) 4-(Pyridin-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2683] 2123
[2684] TLC: Rf 0.16 (methylene chloride:ethyl acetate=1:1);
[2685] NMR (CDCl3): &dgr; 8.66 (d, J=6.0 Hz, 2H), 7.51 (dd, J=7.0, 1.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.36-7.31 (m, 3H), 7.03 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.0 Hz, 1H), 5.21 (s, 2H).
EXAMPLE 73 (7) 4-(4-Trifluoromethylphenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2686] 2124
[2687] TLC: Rf 0.67 (hexane:ethyl acetate=1:2);
[2688] NMR (CDCl3): &dgr; 7.70 (d, J=7.5 Hz, 2H), 7.60-7.30 (m, 5H), 7.10 (d, J=10 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 5.25 (s, 2H).
EXAMPLE 73 (8) 4-(3,5-Dimethylisoxazol-4-ylmethyl) oxy-1,1-dioxidebenzo[b]thiophene[2689] 2125
[2690] TLC: Rf 0.53 (hexane:ethyl acetate=1:2);
[2691] NMR (CDCl3): &dgr; 7.60-7.40 (m, 1H), 7.40-7.30 (m, 2H), 7.10 (d, J=7.5 Hz, 1H), 6.60 (d, J=7.5 Hz,1H), 4.90 (s, 2H), 2.40 (s, 3H), 2.30 (s, 3H).
EXAMPLE 73 (9) 4-(4-Methoxycarbonylphenylmethyl)oxy-1, -dioxidebenzo[b]thiophene[2692] 2126
[2693] TLC: Rf 0.58 (hexane:ethyl acetate=1:2);
[2694] NMR (CDCl3): &dgr; 8.10 (d, J=7.5 Hz, 2H), 7.55-7.30 (m, 5H), 7.10 (d, J=10 Hz, 1H), 6.65 (d, J=7.5 Hz,1H), 5.25 (s, 2H), 3.95 (s, 3H).
EXAMPLE 73 (10) 4-(Benzotriazol-1-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2695] 2127
[2696] TLC: Rf 0.62 (hexane:ethyl acetate 1:2);
[2697] NMR (CDCl3): &dgr; 8.20-8.10 (m, 1H), 7.70-7.30 (m, 7H), 6.65 (s, 2H), 6.60 (d, J=7.5 Hz, 1H).
EXAMPLE 73 (11) 4-(2,6-Dimethylphenyl)carbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene[2698] 2128
[2699] TLC: Rf 0.50 (hexane:ethyl acetate=1:2);
[2700] NMR (CDCl3): &dgr; 7.65-7.40 (m, 4H), 7.20-7.00 (m, 4H), 6.75 (d, J=7.5 Hz, 1H), 4.80 (s, 2H), 2.20 (s, 6H).
EXAMPLE 73 (12) 4-Trimethylsilylmethyloxy-1,1-dioxi debenzo[b]thiophene[2701] 2129
[2702] TLC: Rf 0.60 (hexane:ethyl acetate=1:1);
[2703] NMR (CDCl3): &dgr; 7.50-7.35 (m, 2H), 7.30-7.10 (m, 2H), 6.60 (d, J=7.5 Hz, 1H), 3.70 (s, 2H), 0.20 (s, 9H).
EXAMPLE 73 (13) 4-(Pyridin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2704] 2130
[2705] TLC: Rf 0.31 (hexane:ethyl acetate=1:2);
[2706] NMR (CDCl3): &dgr; 8.70-8.55 (m, 1H), 7.85-7.70 (m, 1H), 7.60-7.20 (m, 5H), 7.10 (d, J=7.5 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 5.35 (s, 2H).
EXAMPLE 73 (14) 4-(2-(Pyridin-3-ylcarbonyl)aminoethyl) oxy-1,1-dioxidebenzo[b]thiophene[2707] 2131
[2708] TLC: Rf 0.33 (ethyl acetate:methanol=9:1);
[2709] NMR (CDCl3): &dgr; 8.98 (dd, J=1.8, 0.9 Hz, 1H), 8.72 (dd, J=4.5, 1.8 Hz, 1H), 8.12 (d, J=8.0, 1.8 Hz, 1H), 7.49-7.42 (m, 2H), 7.28 (d, J=7.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.83 (br, 1H), 6.58 (d, J=7.0 Hz, 1H), 4.30 (t, J=5.4 Hz, 2H), 3.93 (q, J=5.4 Hz, 2H).
EXAMPLE 73 (15) 4-(3-(Pyridin-3-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene[2710] 2132
[2711] TLC: Rf 0.32 (ethyl acetate:methanol 10:1);
[2712] NMR (CDCl3+CD3OD): &dgr; 8.52-8.25 (m, 2H), 7.80-7.18 (m, 5H), 7.07 (d, J=8 Hz, 1H), 6.68 (d, J=7 Hz, 1H), 4.14 (t, J=7 Hz, 2H), 2.87 (t, J=7 Hz, 2H), 2.35-2.10 (m, 2H).
EXAMPLE 73 (16) 4-(2-(Pyridin-2-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene[2713] 2133
[2714] TLC: Rf 0.39 (ethyl acetate:methanol=10:1);
[2715] NMR (CDCl3): &dgr; 8.57 (d, J=5 Hz, 1H), 7.64 (dt, J=2, 7 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.35-6.98 (m, 5H), 6.56 (d, J=7 Hz. 1H), 4.50 (t, J=7 Hz, 2H), 3.29 (t, J=7 Hz, 2H).
EXAMPLE 73 (17) 4-(1-t-Butoxycarbonylpiperidin-4-yl)oxy-1,1-dioxidebenzo[b]thiophene[2716] 2134
[2717] TLC: Rf 0.63 (ethyl acetate hexane=1:1);
[2718] NMR (CDCl3): &dgr; 7.55-7.38 (m, 2H), 7.30 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.23 (d, J=7 Hz, 1H), 4.70-4.50 (m, 1H), 3.85-3.58 (m, 2H), 3.50-3.28 (m, 2H), 2.15-1.88 (m, 2H), 1.88-1.66 (m, 2H), 1.47 (s, 9H).
EXAMPLE 73 (18) 4-(5-Methyl-1-tritylimidazol-4-ylmethyl) oxy-1,1-dioxidebenzo[b]thiophene[2719] 2135
[2720] TLC: Rf 0.11 (hexane:ethyl acetate=1:1);
[2721] NMR (CDCl3): &dgr; 7.55-7.23 (m, 14H), 7.23-7.00 (m, 6H), 6.56 (d, J=7 Hz, 1H), 5.13 (s, 2H), 1.45 (s, 3H).
EXAMPLE 73(19) 4-(1,2,4-oxadiazol-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2722] 2136
[2723] TLC: Rf 0.45 (hexane:ethyl acetate=1:2);
[2724] NMR (DMSO-d6): &dgr; 9.70 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57 (d, J=6.9 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 5.58 (s, 2H).
EXAMPLE 73 (20) 6-(Pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2725] 2137
[2726] TLC: Rf 0.40 (ethyl acetate);
[2727] NMR (CDCl3): &dgr; 8.69 (d, J=1.7 Hz, 1H), 8.62 (dd, J=5.0, 1.7 Hz, 1H), 7.77 (d, J=7.8 Hz, 1i H), 7.39-7.27 (m, 3H), 7.18 (d, J=7.0 Hz, 1H), 7.09 (dd, J=8.2, 2.2 Hz, 1H), 6.58 (d, J=7.0 Hz, 1H), 5.14 (s, 2H).
EXAMPLE 73 (21) 6-(3-Nitrophenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene[2728] 2138
[2729] MS (APCI, Pos.): m/z 318 (M+H)+.
EXAMPLE 73 (22) 6-(3-(t-Butoxycarbonylamino)propyl)oxy-1,1-dioxidebenzo[b]thiophene[2730] 2139
[2731] TLC: Rf 0.14 (hexane:ethyl acetate=2:1);
[2732] NMR (CDCl3): &dgr; 7.27-7.23 (m, 2H), 7.16 (d, J=6.9 Hz, 1H), 7.01 (dd, J=8.3,-2.3 Hz, 1H), 6.60 (d, J=6.9 Hz, 1H), 4.69 (br, 1H), 4.08 (t, J=6.6 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.01 (quint, J=6.6 Hz, 2H), 1.44 (s, 9H).
EXAMPLE 73 (23) 7-t-Butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene[2733] 2140
[2734] TLC: Rf 0.41 (hexane:ethyl acetate=1:1);
[2735] NMR (CDCl3): &dgr; 7.45 (dd, J=8.5, 7.5 Hz, 1H), 7.12 (d, J=6.9 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.66 (d, J=6.9 Hz, 1H); 4.72 (s, 2H), 1.46 (s, 9H).
EXAMPLE 73 (24) 6-(Pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2736] 2141
[2737] TLC: Rf 0.36 (ethyl acetate);
[2738] NMR (CD3OD): &dgr; 8.35 (d, J=3.0 Hz, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.60-7.50 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.45-7.35 (m, 3H), 6.87 (d, J=7.2 Hz, 1H), 5.27 (s, 2H), 3.98 (s, 3H).
EXAMPLE 73 (25) 4,7-Bis(3-hydroxypropyl)-1,1-dioxidebenzo[b]thiophene[2739] 2142
[2740] TLC: Rf 0.44 (ethyl acetate:methanol=9:1);
[2741] NMR (CDCl3): &dgr; 7.34 (d, J=7.0 Hz, 1H), 7.04 (d, J=9.2 Hz,1H), 6.97 (d, J=9.2 Hz, 1H), 6.54 (d, J=7.0 Hz, 1H), 4.24 (t, J=5.8 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.89 (t, J=5.8 Hz, 2H), 3.83 (t, J=5.8 Hz, 2H), 2.00-2.08 (m, 4H).
EXAMPLE 73 (26) 5-Carboxy-4-ethoxy-1,1-dioxidebenzo[b]thiophene[2742] 2143
[2743] TLC: Rf 0.38 (chloroform:methanol=10:1);
[2744] NMR (CD3OD): &dgr; 8.00 (d, J=7 Hz, 1H), 7.61 (dd, J=1, 7 Hz, 1H), 7.52 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.16 (q, J=7 Hz, 2H), 1.42 (t, J=7 Hz, 3H).
EXAMPLE 73 (27) 5-Carboxy-4-butoxy-1,1-dioxidebenzo[b]thiophene[2745] 2144
[2746] TLC: Rf 0.48 (chloroform:methanol=10:1);
[2747] NMR (CD3OD): &dgr; 7.98 (d, J=7 Hz, 1H), 7.58 (dd, J=1, 7 Hz,1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.01 (t, J=7 Hz, 2H), 1.95-1.66 (m, 2H), 1.66-1.36 (m, 2H), 0.99 (t, J=7 Hz, 3H).
EXAMPLE 73 (28) 5-Carboxy-4-hexyioxy-1,1-dioxidebenzo[b]thiophene[2748] 2145
[2749] TLC: Rf 0.50 (chloroform:methanol=10:1);
[2750] NMR (CD3OD): &dgr; 7.98 (d, J=7 Hz, 1H), 7.58 (dd, J=1, 7 Hz, 1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.10 (t, J=7 Hz, 2H), 1.95-1.65 (m, 2H), 1.65-1.05 (m, 6H), 0.92 (t, J=7 Hz, 3H).
EXAMPLE 73 (29) 5-Carboxy-4-octyloxy-1-dioxidebenzo[b]thiophene[2751] 2146
[2752] TLC: Rf 0.50 (chloroform:methanol=10:1);
[2753] NMR (CD3OD): &dgr; 7.98 (d, J=7 Hz, 1H), 7.57 (dd, J=1, 7 Hz, 1H), 7.51 (dd, J=1, 7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 4.10 (t, J=7 Hz, 2H), 1.95-1.65 (m, 2H), 1.65-1.05 (m, 10H), 0.90 (t, J=7 Hz, 3H).
EXAMPLES 74˜74 (5)[2754] By the same procedure as described in Example 32 using carboxylic acid derivative corresponding to 4-carboxy-1,1-dioxidebenzo[b]thiophene and a halogenated compound corresponding to bromoethane, the compounds of the present invention having the following physical data were obtained, with the proviso that in the preparation of the compound of Example 74, 1 mol equivalent of bromoethane was used.
EXAMPLE 74 5-Ethoxycarbonyl-4-hydroxy-1,1-dioxidebenzo[b]thiophene[2755] 2147
[2756] TLC: Rf 0.32 (hexane:ethyl acetate=2:1);
[2757] NMR (CDCl3): &dgr;&pgr;11.37 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.52 (dd, J=7.0, 0.8 Hz, 1H), 7.24 (dd, J=8.0, 0.8 Hz, 1H), 6.66 (d, J=7.0 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).
EXAMPLE 74 (1) 5-Ethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2758] 2148
[2759] TLC: Rf 0.31 (hexane:ethyl acetate=2:1);
[2760] NMR (CDCl3): &dgr; 7.98 (d, J=7.4 Hz, 1H), 7.49 (t, J=7.4 Hz, 2H), 6.75 (d, J=7.4 Hz, 1H), 4.43 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.43 (t, J=7.0 Hz, 3H).
EXAMPLE 74 (2) 5-lsopropyloxycarbonyl-4-methoxy-1,1-dinxidebenzo[b]thiophene[2761] 2149
[2762] TLC: Rf 0.36 (hexane:ethyl acetate=2:1);
[2763] NMR (CDCl3): &dgr; 7.94 (d, J=7.8 Hz, 1H), 7.52-7.42 (m, 2H), 6.74 (d, J=7.2 Hz, 1H), 5.38-5.19 (m, 1H), 3.96 (s, 3H), 1.40 (d, J=6.2 Hz, 6H).
EXAMPLE 74 (3) 5-(2-Methylpropyl)oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2764] 2150
[2765] TLC: Rf 0.42 (hexane:ethyl acetate=2:1);
[2766] NMR (CDCl3): &dgr; 7.97 (d, J=7.8 Hz, 1H), 7.53-7.43 (m, 2H), 6.75 (d, J=7.2 Hz, 1H), 4.15 (d, J=6.8 Hz, 2H), 3.97 (s, 3H), 2.20-1.98 (m, 1H), 1.03 (d, J=6.6 Hz, 6H).
EXAMPLE 74(4) 6-Methoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2767] 2151
[2768] TLC: Rf 0.41 (hexane:ethyl acetate=1:1);
[2769] NMR (CDCl3): &dgr; 7.95 (t, J=1.0 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.46 (dd, J=7.0, 1.0 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H).
EXAMPLE 74 (5) 6-Methoxymethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene[2770] 2152
[2771] TLC: Rf 0.38 (hexane:ethyl acetate=1:1);
[2772] NMR (CDCl3): &dgr; 7.99 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=7.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 5.52 (s, 2H), 4.00 (s, 3H), 3.58 (s, 3H).
EXAMPLES 75˜75(2)[2773] By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and amine derivative corresponding to 2,4-dimethoxybenzylamine hydrochloride, the following compounds of the present invention were obtained.
[2774] With the proviso that in the preparation of the compounds of Example 75 and Example 75 (2), more than 2 mol equivalent of 4-bromomethyl-1,1-dioxidebenzo[b]thiophene versus amine derivative.
EXAMPLE 75 4-(N-(Pyridin-2-ylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene[2775] 2153
[2776] TLC: Rf 0.48 (methanol:methylene chloride=1:10);
[2777] NMR (CDCl3): &dgr; 8.59 (d, J=4.6 Hz, 1H), 7.72-7.55 (m, 3H), 7.55-7.38 (m, 4H), 7.35-7.16 (m, 3H), 7.10 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.0 Hz, 2H), 3.76 (s, 4H), 3.73 (s, 2H).
EXAMPLE 75 (1) 4-(Pyridin-2-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[2778] 2154
[2779] TLC: Rf 0.31 (methylene chloride:methanol=10:1);
[2780] NMR (CD3OD+CDCl3): &dgr; 8.75-8.52 (m, 1H), 7.96-7.72 (m, 4H), 7.64 (t, J=8 Hz, 1H), 7.55-7.25 (m, 2H), 6.93 (d, J=7 Hz, 1H), 4.43 (s, 2H), 4.38 (s, 2H).
EXAMPLE 75 (2) 4-(N-(2,4-Dimethoxyphenylmethyl)-N-(1,1-dioxidebenzo[b]thiophene-4-ylmethyl) amino) methyl-1,1-dioxidebenzo[b]thiophene[2781] 2155
[2782] TLC: Rf 0.57 (ethyl acetate:benzene=1:1);
[2783] NMR (CDCl3): &dgr; 7.65-7.55 (m, 2H), 7.50-7.38 (m, 4H), 7.07-6.99 (m, 1H), 6.87 (d, J=7.0 Hz, 2H), 6.57 (d, J=7.0 Hz, 2H), 6.48-6.40 (m, 2H), 3.81 (s, 3H), 3.63 (s, 3H), 3.60 (s, 4H), 3.45 (s, 2H).
EXAMPLES 76˜76 (1)[2784] By the same procedure as described in Example 1 using a derivative corresponding to 1,1-dioxidebenzo[b]thiophene and thiophenol, the following compounds of the present invention were obtained.
EXAMPLE 76 4,7-Dimethoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2785] 2156
[2786] TLC: Rf 0.27 (hexane:methylene chloride 1:10);
[2787] NMR (CDCl3): &dgr; 7.52-7.47 (m, 2H), 7.35-7.32 (m, 3H), 7.02 (d, J=8.9 Hz, 1H), 6.91 (d, J=8.9 Hz,1H), 5.00 (dd, J=7.0,1.6 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.73 (dd, J=13.9, 7.0 Hz, 1H), 3.59 (dd, J=13.9,1.6 Hz, 1H).
EXAMPLE 76 (1) 6-Bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2788] 2157
[2789] TLC: Rf 0.45 (hexane:ethyl acetate=2:1);
[2790] NMR (CDCl3): &dgr; 7.83 (d, J=1.8 Hz, 1H), 7.75 (dd, J=8.3, 1.8 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 3H), 4.88 (t, J=6.9 Hz, 1H), 3.80 (dd, J=13.8, 6.9 Hz, 1H), 3.50 (dd, J=13.8, 6.9 Hz, 1H).
EXAMPLE 77 5-Acetyloxy-4-nitro-1,1-dioxidebenzo[b]thiophene[2791] 2158
[2792] By the same procedure as described in Example 12 using 5-hydroxy-4-nitro-1,1-dioxidebenzo[b]thiophene instead of the compound prepared in Example 11, the compound of the present invention having the following physical data was obtained.
[2793] TLC: Rf 0.49 (hexane:ethyl acetate=1:1);
[2794] NMR (DMSO-d6): &dgr; 8.32 (dd, J=8.0,1.0 Hz,1H),7.78 (d, J=7.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.69 (dd, J=7.0, 1.0 Hz, 1H), 2.35 (s, 3H).
EXAMPLES 78˜78 (1)[2795] By the same procedure as described in Example 7 using the compounds prepared in Example 35 (39) and Example 35 (47) instead of the compound prepared in example 6 (8), the following compounds of the present invention were obtained.
EXAMPLE 78 4-(Piperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2796] 2159
[2797] TLC: Rf 0.41 and 0.50 (ethyl acetate:acetic acid:water=3:1:1);
[2798] NMR (CD3OD): &dgr; 7.85-7.42 (m, 6H), 7.35-7.18 (m 2H), 5.68-5.50 (m, 1H), 4.15-3.90 (m, 3H), 3.90-3.50 (m, 2H), 3.50-3.30 (m, 1H), 3.20-2.90 (m, 2H), 2.45-2.15 (m, 1H), 2.15-1.40 (m, 4H).
EXAMPLE 78 (1) 5-(2-Aminoethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2799] 2160
[2800] TLC: Rf 0.17 (ethyl acetate:methanol=2:1);
[2801] NMR (DMSO-d6): &dgr; 8.25 (br, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.86-7.65 (m, 6H), 5.99 (d, J=7.2 Hz, 1H), 4.63-4.50 (m, 2H), 4.15-4.00 (m, 2H), 3.30-3.26 (m, 2H).
EXAMPLE 79 4-(2-(2-Hydroxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2802] 2161
[2803] To a solution of the compound prepared in Example 35 (42) (258 mg) in ethanol, was added 47% aqueous solution of hydrobromic acid (1.0 ml). The mixture was refluxed for 1 hour. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate. The mixture was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give the compound of the present invention (174 mg) having the following physical data.
[2804] TLC: Rf 0.22 (ethyl acetate);
[2805] NMR (CDCl3): &dgr; 7.85-7.72 (m, 2H), 7.66-7.34 (m, 4H), 7.25 (d, J=8 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 5.34 (d, J=9 Hz, 1H), 4.19 (d, J=15 Hz, 1H), 4.25-3.95 (m, 3H), 3.95-3.55 (m, 7H), 2.50 (brs, 1H).
EXAMPLE 80 4-(4,5-Dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene[2806] 2162
[2807] The compound prepared in Example 72 (1) (369 mg) was dissolved in diisopropylethylamine (0.55 ml) and methylene chloride (40 ml). The mixture was cooled to −78° C. Thereto was added trifluoromethanesulfonate anhydride (0.30 ml). The mixture was stirred at O° C. for 2.5 hours and thereto was added trifluoromethanesulfonate anhydride (0.15 ml). The mixture was stirred at room temperature for 1 hour. To the reaction mixture, were added ethyl acetate and 1N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by 1N sodium hydroxide and a saturated aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the compound of the present invention (97 mg) having the following physical data.
[2808] TLC: Rf 0.53 (ethyl acetate);
[2809] NMR (CDCl3): &dgr; 8.42 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 4.46 (t, J=9.4 Hz, 2H), 4.13 (t, J=9.4 Hz, 2H).
EXAMPLE 80 (1) 5-(4,5-Dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene[2810] 2163
[2811] By the same procedure as described in Example 80 using the compound prepared in Example 28 (25) instead of the compound prepared in Example 72 (1), the compound of the present invention having the following physical data was obtained.
[2812] TLC: Rf 0.39 (ethyl acetate);
[2813] NMR (CDCl3): &dgr; 8.10 (dd, J=7.8 Hz, 1.2 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.25 (d, J=6.8 Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 4.50 (t, J=9.6 Hz, 2H), 4.11 (t, J=9.6 Hz, 2H).
EXAMPLES 81˜81 (1)[2814] By the same procedure as described in Example 52 using the compounds prepared in Example 45 (10) and Example 35 (63) instead of the compound prepared in example 51, the following compounds of the present invention were obtained.
EXAMPLE 81 5-Carboxy-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2815] 2164
[2816] TLC: Rf 0.22 (ethyl acetate:methanol=2:1);
[2817] NMR (DMSO-d6): &dgr; 7.91 (d, J=8.0 Hz, 1H), 7.86-7.74 (m, 3H), 7.68-7.61 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 5.68 (d, J=8.5 Hz, 1H), 4.19 (d, J=15.5 Hz, 1H), 4.01 (dd, J=15.5, 8.5 Hz, 1H), 3.66 (s, 3H). 3.35 (br, 1H).
EXAMPLE 81 (1)[2818] 4-Carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2165
[2819] Free Compound:
[2820] TLC: Rf 0.11 (chloroform:methanol 9:1);
[2821] NMR (DMSO-d6): &dgr; 13.78 (s, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.91-7.84 (m, 1H), 7.82-7.74 (m, 3H), 7.69-7.61 (m, 2H), 6.27 (dd, J=7.8, 2.1 Hz, 1H), 4.20-3.95 (m, 2H).
[2822] Sodium Salt:
[2823] TLC: Rf 0.11 (chloroform:methanol=9:1);
[2824] NMR (DMSO-d6): &dgr; 8.22 (dd, J=7.4 Hz and 1.4 Hz, 1H), 7.95-7.85 (m, 3H), 7.85-7.70 (m, 2H), 7.70-7.55 (m, 2H), 6.62 (dd, J=8.0 Hz and 2.0 Hz, 1H), 4.10 (dd, J=15 Hz and 8.0 Hz, 1H), 3.95 (dd, J=15 Hz and 2.0 Hz, 1H).
EXAMPLE 82 4-Formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2825] 2166
[2826] To a solution of the compound prepared in Example 45 (20) (1.46 g) in methylene chloride (40 ml), were added pyridinium dichromate (2.44 g) and magnesium sulfate (1.0 g). The mixture was stirred at room temperature for 6 hours. The undissolved ingredients were filtered off. The filtrate was poured onto 1N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was washed by methanol to give the compound of the present invention (1.03 g) having the following physical data.
[2827] TLC: Rf 0.65 (chloroform:methanol=9:1);
[2828] NMR (DMSO-d6): &dgr; 10.29 (s, 1H), 8.29 (dd, J=7.4, 1.2 Hz, 1H), 8.16 (dd, J=7.6,1.2 Hz, 1H), 8.03-7.92 (m, 1H), 7.86-7.72 (m, 3H), 7.71-7.57 (m, 2H), 6.41 (dd, J=8.0, 2.2 Hz, 1H), 4.08 (dd, J=15.2, 8.0 Hz, 1H), 3.97 (dd, J=15.2, 2.2 Hz, 1H).
EXAMPLES 83˜83 (3)[2829] By the same procedure as described in Example 21 using the compounds prepared in Example 73 (2), Example 73 (23), Example 28 (12) and Example 72 (5) instead of the compound prepared in Example 20 (27), the following compounds of the present invention were obtained.
EXAMPLE 83 5-Carboxymethyloxy-1,1-dioxidebenzo[b]thiophene[2830] 2167
[2831] TLC: Rf 0.18 (ethyl acetate:methanol=5:1);
[2832] NMR (DMSO-d6): &dgr; 7.75 (dd, J=8.3, 0.9 Hz, 1H), 7.53 (dd, J=6.9, 0.9 Hz, 1H), 7.34 (d, J=6.9 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.07 (dd, J=8.3, 2.7 Hz, 1H), 4.83 (s, 2H).
EXAMPLE 83 (1) 7-Carboxymethyloxy-1,1-dioxidebenzo[b]thiophene[2833] 2168
[2834] TLC: Rf 0.21 (ethyl acetate:methanol=4:1);
[2835] NMR (DMSO-d6): &dgr; 7.57 (t, J=7.8 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 4.92 (s, 2H).
EXAMPLE 83 (2) 4-((1S)-1-Carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2836] 2169
[2837] TLC: Rf 0.16 (ethyl acetate:methanol=4:1);
[2838] NMR (DMSO-d6): &dgr; 8.89 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.3 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 4.33 (dd, J=7.8, 6.0 Hz, 1H), 2.23-2.12 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).
EXAMPLE 83 (3) 4-((1R)-1-Carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2839] 2170
[2840] TLC: Rf 0.16 (ethyl acetate:methanol=4:1);
[2841] NMR (DMSO-d6): &dgr; 8.89 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.3 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 4.33 (dd, J=7.8, 6.0 Hz, 1H), 2.25-2.13 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H).
EXAMPLE 84 5-(3-Carboxypropyl) oxy-1,1-dioxidebenzo[b]thiophene[2842] 2171
[2843] To a solution of the compound prepared in Example 73 (3) (98 mg) in dimethylsulfoxide (5.0 ml) were added phosphate buffer (pH 7.4, 25 ml) and porcine liver esterase (100 &mgr;l). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto 1 N hydrochloric acid. The mixture was extracted by ethyl acetate. The extract was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the compound of the present invention (90 mg) having the following physical data.
[2844] TLC: Rf 0.26 (chloroform:methanol=9:1);
[2845] NMR (CDCl3): &dgr; 7.62 (d, J=8.4 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.95 (dd, J=8.4, 2.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.73 (d, J=6.8 Hz, 1H), 4.10 (t, J=6.2 Hz, 2H), 2.58 (t, J=7.0 Hz, 2H), 2.24-2.07 (m, 2H).
EXAMPLE 84 (1) 5-((2E)-3-Carboxy-2-propenyl) oxy-1,1-dioxidebenzo[b]thiophene[2846] 2172
[2847] By the same procedure as described in Example 84 using the compound prepared in Example 30 (13) instead of the compound prepared in Example 73 (3), the compound of the present invention having the following physical data was obtained.
[2848] TLC: Rf 0.14 (chloroform:methanol=9:1);
[2849] NMR (CD3OD): &dgr; 7.64 (d, J=8.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 7.16-7.00 (m, 3H), 6.95 (d, J=7.0 Hz, 1H), 6.13 (dt, J=15.8, 2.0 Hz, 1H), 4.89-4.80 (m, 2H).
EXAMPLE 85 5-(4-Phenylbutyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2850] 2173
[2851] To a solution of 4-Phenylbutylamine (164 mg) and the compound prepared in example 15 (366 mg) in methylene chloride (3.0 ml), was added sodium sulfate (1.0 g) at room temperature. The mixture was stirred for 1 hour. To the reaction mixture were added sodium borocyanohydride (63 mg), methanol (3.0 ml) and 4N solution of hydrogen chloride in dioxane (0.3 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. To the residue was added chloroform. The undissolved ingredients were filtered off. The filtrate was concentrated. The residue was purified with column chromatography on silica gel (chloroform:methanol=100:5) to give the compound of the present invention (340 mg) having the following physical data, and then converted into hydrochloride by a known method to give the compound of the present invention having the following physical data.
[2852] Free Compound:
[2853] TLC: Rf 0.42 (chloroform:methanol=10:1);
[2854] NMR (CDCl3): &dgr; 7.80-7.50 (m, 6H), 7.33-7.12 (m, 6H), 5.34 (d, J=4.8 Hz, 1H), 4.15-3.90 (m, 4H), 3.75 (s, 3H), 2.98 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 1.88-1.60 (m, 4H).
[2855] Hydrochloride:
[2856] TLC: Rf 0.42 (chloroform:methanol=10:1);
[2857] NMR (CDCl3): &dgr; 9.49 (bs, 2H), 7.93 (d, J=8.1 Hz, 1H), 7.77-7.70 (m, 2H), 7.65 (t, J=8.1 Hz, 1H), 7.50 (t, J=8.1 Hz, 2H), 7.35-7.12 (m, 6H), 5.27 (d, J=8.1 Hz, 1H), 4.18-4.02 (m, 2H), 3.98 (d, J=15.0 Hz, 1H), 3.88 (s, 3H), 3.85 (dd, J=15.0, 8.1 Hz, 1H), 3.00-2.85 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.00-1.60 (m, 4H).
EXAMPLE 85 (1) 5-(Pyridin-3-ylmethyl)aminomethyl-4-methoxy-3-phenysulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2858] 2174
[2859] By the same procedure as described in Example 85 using the compound prepared in Example 15, and (pyridin-3-ylmethyl)amine instead of 4-phenylbutylamine, the compound of the present invention having the following physical data was obtained. And then, by converting into hydrochloride using the obtained compound by a known method, the compound of the present invention having the following physical data was obtained.
[2860] Free Compound:
[2861] TLC: Rf 0.35 (chloroform:methanol=10:1);
[2862] NMR (CDCl3): &dgr; 8.59 (d, J=2.0 Hz, 1H), 8.55 (dd, J=4.8, 2.0 Hz, 1H), 7.80-7.65 (m, 4H), 7.58 (d, J=6.0 Hz, 1H), 7.43 (dd, J=7.6, 2.0 Hz, 3H), 7.30 (dd, J=7.6, 4.8 Hz, 1H), 5.20 (d, J=8 .2 Hz, 1H), 4.17 (d, J=13.4 Hz, 1H), 3.95-3.70 (m, 5H), 3.80 (s, 3H).
[2863] 2hydrochloride:
[2864] TLC: Rf 0.35 (chloroform:methanol=10:1);
[2865] NMR (DMSO-d6): &dgr; 10.35 (brs, 1H), 10.15 (bs, 1H), 9.03 (s, 1H), 8.85 (d, J=5.2 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.95-7.72 (m, 4H), 7.70-7.55 (m, 3H), 5.85-5.77 (m, 1H), 4.40-4.00 (m, 6H), 3.69 (s, 3H).
EXAMPLE 86 6-Dimethylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2866] 2175
[2867] By the same procedure as described in Example 8 using the compound prepared in Example 35 (68) instead of the compound prepared in Example 7, the compound of the present invention having the following physical data was obtained.
[2868] TLC: Rf 0.48 (hexane:ethyl acetate=1:2);
[2869] NMR (DMSO-d6): &dgr; 7.81-7.74 (m, 3H), 7.66-7.58 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.09 (dd, J=9.0, 2.5 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H), 5.56 (dd, J=9.5, 3.0 Hz,1H), 3.91 (dd, J=15.0, 9.5 Hz, 1H), 3.67 (dd, J=15.0, 3.0 Hz, 1H), 2.99 (s, 6H).
EXAMPLE 87 4-(2-Dimethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2870] 2176
[2871] By the same procedure as described in Example 28 using the compound prepared in Example 81 (1) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and (2-dimethylaminoethyl)amine instead of (pyridin-3-ylmethyl)amine, and then by converting into hydrochloride by known methods, the following compound of the present invention was obtained.
[2872] TLC: Rf 0.62 (chloroform:methanol:triethylamine=8:2:1);
[2873] NMR (DMSO-d6): &dgr; 10.40-10.20 (br, 1H), 9.19 (t, J=5.4Hz, 1H), 8.13 (d, J=6.9 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.84-7.72 (m, 3H), 7.67-7.58 (m, 2H), 6.27 (d, J=9.0 Hz, 1H), 4.13 (dd, J=9.0,15.0 Hz, 1H), 3.96 (d, J=15.0 Hz, 1H), 3.77-3.55 (m, 2H), 3.40-3.22 (m, 2H), 2.87-2.74 (m, 6H).
EXAMPLES 88˜88 (2)[2874] Using the compounds prepared in Example 18 (40), Example 20 (4) and Example 45 (3) instead of the compound prepared in Example 1 by the same procedure as described in Example 3 or by the same reaction using 3-chloroperbenzoic acid instead of OXONE@ as an oxidizer, the following compounds of the present invention were prepared.
EXAMPLE 88 4,7-Bis(pyridin-3-ylmethyloxy)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2875] 2177
[2876] TLC: Rf 0.36 (ethyl acetate:methanol=2:1);
[2877] NMR (CDCl3): &dgr; 8.65-8.60 (m, 3H), 8.57 (dd, J=5.0,1.5 Hz, 1H), 7.90-7.80 (m, 2H), 7.68-7.65 (m, 2H), 7.60-7.55 (m, 1H), 7.41-7.31 (m, 4H), 7.01 (d, J=9.0 Hz,1H), 6.98 (d, J=9.0 Hz, 1H), 5.25 (d, J=13.0 Hz, 1H), 5.21 (dd, J=9.5, 1.0 Hz, 1H), 5.20 (d, J=13.0 Hz,1H), 4.96 (d, J=12.0 Hz, 1H), 4.87 (d, J=12.0 Hz, 1H), 4.12 (dd, J=15.0, 1.0 Hz, 1H), 3.75 (dd, J=15.0, 9.5 Hz, 1H).
EXAMPLE 88 (1) 4-(N-Oxidepyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2878] 2178
[2879] TLC: Rf 0.30 (ethyl acetate:methanol=2:1);
[2880] NMR (DMSO-d6): &dgr; 8.29 (s, 1H), 8.20 (d, J=6.2 Hz, 1H), 7.73-7.57 (m, 4H), 7.51-7.31 (m, 6H), 5.77 (d, J=8.8 Hz, 1H), 5.10 (d, J=12.8 Hz, 1H), 4.90 (d, J=12.8 Hz, 1H), 4.18 (d, J=15.0 Hz, 1H), 3.95 (dd, J=15.0, 8.8 Hz, 1H).
EXAMPLE 88 (2) 4-(2-(N-Oxidepyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2881] 2179
[2882] TLC: Rf 0.23 (ethyl acetate:methanol=9:1);
[2883] NMR (DMSO-d6): &dgr; 8.11 (d, J=6.9 Hz, 2H), 7.79-7.72 (m, 3H), 7.65-7.60 (m, 3H), 7.34 (d, J=7.5 Hz, 1H), 7.28-7.25 (m, 3H), 5.41 (d, J=8.5 Hz, 1H), 4.16 (d, J=15.0 Hz, 1H), 4.15-3.90 (m, 2H), 4.02 (dd, J=15.0, 8.5 Hz, 1H), 2.88-2.66 (m, 2H).
EXAMPLE 89 4-methoxy-3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2884] 2180
[2885] By the same procedure as describe in 1 using the compound prepared in example 28 (27) instead of 1,1-dioxidebenzo[b]thiophene and 4-mercaptphenol instead of thiophenol, the compound of the present invention having the following physical data was obtained.
[2886] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);
[2887] NMR (CDCl3): &dgr; 7.60-7.00 (m, 3H), 7.35 (d, J=7.5 Hz, 2H), 6.80 (d, J=7.5 Hz, 2H), 6.00 (s, 1H), 4.90 (dd, J=5.0, 1.2 Hz, 1H), 3.90 (s, 3H), 3.75-3.50 (m, 2H)
EXAMPLE 90 4-Methoxy-3-(4-(pyridin-3-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2888] 2181
[2889] By the same procedure as described in Example 18 using the compound prepared in Example 89 instead of the compound prepared in Example 9 (12) and a halogenated compound corresponding to 4-nitrobenzylbromide, the compound of the present invention having the following physical data was obtained.
[2890] TLC: Rf 0.22 (ethyl acetate).
EXAMPLE 91 4-Methoxy-3-(4-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[2891] 2182
[2892] By the same procedure as described in Example 3 using the compound prepared in Example 90 instead of the compound prepared in Example 1, the compound of the present invention having the following physical data was obtained.
[2893] TLC: Rf 0.39 (ethyl acetate:triethylamine=95:5);
[2894] NMR (DMSO-d6): &dgr; 9.05 (br.s, 1H), 8.90 (d, J=5.0 Hz, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.00 (dd, J=7.5, 5.0 Hz, 1H), 7.80-8.60 (m, 3H), 7.50-7.15 (m, 4H), 5.60-5.40 (m, 3H), 4.20 (d, J=15 Hz, 1H), 4.00 (dd, J=15, 7.5 Hz, 1H), 3.45 (s, 3H).
Examples 92˜92 (1)[2895] By the same procedure as described in Example 1 using the compounds prepared in Example 28 (27) and Example 28 (26) instead of 1,1-dioxidebenzo[b]thiophene, and thiophenol, the following compounds of the present invention were obtained.
EXAMPLE 92 5-(2-Dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2896] 2183
[2897] TLC: Rf 0.40 (ethyl acetate:methanol:triethylamine=8:1:1);
[2898] NMR (CDCl3): &dgr; 8.10 (d, J=8.0 Hz, 1H), 7.67 (br, 1H), 7.55-7.48 (m, 3H), 7.39-7.36 (m, 3H), 5.10 (dd, J=6.5, 2.0 Hz, 1H), 4.06 (s, 3H), 3.71 (dd, J=14.0, 6.5 Hz, 1H), 3.61 (dd, J=14.0, 2.0 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 2.29 (s, 6H).
EXAMPLE 92 (1) 5-(Pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro 1,1-dioxidebenzo[b]thiophene[2899] 2184
[2900] TLC: Rf 0.46 (ethyl acetate:methanol=9:1);
[2901] NMR (CDCl3): &dgr; 8.60-8.52 (m, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.77-7.74 (m, 2H), 7.53-7.45 (m, 3H), 7.37-7.30 (m, 4H), 5.03 (dd, J=6.5, 2.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.70 (dd, J=14.0, 6.5 Hz, 1H), 3.58 (dd, J=14.0, 2.0 Hz, 1H).
EXAMPLE 93 4-(2-(Piperidin-1-yl)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene[2902] 2185
[2903] By the same procedure as described in Example 31 using 4-bromomethyl-1,1-dioxidebenzo[b]thiophene, and 1-(2-aminoethyl)piperidine instead of 2,4-dimethoxybenzylamine -hydrochloride, the compound of the present invention having the following physical data was obtained. And then, the obtained compound was converted into hydrochloride by a known method to give the compound of the present invention having the following physical data.
[2904] Free Compound:
[2905] TLC: Rf 0.16 (ethyl acetate:methanol:triethylamine=90:5:5);
[2906] NMR (CDCl3): &dgr; 7.75-7.60 (m, 2H), 7.60-7.40 (m, 2H), 6.70 (d, J=7.5 Hz, 1H), 3.90 (s, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.50-2.20 (m, 4H), 2.40 (t, J=7.5 Hz, 2H), 1.65-1.35 (m, 6H).
[2907] 2hydrochloride:
[2908] TLC: Rf 0.28 (ethyl acetate:methanol:triethylamine=8:1:0.5);
[2909] NMR (DMSO-d6+pyridine-d5): &dgr; 8.15 (d, J=7.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 4.40 (s, 2H), 3.55-3.30 (m, 4H), 3.30-3.10 (m, 4H), 1.90-1.70 (m, 4H), 1.65-1.50 (m, 2H).
EXAMPLE 94 4-(2-(Piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2910] 2186
[2911] By the same procedure as described in Example 27 using the compound prepared in Example 93 instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, the compound of the present invention having the following physical data was obtained. And then, the obtained compound was converted into hydrochloride by a known method to give the compound of the present invention having the following physical data.
[2912] Free Compound:
[2913] TLC: Rf 0.18 (ethyl acetate:methanol:triethylamine=90:5:5);
[2914] NMR (CDCl3): &dgr; 7.80-7.40 (m, 8H), 6.10 (d, J=10 Hz, 1H), 4.60 (d, J=15 Hz, 1H), 3.95 (d, J=15 Hz, 1H), 3.90 (d, J=15 Hz, 1H), 3.75 (dd, J=15, 10 Hz, 1H), 2.80-2.60 (m, 2H), 2.60-2.20 (m, 6H), 1.60-1.30 (m, 6H).
[2915] 2hydrochloride:
[2916] TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1:0.5);
[2917] NMR (DMSO-d6+pyridine-d5): &dgr; 8.35 (d, J=7.5 Hz, 1H), 8.00-7.75 (m, 5H), 7.65 (t, J=7.5 Hz, 2H), 6.70 (d, J=7.5 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 4.50 (d, J=15 Hz, 1H), 4.20-3.95 (m, 2H), 3.65-3.35 (m, 4H), 3.30-3.00 (m, 4H), 2.00-1.70 (m, 4H), 1.70-1.40 (m, 2H).
EXAMPLE 95 4-t-Butoxycarbonylaminobenzo[b]thiophene[2918] 2187
[2919] To a suspension of 4-carboxybenzo[b]thiophene (3.2 g) in t-butanol (170 ml), were added triethylamine (7.5 ml) and diphenylphosphorylamide (4.2 ml). The mixture was stirred at 95° C. for 2 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatopgaphy on silica gel (hexane:ethyl acetate=5:1) to give the compound of the present invention (3.0 g) having the following physical data.
[2920] TLC: Rf 0.41 (hexane:ethyl acetate=3:1); NMR (CDCl3): &dgr; 7.81-7.78 (m, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.44-7.24 (m, 3H), 6.74 (br, 1H), 1.55 (s, 9H).
EXAMPLE 96 4-t-Butoxycarbonylamino-1,1-dioxidebenzo[b]thiophene[2921] 2188
[2922] To a solution of the compound prepared in Example 95 (3.0 g) in chloroform (100 ml) was added m-chloroperbenzoic acid (8.2 g) at 0° C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was extracted with ethyl acetate. The extract was washed by an aqueous solution of sodium hydroxide, water and a saturated solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in methylene chloride and was allowed to stand overnight. The crystals that appeared were filtered. The filtrate was concentrated. The residue was purified with column chromatography on silica gel (methylene chloride), combined with the said crystals, to give the compound of the present invention (3.0 g) having the following physical data.
[2923] TLC: Rf 0.41 (hexane:ethyl acetate=1:1); NMR (CDCl3): &dgr; 7.83-7.80 (m, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.31 (dd, J=7.2, 1.0 Hz,1H), 6.70 (d, J=7.2 Hz,1H), 6.54 (br,1H), 1.53 (s, 9H).
EXAMPLE 97 4-Amino-1,1-dioxidebenzo[b]thiophene hydrochloride[2924] 2189
[2925] To a solution of the compound prepared in Example 96 (2.5 g) in ethyl acetate (30 ml) was added 4N solution of hydrogen chloride in ethyl acetate (10 ml). The mixture was stirred at room temperature for 3 hours. After removing the solvent, the residue was washed by ethyl acetate to give the compound of the present invention (1.8 g) having the following physical data.
[2926] TLC: Rf 0.29 (hexane:ethyl acetate=1:2);
[2927] NMR (CD3OD): &dgr; 7.63 (dd, J=7.0, 1.0 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (dt, J=7.5,1.0 Hz, 1H), 7.42 (dd, J=7.5, 1.0 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H).
EXAMPLE 98 4-(4-Fluorobenzylcarbonylamino)-1,1-dioxidebenzo[b]thiophene[2928] 2190
[2929] To a solution of the compound prepared in Example 97 (100 mg), 4-fluorophenylacetic acid (192 mg) and triethylamine (1 ml) in dimethylformamide (3 ml) was added propanephosphonic acid cyclic anhydride (50 % solution in dimethylformamide; 3 ml). The mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added ethyl acetate. The mixture was washed by water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and concentrated. The residue was purified with column chromatography on silica gel (hexane:ethyl acetate=1:1), followed by recrystallization from ethyl acetate-hexane to give the compound of the present invention having the following physical data.
[2930] TLC: Rf 0.63 (ethyl acetate);
[2931] NMR (DMSO-d6): &dgr; 10.27 (s, 1H), 7.88-7.82 (m, -1H), 7.64 (d, J=7.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.41-7.34 (m, 3H), 7.16 (t, J=9.0 Hz, 2H), 3.75 (s, 2H).
EXAMPLES 98 (1)˜98 (5)[2932] By the same procedure as described in Example 98 using the compound prepared in Example 97 and a carboxylic acid derivative corresponding to 4-fluorophenylacetic acid, the compounds of the present invention having the following physical data.
EXAMPLE 98 (1) 4-(Pyridin-3-ylcarbonyl)amino-1,1-dioxidebenz[b]thiophene[2933] 2191
[2934] TLC: Rf 0.18 (ethyl acetate);
[2935] NMR (DMSO-d6): &dgr; 10.69 (s, 1H), 9.17 (d, J=2.0 Hz, 1H), 8.80 (dd, J=5.0, 2.0 Hz,1H), 8.34 (dt, J=7.8, 2.0 Hz, 1H), 7.82 (dd, J=7.5, 1.5 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (dd, J=7.8, 5.0 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H).
EXAMPLE 98 (2) 4-(3-Chlorobenzoyl) amino-1,1-dioxidebenzo[b]thiophene[2936] 2192
[2937] TLC: Rf 0.25 (hexane:ethyl acetate=1:1);
[2938] NMR (DMSO-d6): &dgr; 10.62 (s, 1H), 8.07 (t, J=1.5Hz, 1H), 7.96 (dt, J=7.7,1.5 Hz, 1H), 7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.73-7.64 (m, 4H), 7.60 (t, J=7.7 Hz, 1H), 7.35 (d, J=6.6 Hz,1H).
EXAMPLE 98 (3) 4-Benzylcarbonylamino-1,1-dioxidebenzo[b]thiophene[2939] 2193
[2940] TLC: Rf 0.45 (hexane:ethyl acetate=1:2);
[2941] NMR (CDCl3): &dgr; 7.75-7.72 (m, 1H), 7.48-7.35 (m, 7H), 7.29 (br, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H), 3.79 (s, 2H).
EXAMPLE 98 (4) 4-(Dimethylaminoacetyl)amino-1,1-dioxidebenzo[b]thiophene[2942] 2194
[2943] TLC: Rf 0.31 (ethyl acetate:methanol=4:1);
[2944] NMR (CDCl3): &dgr; 9.52 (br, 1H), 8.06 (m, 1H), 7.56-7.48 (m, 2H), 7.28-7.25 (m, 1H), 6.73 (d, J=7.0 Hz, 1H), 3.15 (s, 2H), 2.44 (s, 6H).
EXAMPLE 98 (5) 4-Acetylamino-1,1-dioxidebenzo[b]thiophene[2945] 2195
[2946] TLC: Rf 0.25 (ethyl acetate);
[2947] NMR (DMSO-d6): &dgr; 1 0.05 (s, 1H), 7.89-7.83 (m, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.33 (d, J=7.0 Hz, 1H), 2.12 (s, 3H).
EXAMPLES 99˜99 (10)[2948] By the same procedure as described in Example 28 using 4-carboxy-1,1-dioxidebenzo[b]thiophene (prepared in Example 107 hereinafter described) and a corresponding amine derivative instead of (pyridin-3-ylmethyl)amine, and if necessary, by converting into the corresponding salt by known methods by a known method, the compounds of the present invention having the following physical data were obtained.
EXAMPLE 99 4-(3-(2-Oxopyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2949] 2196
[2950] TLC: Rf 0.36 (chloroform:methanol=9:1);
[2951] NMR (CDCl3): &dgr; 8.19 (dd, J=7.0 Hz and 1.0 Hz, 1H), 8.05 (broad s, 1H), 7.95 (dd, J=8.0 Hz and 1.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 3.50-3.35 (m, 6H), 2.46 (t, J=8.0 Hz, 2H), 2.20-2.00 (m, 2H), 1.90-1.70 (m, 2H).
EXAMPLE 99 (1) 4-(2-Dimethylaminoethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2952] 2197
[2953] TLC: Rf 0.20 (ethyl acetate:acetic acid:water=3:1:1);
[2954] NMR (CDCl3): &dgr; 8.03 (dd, J=7.2 Hz and 1.0 Hz, 1H), 7.79 (dt, J=7.8 Hz and 1.0 Hz, 1H), 7.69 (dd, J=7.8 Hz and 1.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.49 (m, 2H), 2.67 (t, J=6.0 Hz, 2H), 2.58 (q, J=7.2 Hz, 4H), 1.04 (t, J=7.2 Hz, 6H).
EXAMPLE 99 (2) 4-(2-(N-Ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2955] 2198
[2956] TLC: Rf 0.61 (chloroform:methanol 9:1);
[2957] NMR (CDCl3): &dgr; 7.91 (d, J=7.0 Hz, 1H), 7.74 (m, 1H), 7.55-7.40 (m, 2H), 7.13 (dd, J=9.0 Hz and 7.4 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 6.70-6.55 (m, 3H), 6.35 (broad s, 1H), 3.75-3.50 (m, 4H), 3.19 (q, J=7.0 Hz, 2H), 2.29 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
EXAMPLE 99 (3) 4-(2,4,6-Trimethoxybenzyl) carbamoyl-1,1-dioxidebenzo[b]thiophene[2958] 2199
[2959] TLC: Rf 0.63 (chloroform:methanol=9:1);
[2960] NMR (CDCl3+DMSO-d6): &dgr; 7.89 (d, J=7.0 Hz, 1H), 7.80-7.65 (m, 3H), 7.55 (t, J=7.4 Hz, 1H), 6.88 (d, J=7.0 Hz, 1H), 6.17 (s, 2H), 4.56 (d, J=4.8 Hz, 2H), 3.84 (s, 6H), 3.82 (s, 3H).
EXAMPLE 99 (4) 4-(4-(2-Hydroxyethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thioiphene.hydrochloride[2961] 2200
[2962] TLC: Rf 0.33 (methylene chloride:methanol=10:1);
[2963] NMR (DMSO-d6): &dgr; 8.00-7.93 (m, 1H), 7.76-7.66 (m, 2H), 7.58 (d, J=6.9 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 5.40 (bs, 1H), 4.64-4.46 (m, 1H), 6.85-3.73 (m, 2H), 3.70-3.00 (m, 10H).
EXAMPLE 99 (5) 4-(4-Benzyloxycarbonylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene[2964] 2201
[2965] TLC: Rf 0.64 (methylene chloride:methanol=10:1);
[2966] NMR (CDCl3): &dgr; 7.78 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.36 (s, 5H), 7.32 (d, J=6.9 Hz, 1H), 6.79 (d, J=6.9 Hz, 1H), 5.16 (s, 2H), 3.88-3.72 (m, 2H), 3.70-3.56 (m, 2H), 3.54-3.40 (m, 2H), 3.40-3.25 (m, 2H).
EXAMPLE 99 (6) 4-(N-Ethyl-N-2-(piperidin-1-yl) ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2967] 2202
[2968] TLC: Rf 0.25 (chloroform:methanol=9:1); NMR (CDCl3): &dgr; 7.80-7.20 (m, 4H), 6.75 (d, J=6.8 Hz, 1H), 3.80-3.50 (m, 2H), 3.35-3.10 (m, 2H), 2.70-2.10 (m, 6H), 1.70-1.20 (m, 6H), 1.26 and 1.06 (each t, J=7.0 Hz, total 3H).
EXAMPLE 99 (7) 4-(3-(Imidazol-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2969] 2203
[2970] TLC: Rf 0.43 (chloroform:methanol=4:1);
[2971] NMR (CDCl3): &dgr; 7.95 (d, J=7.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.55 (broad s, 1H), 7.41 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.76 (d, J=7.0 Hz, 1H), 4.07 (t, J=6.6 Hz, 2H), 3.44 (q, J=6.6 Hz, 2H), 2.14 (m, 2H).
EXAMPLE 99 (8) 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)carbamoyl-1,1-dioxidebenzo[b]thiophene[2972] 2204
[2973] TLC: Rf 0.30 (methylene chloride:methanol=9:1);
[2974] NMR (CDCl3): &dgr; 7.85-7.30 (m, 4H), 6.76 (d, J=7.2 Hz, 1H), 3.74 and 3.30 (each t, J=6.0 Hz, total 2H), 3.14 and 2.88 (each s, total 3H), 2.70-2.10 (m, 6H), 1.70-1.30 (m, 6H).
EXAMPLE 99 (9) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene[2975] 2205
[2976] TLC: Rf 0.26 (ethyl acetate);
[2977] NMR (DMSO-d6): &dgr; 8.00-7.92 (m, 1H), 7.74-7.65 (m, 2H), 7.56 (d, J=6.9 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.21 (s, 1H), 7.03-6.95 (m, 2H), 6.07 (s, 2H), 4.64-4.50 (m, 1H), 4.28-4.15 (m, 2H), 3.70-2.96 (m, 8H).
EXAMPLE 99 (10) 4-(4-((2E)-3-Phenyl-2-propenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene hydrochloride[2978] 2206
[2979] TLC: Rf 0.10 (ethyl acetate);
[2980] NMR (DMSO-d6): &dgr; 8.00-7.92 (m, 1H), 7.76-7.65 (m, 2H),7.58 (d, J=6.9 Hz, 1H), 7.53-7.46 (m, 2H),7.51 (d, J=6.9 Hz, 1H), 7.45-7.28 (m, 3H), 6.84 (d, J=15.3 Hz, 1H), 6.47-6.33 (m, 1H), 4.60 (m,1H), 3.98-3.84 (m, 2H), 3.70-2.97 (m, 8H).
EXAMPLES 100˜100 (24)[2981] By the same procedure as described in Example 28 using the compound prepared in Example 81 (1) instead of 4-carboxy-1,1-dioxidebenzo[b]thiophene, and an amine derivative instead of (pyridin-3-yl)ethylamine, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention having the following physical data were obtained.
EXAMPLE 100 4-(Furan-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2982] 2207
[2983] TLC: Rf 0.43 (hexane:ethyl acetate=1:2);
[2984] NMR (DMSO-d6): 8 9.29 (t, J=5.5 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.79-7.76 (m, 3H), 7.67-7.60 (m, 3H), 6.48-6.35 (m, 2H), 6.25 (d, J=9.0 Hz, 1H), 4.55 (dd, J=15.5, 5.5 Hz, 1H), 4.40 (dd, J=15.5, 5.5 Hz, 1H), 4.10 (dd, J=15.3, 9.0 Hz, 1H), 4.00 (d, J=15.3 Hz, 1H).
EXAMPLE 100 (1) 4-(2,4,6-Trimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2985] 2208
[2986] TLC: Rf 0.55 (ethyl acetate);
[2987] NMR (DMSO-d6): &dgr; 8.40 (t, J=4.8 Hz, 1H), 7.89-7.86 (m, 2H), 7.86-7.69 (m, 4H), 7.67-7.58 (m, 2H), 6.25 (s, 2H), 6.18 (dd, J=8.1, 2.1 Hz, 1H), 4.46-4.30 (m, 2H), 4.11-3.94 (m, 2H), 3.77 (s, 9H).
EXAMPLE 100 (2) 4-(3-(2-Oxopyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2988] 2209
[2989] TLC: Rf 0.44 (ethyl acetate:methanol=2:1);
[2990] NMR (CDCl3): &dgr; 8.20-8.08 (m, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.83-7.62 (m, 5H), 7.59-7.49 (m, 2H), 6.40 (dd, J=9.3, 1.2 Hz, 1H), 3.89-3.61 (m, 4H), 3.51-3.33 (m, 2H), 3.32-3.20 (m, 1H), 3.20-3.06 (m, 1H), 2.53-2.33 (m, 2H), 2.15-1.88 (m, 3H), 1.85-1.74 (m,1H).
EXAMPLE 100 (3) 4-((3S)-1-Benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2991] 2210
[2992] More Polar Compound:
[2993] TLC: Rf 0.27 (methanol:ethyl acetate:triethylamine=1:8:0.05);
[2994] NMR (CDCl3): &dgr; 7.90-7.80 (m, 4H), 7.75-7.66 (m, 2H), 7.62-7.53 (m, 2H), 7.37-7.13 (m, 5H), 6.70 (d, J=8.7 Hz, 1H), 6.24-6.17 (m, 1H), 4.74-4.62 (m, 1H), 3.80 (dd, J=15.0,1.5 Hz, 1H), 3.68 (d, J=12.9 Hz, 1H), 3.63 (dd, J=15.0, 9.3 Hz, 1H), 3.57 (d, J=12.9 Hz, 1H), 3.00-2.86 (m, 2H), 2.72 (dd, J=9.9, 6.3 Hz, 1H), 2.51-2.31 (m, 2H), 1.89-1.77 (m, 1H).
[2995] Less Polar Compound:
[2996] TLC: Rf 0.35 (methanol:ethyl acetate:triethylamine=1:8:0.05);
[2997] NMR (CDCl3): &dgr; 7.94-7.87 (m, 2H), 7.87-7.78 (m, 2H), 7.75-7.66 (m, 2H), 7.64-7.56 (m, 2H), 7.41-7.23 (m, 5H), 6.73 (d, J=8.1 Hz, 1H), 6.28-6.21 (m, 1H), 4.71-4.59 (m, 1H), 3.80 (dd, J=14.7, 1.2 Hz, 1H), 3.64 (s, 2H), 3.62 (dd, J=14.7, 9.3 Hz, 1H), 2.95-2.84 (m, 1H), 2.80-2.67 (m, 2H), 2.46-2.30 (m, 2H), 2.12-1.95 (m, 1H).
[2998] The determination of the absolute configuration of * is not performed, but the said more polar and less polar isomers are each single optically active compounds.
EXAMPLE 100 (4) 4-(2-(Pyrrolidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[2999] 2211
[3000] Free Compound:
[3001] TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=4:2:0.5);
[3002] NMR (CDCl3): &dgr; 7.93-7.78 (m, 4H), 7.75-7.66 (m, 2H), 7.63-7.53 (m, 2H), 7.10 (brs, 1H), 6.31-6.24 (m, 1H), 3.83 (dd, J=15.0, 1.5 Hz, 1H), 3.73-3.49 (m, 3H), 2.80 (t, J=5.7 Hz, 2H), 2.69-2.53 (m, 4H), 1.86-1.73 (m, 4H).
[3003] Hydrochloride:
[3004] TLC: Rf 0.37 (ethyl acetate:methanol:triethylamine=4:2:0.5);
[3005] NMR (DMSO-d6): &dgr; 9.18 (t, J=5.4 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.96-7.90 (m, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.81-7.72 (m, 3H), 7.67-7.58 (m, 2H), 6.27 (d, J=9.3 Hz, 1H), 4.13 (dd, J=15.6, 9.3 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.78-3.50 (m, 4H), 3.48-3.28 (m, 2H), 3.06-2.94 (m, 2H), 2.09-1.78 (m, 4H).
EXAMPLE 100 (5) 4-(2-Diethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3006] 2212
[3007] Free Compound:
[3008] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=4:2:0.5);
[3009] NMR (CDCl3): &dgr; 7.92-7.80 (m, 4H), 7.76-7.66 (m, 2H), 7.62-7.56 (m, 2H), 7.03 (brs, 1H), 6.29 (dd, J=9.0, 1.5 Hz, 1H), 3.84 (dd, J=14.4, 1.5 Hz, 1H), 3.72-3.44 (m, 3H), 2.73 (t, J=6.0 Hz, 2H), 2.60 (q, J=7.2 Hz, 4H), 1.04 (t, J=7.2 Hz, 6H).
[3010] Hydrochloride:
[3011] TLC: Rf 0.49 (ethyl acetate:methanol:triethylamine=4:2:0.5);
[3012] NMR (DMSO-d6): &dgr; 10.32 (brs, 1H), 9.30-9.20 (m, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.82-7.72 (m, 3H), 7.68-7.58 (m, 2H), 6.29 (d, J=9.3 Hz, 1H), 4.12 (dd, J=15.6, 9.3 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.80-3.57 (m, 2H), 3.40-3.08 (m, 6H), 1.24 (t, J=7.2 Hz, 6H).
EXAMPLE 100 (6) 4-(2-(N-Ethyl-N-(3-methylphenyl)amino)ethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3013] 2213
[3014] Free Compound:
[3015] TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5);
[3016] NMR (CDCl3): &dgr; 7.94-7.87 (m, 2H), 7.82 (d, J=6.9 Hz, 1H), 7.75-7.67 (m, 1H), 7.67-7.54 (m, 4H), 7.17-7.11 (m, 1H), 6.72-6.64 (m, 2H), 6.56 (d, J=7.8 Hz, 1H), 6.49 (brs, 1H), 6.26 (dd, J=9.0, 1.2 Hz, 1H), 3.81 (dd, J=14.7, 1.2 Hz, 1H), 3.77-3.47 (m, 5H), 3.43 (q, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.15 (t, J=7.2 Hz, 3H).
[3017] Hydrochloride:
[3018] TLC: Rf 0.47 (ethyl acetate:triethylamine=6:0.5);
[3019] NMR (CD3OD): &dgr; 7.98-7.60 (m, 6H), 7.59-7.26 (m, 6H), 6.36-6.15 (m, 1H), 4.09-3.89 (m, 4H), 3.88-3.40 (m, 4H), 2.44 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).
EXAMPLE 100 (7) 4-(N-Ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3020] 2214
[3021] Free Compound:
[3022] TLC: Rf 0.29 (methylene chloride:methanol=6:1);
[3023] NMR (CDCl3): &dgr; 8.00-7.55 (m, 8H), 5.85 (d, J=8 Hz, 1H), 3.85-3.30 (m, 6H), 2.85-2.50 (m, 2H), 2.55 (m, 2H), 2.40 (m, 2H), 1.80-1.40 (m, 6H), 1.34 and 1.36 (each t, J=7 Hz, total 3H).
[3024] Hydrochloride:
[3025] TLC: Rf 0.29 (methylene chloride:methanol=6:1);
[3026] NMR (CDCl3+DMSO-d6): &dgr; 11.30 (broad s, 1H), 7.95-7.60 (m, 8H), 5.89 (d, J=8 Hz, 1H), 4.20-3.80 (m, 3H), 3.80-3.20 (m, 7H), 3.00 (m, 2H), 2.11 (m, 2H), 2.00 (m, 3H), 1.50 (m, 1H), 1.41 (t, J=7 Hz, 3H).
EXAMPLE 100 (8) 4-(3-(Imidazol-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3027] 2215
Free Compound:[3028] TLC: Rf 0.50 (methylene chloride:methanol=4:1);
[3029] NMR (CDCl3): &dgr; 7.90-7.50 (m, 9H), 7.56 (s, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 6.27 (dd, J=2 Hz and 7 Hz, 1H), 4.20-3.95 (m, 2H), 3.80-3.55 (m, 3H), 3.30 (m, 1H), 2.13 (m, 2H).
[3030] Hydrochloride:
[3031] TLC: Rf 0.50 (methylene chloride:methanol=4:1);
[3032] NMR (CDCl3+DMSO-d6): &dgr; 9.59 (s, 1H), 9.49 (t-like, 1H), 8.23 (t, J=4.4 Hz, 1H), 7.85-7.60 (m, 5H), 7.60-7.40 (m, 4H), 7.29 (s, 1H), 6.23 (dd, J=4.0 Hz and 6.8 Hz, 1H), 4.65-4.35 (m, 2H), 3.82 (m, 2H), 3.65 (m, 1H), 3.25 (m, 1H), 2.40 (m, 1H), 2.20 (m, 1H).
EXAMPLE 100 (9) 4-((3R)-1-Benzylpyrrolidin-3-yl)carbamoyl-3-phenylsuilfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3033] 2216
[3034] Less Polar Compound:
[3035] TLC: Rf 0.35 (methanol:ethyl acetate:triethylamine=1:8:0.05);
[3036] NMR (CDCl3) &dgr; 7.94-7.87 (m, 2H), 7.87-7.78 (m, 2H), 7.75-7.67 (m, 2H), 7.64-7.56 (m, 2H), 7.38-7.26 (m, 5H), 6.68 (d, J=8.1 Hz, 1H), 6.28-6.20 (m, 1H), 4.73-4.59 (m, 1H), 3.80 (dd, J=14.7, 1.5 Hz, 1H), 3.66 (s, 2H), 3.63 (dd, J=14.7, 9.3 Hz, 1H), 2.96-2.87 (m, 1H), 2.82-2.66 (m, 2H), 2.47-2.30 (m, 2H), 2.12-1.86 (m, 1H).
[3037] More Polar Compound:
[3038] TLC: Rf 0.27 (methanol:ethyl acetate:triethylamine=1:8:0.05);
[3039] NMR (CDCl3): &dgr; 7.90-7.78 (m, 4H), 7.74-7.65 (m, 2H), 7.62-7.52 (m, 2H), 7.36-7.13 (m, 5H), 6.79 (d, J=8.4 Hz, 1H), 6.25-6.18 (m, 1H), 4.72-4.60 (m, 1H), 3.80 (dd, J=15.0,1.5 Hz, 1H), 3.65 (d, J=12.9 Hz, 1H), 3.62 (dd, J=15.0, 9.0 Hz, 1H), 3.54 (d, J=12.9 Hz, 1H), 2.96-2.83 (m, 2H), 2.72 (dd, J=9.9, 6.3 Hz, 1H), 2.49-2.32 (m, 2H), 1.90-1.73 (m, 1H).
[3040] The determination of the absolute configuration of * is not performed, but the said more polar and less polar isomers are each single optically active compounds.
EXAMPLE 100 (10) 4-(3-(Pyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3041] 2217
[3042] Free Compound:
[3043] TLC: Rf 0.25 (methanol:ethyl acetate:triethylamine=2:4:0.5);
[3044] NMR (CDCl3): &dgr; 9.16-9.06 (m, 1H), 7.91-7.84 (m, 2H), 7.84-7.77 (m, 2H), 7.75-7.62 (m, 2H), 7.61-7.53 (m, 2H), 6.44-6.37 (m, 1H), 3.85 (dd, J=14.7, 1.2 Hz, 1H), 3.80-3.61 (m, 2H), 3.59-3.44 (m, 1H), 2.91-2.72 (m, 2H), 2.71-2.59 (m, 4H), 2.00-1.63 (m, 6H).
[3045] Hydrochloride:
[3046] TLC: Rf 0.26 (methanol:ethyl acetate:triethylamine=2:4:0.5);
[3047] NMR (DMSO-d6): &dgr; 10.43 (brs, 1H), 9.00 (t, J=5.7 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.90-7.74 (m, 4H), 7.71-7.61 (m, 2H), 6.30 (d, J=9.0 Hz, 1H), 4.11 (dd, J=15.0, 9.0 Hz, 1H), 3.94 (d, J=15.0 Hz, 1H), 3.60-3.10 (m, 6H), 3.10-2.78 (m, 2H), 2.11-1.73 (m, 6H).
EXAMPLE 100 (11) 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3048] 2218
[3049] Free Compound:
[3050] TLC: Rf 0.29 (methylene chloride:methanol=6:1);
[3051] NMR (CDCl3): &dgr; 8.05-7.55 (m, 8H), 5.88 (dd, J=8.8 Hz and 2.0 Hz, 1H), 4.00-3.55 and 3.30 (each m, total 4H), 3.20 and 3.17 (each s, total 3H), 2.80-2.35 (m, 6H), 1.70-1.40 (m, 6H)
[3052] Hydrochloride:
[3053] TLC: Rf 0.29 (methylene chloride:methanol=6:1);
[3054] NMR (DMSO-d6): &dgr; 10.49 (broad s, 1H), 8.15 (d, J=6.2 Hz, 1H), 8.00-7.60 (m, 7H), 5.87 (d, J=8.8 Hz, 1H), 4.25-3.70 (m, 4H), 3.70-2.80 (m, 6H), 3.33 and 3.16 (each s, total 3H), 2.00-1.60 (m, 5H), 1.44 (m, 1H).
EXAMPLE 100 (12) 4-(3,5-Dimethoxybenzyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3055] 2219
[3056] TLC: Rf 0.45 (methylene chloride:ethyl acetate=4:1);
[3057] NMR (DMSO-d6): &dgr; 9.26 (t, J=5.8 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.91 (dd, J=7.6, 1.0 Hz, 1H), 7.84 (dd, J=7.0, 1.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 6.51 (d, J=2.2 Hz, 2H), 6.39 (t, J=2.2 Hz, 1H), 4.42 (d, J=5.8 Hz, 2H), 3.73 (s, 6H).
EXAMPLE 100 (13) 4-(3-(Piperidin-1-yl) propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[3058] 2220
[3059] TLC: Rf 0.30 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[3060] NMR (DMSO-d6): &dgr; 10.40 (broad s, 1H), 9.08 (t, J=5.3 Hz, 1H), 8.10-7.60 (m, 8H), 6.33 (d, J=9.2 Hz, 1H), 4.13 (dd, J=15.0 Hz and 9.2 Hz, 1H), 3.94 (d, J=15.0 Hz, 1H), 3.60-3.00 (m, 6H), 2.80 (m, 2H),2.05 (t, J=6.5 Hz, 2H), 1.73 (m, 5H), 1.36 (m,1H).
EXAMPLE 100 (14) 4-(2-Diisopropylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3061] 2221
[3062] TLC: Rf 0.46 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[3063] NMR (DMSO-d6): &dgr; 10.01 (s, 1H), 9.27 (t, J=5.7 Hz, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.88 (t, J=7.0 Hz, 1H), 7.80-7.76 (m, 3H), 7.68-7.60 (m, 2H), 6.36 (d, J=9.0 Hz, 1H), 4.11 (dd, J=15.3 Hz and 9.0 Hz, 1H), 3.96 (d, J=15.3 Hz,1H), 3.90-3.60 (m, 4H), 3.33 (m, 1H), 3.18 (m, 1H), 1.42 (d, J=6.6 Hz, 3H), 1.38 (d, J=6.6 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.32 (d, J=6.6 Hz, 3H).
EXAMPLE 100 (15) 4-(2-(Morpholin-4-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzolb]thiophene.hydrochloride[3064] 2222
[3065] TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[3066] NMR (DMSO-d6): &dgr; 11.14 (broad s, 1H), 9.27 (broad t-like, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.82-7.70 (m, 3H), 7.70-7.60 (m, 2H), 6.30 (d, J=8.4 Hz, 1H), 4.14 (dd, J=15.6 Hz and 8.4 Hz, 1H), 4.00-3.65 (m, 7H), 3.65-3.00 (m, 6H).
EXAMPLE 100 (16) 4-(N-2-(Piperidin-1-yl)ethyl-N-propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[3067] 2223
[3068] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[3069] NMR (DMSO-d6): &dgr; 10.70 and 10.66 (each broad s, total 1H), 8.00-7.65 (m, 8H), 5.83 (d, J=8.7 Hz, 1H), 4.14 (dd, J=15.3 Hz and 8.7 Hz, 1H), 4.00-3.70 (m, 3H), 3.65-3.10 (m, 6H), 3.10-2.80 (m, 2H), 2.00-1.60 (m, 6H), 1.40 (m, 1H), 0.98 and 0.86 (each t, J=7.2 Hz, total 3H).
EXAMPLE 100 (17) 4-(N-2-(Piperidin-1-yl)ethyl-N-isopropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3070] 2224
[3071] TLC;Rf 0.55 (ethyl acetate:methanol:triethylamine=8:1.5:0.5);
[3072] NMR (DMSO-d6): &dgr; 10.78 (broad s, 1H), 8.00-7.60 (m, 8H), 5.90 (d, J=9.2 Hz, 1H), 4.40-4.03 (m, 3H), 4.00-2.80 (m, 8H), 2.00-1.60 (m, 5H), 1.40 (m, 1H), 1.44 and 1.28 and 1.04 (each d, J=6.4 Hz, total 6H).
EXAMPLE 100 (18) 4-(4-Benzoylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3073] 2225
[3074] TLC: Rf 0.48 (methylene chloride:methanol=10:1);
[3075] NMR (DMSO-d6): &dgr; 7.95-7.80 (m, 3H), 7.80-7.56 (m, 5H), 7.42 (s, 5H), 5.92 (dd, J=9.0, 1.5 Hz, 1H), 4.40-4.00 (m, 2H), 3.90-3.40 (m, 6H), 3.72 (dd, J=15.0, 1.5 Hz, 1H), 3.65 (dd, J=15.0, 9.0 H z, 1H).
EXAMPLE 100 (19) 4-(4-(4-Ethylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3076] 2226
[3077] TLC: Rf 0.55 (methylene chloride:methanol 10:1);
[3078] NMR (DMSO-d6): &dgr; 7.88-7.73 (m, 6H), 7.67-7.63 (m, 2H), 7.47 (d, J=7.0 Hz, 2H), 7.21 (d, J=7.0 Hz, 2H), 5.87 (dd, J=10.0, 1.5 Hz, 1H), 4.16 (bs, 2H), 4.05 (dd, J=15.0, 10.0 HZ, 1H), 3.79 (dd, J=15.0, 1.5 Hz, 1H), 3.30-2.90 (m, 8H), 2.58 (q, J=8.0 Hz, 2H), 1.17 (t, J=8.0 Hz, 3H).
EXAMPLE 100 (20) 4-(4-(4-Phenylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1dioxidebenzo[b]thiophene.hydrochloride[3079] 2227
[3080] TLC: Rf 0.55 (methylene chloride:methanol=10:1);
[3081] NMR (DMSO-d6): &dgr; 7.88-7.78 (m, 3H), 7.78-7.72 (m, 3H), 7.67-7.58 (m, 7H), 7.48-7.41 (m, 3H), 7.38-7.34 (m, 1H), 5.88 (d, J=9.5 Hz, 1H), 4.21 (bs, 2H), 4.10-3.70 (m, 8H), 4.06 (dd, J=15.5, 9.5 Hz, 1H), 3.79 (d, 15.5 Hz, 1H), 3.19 (s, 2H).
EXAMPLE 100 (21) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3082] 2228
[3083] TLC: Rf 0.54 (methylene chloride:methanol=10:1);
[3084] NMR (DMSO-d6): &dgr; 7.86-7.76 (m, 4H), 7.74 (d, J=8.0 Hz, 2H), 7.64 (t, J=8.0 Hz, 2H), 7.08 (bs, 1H), 6.98-6.92 (m, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.96-5.92 (m, 2H), 5.86 (d, J=8.5 Hz, 1H), 4.15-3.70 (m, 2H), 4.04 (dd, J=15.0, 8.5 Hz, 1H), 3.78 (d, J=15.0 Hz, 1H), 3.15-2.80 (m, 8H).
EXAMPLE 100 (22) 4-(4-Benzyloxycarbonylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3085] 2229
[3086] TLC: Rf 0.80 (methylene chloride:methanol=10:1);
[3087] NMR (DMSO-d6): &dgr; 7.96-7.80 (m, 4H), 7.76 (d, J=7.5 Hz, 2H), 7.66 (t, J=7.5 Hz, 2H), 7.45-7.36 (m, 5H), 5.89 (d, J=8.7 Hz, 1H), 5.11 (s, 2H), 4.13 (dd, J=14.7, 8.7 Hz, 1H), 3.93 (d, J=14.7 Hz, 1H), 3.80-3.40 (m, 8H).
EXAMPLE 100 (23) 4-(4-(2-Methylphenyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-diozidebenzo[b]thiophene hydrochloride[3088] 2230
[3089] TLC: Rf 0.80 (methylene chloride:methanol=10:1);
[3090] NMR (DMSO-d6): &dgr; 7.97-7.90 (m, 2H), 7.90-7.74 (m, 4H), 7.74-7.63 (m, 2H), 7.23-7.10 (m, 2H), 7.10-6.83 (m, 2H), 5.92 (d, J=9.6 Hz, 1H), 4.15 (dd, J=15.3, 9.6 Hz, 1H), 3.93 (d, J=15.3 Hz, 1H), 3.92-3.80 (m, 2H), 3.08-2.90 (m, 6H), 2.30 (s, 3H).
EXAMPLE 100 (24) 4-(4-(4-Methoxyphenyl) piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[3091] 2231
[3092] TLC: Rf 0.75 (methylene chloride:methanol=10:1); NMR (DMSO-d6): &dgr; 8.02-7.92 (m, 2H), 7.92-7.73 (m, 4H), 7.72-7.64 (m, 2H), 7.36-7.14 (m, 2H), 7.00-6.90 (m, 2H), 5.91 (d, J=9.6 Hz, 1H), 4.20-3.76 (m, 4H), 4.14 (dd, J=15.3, 9.6 Hz, 1H), 3.93 (d, J=15.3 Hz, 1H), 3.72 (s, 3H), 3.45-3.26 (m, 4H).
EXAMPLES 101˜101 (1)[3093] By the same procedure as described in Example 1 using the compounds prepared in Examples 28 (11) and 73 (16) instead of 1,1-dioxidebenzo[b]thiophene, the following compounds of the present invention were obtained.
EXAMPLE 101 4-2-(Piperidin-1-yl)ethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3094] 2232
[3095] TLC: Rf 0.40 (methanol:water:acetic acid=1:1:0.1);
[3096] NMR (CDCl3): &dgr; 7.81 (dd, J=7.6, 1.1 Hz, 1H), 7.75 (dd, J=7.6, 1.1 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.38-7.35 (m, 3H), 6.91 (br, 1H), 5.74 (dd, J=7.3, 1.3 Hz, 1H), 3.72 (dd, J=13.9, 7.3 Hz, 1H), 3.68-3.58 (m, 1H), 3.60 (dd, J=13.9, 1.3 Hz, 1H), 3.55-3.45 (m, 1H), 2.55 (t, J=5.8 Hz, 2H), 2.38 (br, 4H), 1.56-1.48 (m, 4H), 1.44-1.39 (m, 2H).
EXAMPLE 101 (1) 4-(2-(Pyridin-2-yl)ethyl)oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene[3097] 2233
[3098] TLC: Rf 0.30 (hexane:ethyl acetate=1:1);
[3099] NMR (CDCl3): &dgr; 8.54 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 7.54 (dt, J=7.7, 1.7 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.34-7.22 (m, 5H), 7.15-7.10 (m, 2H), 4.91 (dd, J=6.9, 1.8 Hz, 1H), 4.52 (t, J=6.6 Hz, 2H), 3.66 (dd, J=13.8, 6.9 Hz, 1H), 3.57 (dd, J=13.8, 1.8 Hz, 1H), 3.31 (t, J=6.6 Hz, 2H).
EXAMPLE 102 4-(2-(Piperidin-1-yl)ethyl)carbamoyl-3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3100] 2234
[3101] By the same procedure as described in Example 27 using the compound prepared in Example 28 (11) instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and 4-nitrobenzenesulfonic acid sodium salt instead of benzenesulfonic acid sodium salt, and if necessary, by converting into hydrochloride by a known method, the compounds of the present invention having the following physical data were obtained.
[3102] Free Compound:
[3103] TLC: Rf 0.40(methanol:water:acetic acid=5:5:0.5);
[3104] NMR (CDCl3): &dgr; 8.35 (d, J=8.7 Hz, 2H), 8.01 (d, J=8.7 Hz, 2H), 7.91 (dd, J=7.5,1.7 Hz, 1H), 7.81 (dd, J=7.5, 1.7 Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 7.59 (br, 1H), 6.42 (dd, J=9.2, 1.5 Hz, 1H), 3.88 (dd, J=15.0,1.5 Hz, 1H), 3.75 (dd, J=15.0, 9.2 Hz, 1H), 3.75-3.64 (m, 1H), 3.57-3.48 (m, 1H), 2.77-2.65 (m, 2H), 2.53 (br, 4H), 1.66-1.57 (m, 4H), 1.52-1.45 (m, 2H).
[3105] Hydrochloride:
[3106] TLC: Rf 0.40 (methanol:water:acetic acid=5:5:0.5);
[3107] NMR (DMSO-d6): &dgr; 9.98 (br, 1H), 9.28 (br, 1H), 8.42 (d, J=8.7 Hz, 2H), 8.11 (d, J=7.5 Hz, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.97 (d, J=7.5 Hz, 1H), 7.89 (t, J=7.5 Hz, 1H), 6.41 (dd, J=7.3, 3.2 Hz, 1H), 4.16 (dd, J=15.5, 7.3 Hz, 1H), 4.10 (dd, J=15.5, 3.2 Hz, 1H), 3.72-3.70 (m, 2H), 3.57-3.48 (m, 2H), 3.32-3.25 (m, 2H), 2.96 (br, 2H), 1.82-1.68 (m, 5H), 1.45-1.35 (m, 1H).
EXAMPLES 103˜103 (41)[3108] By the same procedure as described in Example 31 using 4-methylsulfonyloxymethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene instead of 4-bromomethyl-1,1-dioxidebenzo[b]thiophene and an amine derivative corresponding to 2,4-dimethoxybenzylamine hydrochloride, and if necessary, by converting into the corresponding salt by a known method, the following compounds of the present invention were obtained.
EXAMPLE 103 4-(N-2-(Piperidin-1-yl)ethyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3109] 2235
[3110] TLC: Rf 0.48 (methanol:ethyl acetate:triethylamine=2:8:0.5);
[3111] NMR (CD3OD+D2O (4 drops)): &dgr; 8.16 (d, J=7.5 Hz, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.85-7.73 (m, 4H), 7.64-7.55 (m, 2H), 6.18-6.10 (m, 1H), 4.93 (d, J=14.4 Hz, 1H), 4.60 (d, J=14.4 Hz, 1H), 4.03 (dd, J=15.6, 9.0 Hz, 1H), 3.84 (dd, J=15.6, 0.9 Hz, 1H), 3.72-3.00 (m, 8H), 2.74 (s, 3H), 2.00-1.55 (m, 6H).
EXAMPLE 103 (1) 4-(2-(N-Ethyl-N-3-methylphenyl)aminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride[3112] 2236
[3113] TLC: Rf 0.45 (ethyl acetate:triethylamine=6:0.5);
[3114] NMR (DMSO-d6): &dgr; 9.64 (brs, 2H), 8.21 (d, J=6.3 Hz, 1H), 7.89-7.74 (m, 5H), 7.67-7.58 (m, 2H), 7.18-7.04 (m, 1H), 6.96-6.50 (m, 3H), 6.46 (dd, J=6.9, 3.0 Hz, 1H), 4.73-4.59 (m, 1H), 4.49-4.35 (m, 1H), 3.97-3.80 (m, 2H), 3.80-3.58 (m, 2H), 3.50-3.33 (m, 2H), 3.29-3.10 (m, 2H), 2.25 (s, 3H), 1.06 (t, J=6.9 Hz, 3H).
EXAMPLE 103 (2) 4-(N-Benzyl-N-ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[3115] 2237
[3116] TLC: Rf 0.67 (ethyl acetate:triethylamine=6:0.5);
[3117] NMR (CD3OD+pyridine-d5) &dgr; 7.92 (d, J=7.2 Hz, 1H), 7.71-7.58 (m, 4H), 7.57-7.45 (m, 3H), 7.32-7.15 (m, 5H), 5.84 (dd, J=8.4, 1.8 Hz, 1H), 4.33 (d, J=14.7Hz, 1H), 3.90-3.62 (m, 4H),3.60 (d, J=13.2 Hz, 1H), 2.65 .(q, J=7.2Hz, 2H), 1.14 (t, J=7.2 Hz, 3H).
EXAMPLE 103 (3) 4-(2-Diethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene-2hydrochloride[3118] 2238
[3119] TLC: Rf 0.35 (methanol ethyl acetate triethylamine=2:8:0.5);
[3120] NMR (DMSO-d6): &dgr; 10.66 (brs, 1H), 9.96 (brs, 1H), 9.76 (brs, 1H), 8.26-8.26 (m, 1H), 7.91-7.74 (m, 5H), 7.67-7.57 (m, 2H), 6.54-6.45 (m, 1H), 4.83-4.65 (m, 1H), 4.60-4.42 (m, 1H), 3.96-3.82 (m, 2H), 3.70-3.37 (m, 4H), 3.28-3.10 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).
EXAMPLE 103 (4) 4-(4-Methylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3121] 2239
[3122] TLC: Rf 0.47 (ethyl acetate:triethylamine=6:0.5);
[3123] NMR (DMSO-d6): &dgr; 9.83 (brs, 1H), 9.54 (brs, 1H), 8.16 (d, J=6.9 Hz, 1H), 7.89-7.75 (m, 3H), 7.75-7.68 (m, 2H), 7.68-7.59 (m, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 6.29 (dd, J=4.8, 3.9 Hz, 1H), 4.72-4.58 (m, 1H), 4.44-4.32 (m, 1H), 4.25 (brs, 2H), 3.93-3.80 (m, 2H), 2.32 (s, 3H).
EXAMPLE 103 (5) 4-(N-Ethyl-N-2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3124] 2240
[3125] TLC: Rf 0.47 (methanol ethyl:acetate triethylamine=2:8:0.5);
[3126] NMR (CD3OD+D2O (1 drop)) &dgr; 8.24 (d, J=7.5 Hz, 1H), 7.92-7.69 (m, 5H), 7.61-7.52 (m, 2H), 6.21-6.10 (m, 1H), 5.15 (d, J=14.4 Hz, 1H), 4.70 (d, J=14.4 Hz, 1H), 4.05 (dd, J=15.3, 9.0 Hz, 1H), 3.84 (dd, J=15.3, 0.9 Hz, 1H), 3.76-2.80 (m, 10H), 1 98-1.50 (m, 6H), 1.45 (t, J=7.2 Hz, 3H).
EXAMPLE 103 (6) 4-(2-Methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3127] 2241
[3128] TLC: Rf 0.49 (ethyl acetate:triethylamine=6:0.5);
[3129] NMR (DMSO-d6): &dgr; 9.51 (brs, 2H), 8.21-8.11 (m, 1H), 7.89-7.775 (m, 3H), 7.74-7.58 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.16-6.06 (m, 1H), 4.77-4.62 (m, 1H), 4.52-4.37 (m, 1H), 4.31-4.12 (m, 2H), 3.95-3.82 (m, 2H), 3.81 (s, 3H).
EXAMPLE 103 (7) 4-(3-Phenylpropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3130] 2242
[3131] TLC: Rt 0.37 (ethyl acetate:triethylamine=6:0.5);
[3132] NMR (DMSO-d6): &dgr; 9.50 (brs, 1H), 8.16 (d, J=6.3 Hz, 1H), 7.90-7.73 (m, 5H), 7.68-7.58 (m, 2H), 7.35-7.16 (m, 5H), 6.44 (dd, J=6.9, 3.0 Hz, 1H), 4.69-4.54 (m, 1H), 4.45-4.31 (m , 1H), 3.95-3.79 (m, 2H), 3.14-2.95 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 2.09-1.91 (m, 2H).
EXAMPLE 103 (8) 4-(3,5-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3133] 2243
[3134] TLC: Rf 0.43(ethyl acetate:triethylamine=6:0.5);
[3135] NMR (DMSO-d6): &dgr; 9.94 (brs, 1H), 9.65 (brs, 1H), 8.17 (d, J=6.9 Hz, 1H), 7.90-7.75 (m, 3H), 7.75-7.67 (m, 2H), 7.67-7.58 (m, 2H), 6.87 (d, J=2.1 Hz, 2H), 6.55 (t, J=2.1 Hz, 1H), 6.30 (t, J=4.5 Hz, 1H), 4.72-4.57 (m, 1H), 4.43-4.28 (m, 1H), 4.23 (brs, 2H), 4.00-3.67 (m, 2H), 3.75 (s, 6H).
EXAMPLE 103 (9) 4-((3R)-1-Benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3136] 2244
[3137] TLC: Rf 0.45(methanol:ethyl acetate:triethylamine=2:8:0.5);
[3138] NMR (CD3OD): &dgr; 8.20 (d, J=6.9 Hz, 1H), 7.91-7.70 (m, 5H), 7.66-7.54 (m, 4H), 7.53-7.43 (m, 3H), 6.18-6.05 (m, 1H), 4.77 (d, J=14.1 Hz, 1H), 4.67-4.32 (m, 4H), 4.02-3.66 (m, 5H), 3.62-3.38 (m, 1H), 2.88-2.40 (m, 2H).
EXAMPLE 103 (10) 4-((3S)-1-Benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride[3139] 2245
[3140] TLC: Rf 0.45(methanol:ethyl acetate:triethylamine=2:8:0.5);
[3141] NMR (CD3OD): &dgr; 8.20 (d, J=6.9 Hz, 1H), 7.91-7.70 (m, 5H), 7.66-7.54 (m, 4H), 7.53-7.43 (m, 3H), 6.18-6.04 (m, 1H), 4.78 (d, J=12.9 Hz, 1H), 4.68-4.32 (m, 4H), 4.02-3.66 (m, 5H), 3.62-3.38 (m, 1H), 2.88-2.40 (m, 2H).
EXAMPLE 103 (11) 4-(2-Phenylethyl)aminomethyl-3-phenylsulfonyl-2,3-dohydro-1,1-dioxidebenzo[b]thiophene[3142] 2246
[3143] Free Compound:
[3144] TLC: Rf 0.28 (ethyl acetate);
[3145] NMR (CDCl3): &dgr; 7.65-7.40 (m, 8H), 7.30-7.15 (m, 5H), 5.90 (dd, J=9.3, 0.9 Hz, 1H), 4.66 (d, J=14.2 Hz, 1H), 3.92 (d, J=14.2 Hz, 1H), 3.73 (dd, J=15.0, 0.9 Hz, 1H), 3.42 (dd, J=15.0, 9.3 Hz, 1H), 3.01-2.74 (m, 4H).
[3146] Hydrochloride:
[3147] TLC: Rf 0.28 (ethyl acetate);
[3148] NMR (DMSO-d6): &dgr; 9.55 (br, 1H), 9.35 (br, 1H), 8.18 (dd, J=6.2, 2.5 Hz, 1H), 7.94-7.87 (m, 2H), 7.82-7.78 (m, 3H), 7.67-7.62 (m, 2H), 7.38-7.33 (m, 2H), 7.29-7.25 (m, 3H), 6.41 (dd, J=7.5, 2.1 Hz, 1H), 4.69-4.6 5 (m, 1H), 4.45-4.41 (m, 1H), 3.92 (dd, J=15.3, 7.5 Hz, 1H), 3.84 (dd, J=15.3, 2.1 Hz, 1H), 3.32-3.25 (m, 2H), 3,08-2.98 (m, 2H).
EXAMPLE 103 (12) 4-(N-Benzyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3149] 2247
[3150] Free Compound:
[3151] TLC: Rf 0.42 (hexane:ethyl acetate=1:2);
[3152] NMR (CDCl3): &dgr; 7.71 (dd, J=7.2,1.2 Hz, 1H), 7.64-7.49 (m, 5H), 7.44-7.39 (m, 2H), 7.34-7.20 (m, 5H), 6.08 (dd, J=9.3, 1.0 Hz, 1H), 4.66 (d, J=14.1 Hz, 1H), 3.88 (dd, J=15.0, 1.0 Hz, 1H), 3.69 (dd, J=15.0, 9.3 Hz, 1H), 3.61 (d, J=12.9 Hz, 1H), 3.53 (d, J=14.1 Hz, 1H), 3.47 (d, J=12.9 Hz, 1H), 2.16 (s, 3H).
[3153] Hydrochloride:
[3154] TLC: Rf 0.42 (hexane:ethyl acetate=1:2);
[3155] NMR (CD3OD+pyridine-d5): &dgr; 7.92 (d, J=7.5 Hz, 1H), 7.73-7.63 (m, 5H), 7.56-7.50 (m, 2H), 7.37-7.31 (m, 5H), 5.99 (dd, J=7.0, 3.0 Hz, 1H), 4.52 (d, J=14.4 Hz, 1H), 3.94-3.85 (m, 3H), 3.83 (d, J=13.0 Hz, 1H), 3.76 (d, J=13.0 Hz, 1H), 2.32 (s, 3H).
EXAMPLE 103 (13) 4-(3-(2-Oxopyrrolidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3156] 2248
[3157] Free Compound:
[3158] TLC: Rf 0.27 (ethyl acetate:methanol:triethylamine=8:1:1);
[3159] NMR (CDCl3): &dgr; 7.72 (dd, J=7.5, 1.5 Hz, 1H), 7.65-7.54 (m, 4H), 7.51 (dd, J=7.5, 1.5 Hz, 1H), 7.47-7.42 (m, 2H), 5.98 (t-like, J=5.1 Hz, 1H), 4.56 (d, J=13.8 Hz, 1H), 3.91-3.87 (m, 3H), 3.40-3.30 (m, 4H), 2.67-2.53 (m, 2H), 2.41-2.38 (m, 2H), 2.05-1.95 (m, 2H), 1.78-1.69 (m, 2H).
[3160] Hydrochloride:
[3161] TLC: Rf 0.27 (ethyl acetate:methanol:tiethylamine=8:1:1);
[3162] NMR (DMSO-d6): &dgr; 9.32 (m, 1H), 9.08 (m, 1H), 8.14 (dd, J=6.3, 2.1 Hz, 1H), 7.90-7.78 (m, 5H), 7.67-7.62 (m, 2H), 6.40 (dd, J=7.5, 2.0 Hz, 1H), 4.66-4.60 (m, 1H), 4.43-4.37 (m, 1H), 3.94-3.81 (m, 2H), 3.38-3.25 (m, 4H), 3.03-2.97 (m, 2H), 2.26 (t, J=8.0 Hz, 2H), 1.99-1.83 (m, 4H).
EXAMPLE 103 (14) 4-(4-Aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3163] 2249
[3164] Free Compound:
[3165] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1:1);
[3166] NMR (DMSO-d6): &dgr; 7.90 (dd, J=7.0, 2.0 Hz, 1H), 7.80-7.61 (m, 7H), 6.97 (d, J 8.5 Hz, 2H), 6.52 (d, J=8.5 Hz, 2H), 5.81 (dd, J=8.0, 1.8 Hz, 1H), 4.93 (s, 2H), 4.01 (d, J=14.7 Hz, 1H), 3.91 (dd, J=15.0, 8.0 Hz, 1H), 3.84 (dd, J=15.0, 1.8 Hz, 1H), 3.77 (d, J=14.7 Hz, 1H), 3.48 (s, 2H).
[3167] Hydrochloride:
[3168] TLC: Rf 0.47 (ethyl acetate:methanol:triethylamine=8:1:1);
[3169] NMR (DMSO-d6): &dgr; 9.90 (br, 1H), 9.59 (br, 1H), 8.18 (dd, J=7.0, 1.5 Hz, 1H), 7.88-7.60 (m, 9H), 7.21 (d, J=7.8 Hz, 2H), 6.37-6.34 (m, 1H), 4.70-4.64 (m, 1H), 4.42-4.32 (m, 1H), 4.28 (s, 2H), 3.93-3.82 (m, 2H).
EXAMPLE 103 (15) 4-(4-((2E)-3-Phenyl-2-propenyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3170] 2250
[3171] Free Compound:
[3172] TLC: Rf 0.48 (ethyl acetate:methanol=9:1);
[3173] NMR (CDCl3): &dgr; 7.65-7.20 (m, 13H), 6.52 (d, J=15.9 Hz, 1H), 6.30 (dd, J=9.3, 1.2 Hz, 1H), 6.26 (dt, J=15.9, 6.8 Hz, 1H), 4.70 (d, J=14.3 Hz, 1H), 3.91 (dd, J=15.0, 1.2 Hz, 1H), 3.73 (dd, J=15.0, 9.3 Hz, 1H), 3.42 (d, J=14.3 Hz, 1H), 3.16 (d, J=6.8 Hz, 2H), 2.60-2.40 (m, 8H).
[3174] Hydrochloride:
[3175] TLC: Rf 0.48 (ethyl acetate:methanol=9:1);
[3176] NMR (CD3OD+D2O): 5 7.93 (d, J=7.0 Hz, 1H), 7.78-7.72 (m, 4H), 7.66 (d, J=7.0 Hz, 1H), 7.61-7.50 (m, 2H), 7.41-7.33 (m, 3H), 6.95 (d, J=15.6 Hz, 1H), 6.33 (dt, J=15.6, 7.7 Hz, 1H), 6.16 (d, J=9.0 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.02 (dd, J=15.0,9.0Hz, 1H), 3.96 (d, J=7.7Hz, 2H), 3.89 (d, J=15.0Hz, 1H), 3.85 (d, J=14.5 Hz, 1H), 3.42 (br, 4H), 3.29 (br, 4H).
EXAMPLE 103 (16) 4-(2-Aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3177] 2251
[3178] Free Compound:
[3179] TLC: Rf 0.30 (ethyl acetate);
[3180] NMR (CDCl3): &dgr; 7.74 (d, J=7.5 Hz, 1H), 7.65-7.55 (m, 2H), 7.51-7.39 (m, 5H), 7.09 (dt, J=7.5, 1.5 Hz, 1H), 6.97 (dd, J=7.5, 1.5 Hz, 1H), 6.67 (dt, J=7.5, 1.5 Hz, 1H), 6.63 (dd, J=7.5, 1.5 Hz, 1H), 5.43 (dd, J=9.5, 1.2 Hz, 1H), 4.29 (d, J=14.3 Hz, 1H), 4.02 (d, J=14.3 Hz, 1H), 3.88 (d, J=12.6 Hz, 1H), 3.82 (dd, J=15.0, 1.2 Hz, 1H), 3.81 (d, J=12.6 Hz, 1H), 3.66 (dd, J=15.0, 9.5 Hz, 1H).
[3181] Hydrochloride:
[3182] TLC: Rf 0.30 (ethyl acetate); NMR (DMSO-d6): &dgr; 8.17 (dd, J=6.3, 2.4 Hz, 1H), 7.87-7.71 (m, 5H), 7.66-7.61 (m, 2H), 7.50 (br, 2H), 7.29 (dd, J=7.5, 1.2 Hz, 1H), 7.13 (dt, J=7.5, 1.2 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.63 (t, J=7.5 Hz, 1H), 6.21 (t-like, J=5.0 Hz, 1H), 4.72 (d, J=13.8 Hz, 1H), 4.46 (d, J=13.8 Hz, 1H), 4.26-4.17 (m, 2H), 3.93-3.82 (m, 2H).
EXAMPLE 103 (17) 4-(4-Benzylpiperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3183] 2252
[3184] Free Compound:
[3185] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[3186] NMR (CDCl3) &dgr; 7.66-7.56 (m, 4H), 7.53-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.30-7.25 (m, 2H), 7.21-7.11 (m, 3H), 6.36 (d, J=9.3 Hz, 1H), 4.62 (d, J=14.4 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.71 (dd, J=15.0, 9.3 Hz, 1H), 3.35 (d, J=14.4 Hz, 1H), 3.04-3.00 (m, 1H), 2.53 (d, J=6.9 Hz, 2H), 2.55-2.50 (m, 1H), 2.05 (dt, J=11.5, 2.5 Hz, 1H), 1.85 (dt, J=11.5, 2.5 Hz, 1H), 1.74-1.68 (m, 1H), 1.62-1.15 (m, 2H), 1.35 (dt, J=12.0, 3.5 Hz, 1H), 1.16-1.02 (m, 1H).
[3187] Hydrochloride:
[3188] TLC: Rf 0.50 (hexane:ethyl acetate=1:1);
[3189] NMR (DMSO-d6): &dgr; 10.42 (br, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.92-7.72 (m, 5H), 7.65-7.60 (m, 2H), 7.31-7.15 (m, 5H), 6.30 (d, J=9.0 Hz, 1H), 4.72 (dd, J=13.8, 5.3 Hz, 1H), 4.53 (dd, J=13.8,5.3 Hz, 1H), 4.02 (dd, J=15.3,9.0 Hz, 1H), 3.83 (d, J=15.3 Hz, 1H), 3.42-3.39 (m, 1H), 3.12-3.00 (m, 3H), 2.60-2.42 (m, 2H), 1.79-1.49 (m, 5H).
EXAMPLE 103 (18) 4-(4-Chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3190] 2253
[3191] Free Compound:
[3192] TLC: Rf 0.43(ethyl acetate);
[3193] NMR (CDCl3): &dgr; 7.75 (dd, J=7.0,1.2 Hz, 1H), 7.66-7.51 (m, 5H), 7.47-7.42 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.81 (dd, J=9.3,1.3 Hz, 1H), 4.48 (d, J=14.0 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 3.86 (dd, J=15.0,1.3 Hz, 1H), 3.84 (d, J=13.3 Hz, 1H), 3.78 (d, J=13.3 Hz, 1H), 3.68 (dd, J=15.0, 9.3 Hz, 1H).
[3194] Hydrochloride:
[3195] TLC: Rf 0.43 (ethyl acetate);
[3196] NMR (DMSO-d6): &dgr; 9.86 (br, 1H), 9.55 (br, 1H), 8.16 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.72 (m, 5H), 7.67-7.62 (m, 4H), 7.53 (d, J=8.4 Hz, 2H), 6.31 (dd, J=6.2, 3.5 Hz, 1H), 4.70-4.66 (m, 1H), 4.43-4.39 (m, 1H), 4.32 (s, 2H), 3.90 (dd, J=15.5, 6.2 Hz, 1H), 3.84 (dd, J=15.5, 3.5 Hz, 1H).
EXAMPLE 103 (19) 4-(3-Chlorobenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3197] 2254
[3198] Free Compound:
[3199] TLC: Rf 0.51 (ethyl acetate);
[3200] NMR (CDCl3): &dgr; 7.76 (dd, J=7.0, 1.2 Hz, 1H), 7.67-7.40 (m, 7H), 7.30-7.14 (m, 4H), 5.80 (dd, J=9.2,1.4 Hz, 1H), 4.48 (d, J=14.0 Hz, 1H), 3.99 (d, J=14.0 Hz, 1H), 3.87 (dd, J=15.4, 1.4 Hz, 1H), 3.86 (d, J=13.6 Hz, 1H), 3.77 (d, J=13.6 Hz, 1H), 3.69 (dd, J=15.4, 9.2 Hz, 1H).
[3201] Hydrochloride:
[3202] TLC: Rf 0.51 (ethyl acetate);
[3203] NMR (DMSO-d6): &dgr; 9.92 (br, 1H), 9.62 (br, 1H), 8.18 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.74 (m, 6H), 7.67-7.59 (m, 3H), 7.52-7.45 (m, 2H), 6.39 (dd, J=5.7, 4.2 Hz, 1H), 4.74-4.69 (m, 1H), 4.44-4.40 (m, 1H), 4.35 (s, 2H), 3.90 (dd, J=15.6, 5.7 Hz, 1H), 3.84 (dd, J=15.6, 4.2 Hz, 1H).
EXAMPLE 103 (20) 4-(3-Methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3204] 2255
[3205] Free Compound:
[3206] TLC: Rf 0.41 (ethyl acetate);
[3207] NMR (CDCl3): &dgr; 7.75 (dd, J=7.2, 1.2 Hz, 1H), 7.65-7.50 (m, 5H), 7.46-7.40 (m, 2H), 7.26-7.21 (m, 1H), 6.86-6.79 (m, 3H), 5.81 (dd, J=9.3, 1.2 Hz, 1H), 4.48 (d, J=14.1 Hz, 1H), 3.98 (d, J=14.1 Hz, 1H), 3.84 (d, J=13.5 Hz, 1H), 3.84 (dd, J=15.0, 1.2 Hz, 1H), 3.80 (s, 3H), 3.74 (d, J=13.5 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
[3208] Hydrochloride:
[3209] TLC: Rf 0.41 (ethyl acetate);
[3210] NMR (DMSO-d6): &dgr; 9.83 (br, 1H), 9.55 (br, 1H), 8.16 (dd, J=6.6, 1.8 Hz, 1H), 7.89-7.78 (m, 3H), 7.73-7.61 (m, 4H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 7.00 (dd, J=7.9,2.5Hz, 1H), 6.27 (dd, J=6.0,3.9Hz, 1H), 4.70-4.65 (m, 1H), 4.42-4.37 (m,1H), 4.29 (br, 2H), 3.89 (dd, J=15.5, 6.0 Hz, 1H), 3.84 (dd, J=15.5, 3.9 Hz, 1H), 3.78 (s, 3H).
EXAMPLE 103 (21) 4-(3,4-Dichlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3211] 2256
[3212] Free Compound:
[3213] TLC: Rf 0.42(ethyl acetate);
[3214] NMR (CDCl3): &dgr; 7.77 (dd, J=7.2, 1.2 Hz, 1H), 7.67-7.52 (m, 5H), 7.47-7.39 (m, 4H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 5.76 (dd, J=9.5, 1.2 Hz, 1H), 4.45 (d, J=13.8 Hz, 1H), 4.00 (d, J=13.8 Hz, 1H), 3.86 (dd, J=15.0, 1.2 Hz, 1H), 3.84 (d, J=13.8 Hz, 1H), 3.78 (d, J=13.8 Hz, 1H), 3.70 (dd, J=15.0, 9.5 Hz, 1H).
[3215] Hydrochloride:
[3216] TLC: Rf 0.42 (ethyl acetate);
[3217] NMR (DMSO-d6): &dgr; 9.94 (br, 1H), 9.62 (br, 1H), 8.17 (dd, J=6.6, 2.1 Hz, 1H), 7.96 (d, J=1.8 Hz,1H), 7.89-7.73 (m, 6H), 7.67-7.60 (m, 3H), 6.40 (dd, J=5.5, 4.2 Hz, 1H), 4.75-4.68 (m, 1H), 4.45-4.40 (m, 1H), 4.35 (s, 2H), 3.95 (dd, J=15.5, 5.5 Hz, 1H), 3.85 (dd, J=15.5, 4.2 Hz, 1H).
EXAMPLE 103 (22) 4-(1,3-Dioxaindan-5-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3218] 2257
[3219] Free Compound:
[3220] TLC: Rf 0.43(ethyl acetate);
[3221] NMR (CDCl3): &dgr; 7.73 (dd, J=7.5, 1.2 Hz, 1H), 7.65-7.49 (m, 5H), 7.46-7.41 (m, 2H), 6.77 (d, J=1.5 Hz,1H), 6.74 (d, J=8.0 Hz, 1H), 6.69 (dd, J=8.0, 1.5 Hz, 1H), 5.95-5.94 (m, 2H), 5.88 (dd, J=9.5,1.0 Hz, 1H), 4.50 (d, J=14.0 Hz,1H), 3.96 (d, J=14.0 Hz, 1H), 3.86 (dd, J=15.0, 1.0 Hz, 1H), 3.77 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.68 (dd, J=15.0, 9.5 Hz, 1H).
[3222] Hydrochloride:
[3223] TLC: Rf 0.43 (ethyl acetate);
[3224] NMR (DMSO-d6): &dgr; 9.78 (br, 1H), 9.47 (br, 1H), 8.15 (dd, J=6.6, 1.8 Hz, 1H), 7.88-7.72 (m, 5H), 7.66-7.61 (m, 2H), 7.25 (d, J=1.5 Hz, 1H), 7.08 (dd, J=7.8, 1.5 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.30 (t-like, J=4.5 Hz, 1H), 6.05 (s, 2H), 4.67-4.61 (m, 1H), 4.38-4.33 (m, 1H), 4.23 (s, 2H), 3.93-3.83 (m, 2H).
EXAMPLE 103 (23) 4-(2,3-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3225] 2258
[3226] Free Compound:
[3227] TLC: Rf 0.36(ethyl acetate);
[3228] NMR (CDCl3): &dgr; 7.71 (dd, J=7.0, 1.3 Hz, 1H), 7.63-7.48 (m, 5H), 7.45-7.39 (m, 2H), 7.00 (t, J=7.8 Hz, 1H), 6.84 (dd, J=7.8, 1.5 Hz, 1H), 6.78 (dd, J=7.8, 1.5 Hz, 1H), 6.06 (dd, J=9.3, 1.3 Hz, 1H), 4.52 (d, J=14.1 Hz, 1H), 3.92 (d, J=14.1 Hz, 1H), 3.86 (s, 3H), 3.85 (dd, J=15.0, 1.3 Hz, 1H), 3.80 (d, J=13.3 Hz, 1H), 3.76 (s, 3H), 3.73 (dd, J=15.0, 9.3 Hz, 1H), 3.69 (d, J=13.3 Hz, 1H).
[3229] Hydrochloride:
[3230] TLC: Rf 0.36 (ethyl acetate);
[3231] NMR (DMSO-d6): &dgr; 9.70-9.60 (br, 2H), 8.17 (dd, J=6.6, 2.1 Hz, 1H), 7.89-7.73 (m, 5H), 7.67-7.62 (m, 2H), 7.25-7.21 (m, 1H), 7.15-7.13 (m, 2H), 6.12 (dd, J=6.8, 2.5 Hz, 1H), 4.71-4.67 (m, 1H), 4.45-4.41 (m, 1H), 4.32-4.20 (m, 2H), 3.93-3.83 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H).
EXAMPLE 103 (24) 4-(3,4,5-Trimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3232] 2259
[3233] Free Compound:
[3234] TLC: Rf 0.20(ethyl acetate);
[3235] NMR (CDCl3): &dgr; 7.79 (dd, J=7.2, 1.2 Hz, 1H), 7.66-7.52 (m, 5H), 7.47-7.42 (m, 2H), 6.54 (s, 2H), 5.72 (dd, J=9.3, 1.2 Hz, 1H), 4.45 (d, J=14.0 Hz, 1H), 4.03 (d, J=14.0 Hz, 1H), 3.86 (s, 6H), 3.84 (s, 3H), 3.84 (dd, J=15.0, 1.2 Hz, 1H), 3.82 (d, J=13.5 Hz, 1H), 3.74 (d, J=13.5 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
[3236] Hydrochloride:
[3237] TLC: Rf 0.20 (ethyl acetate);
[3238] NMR (DMSO-d6): &dgr; 9.98 (br, 1H), 9.63 (br, 1H), 8.18 (dd, J=6.6, 1.5 Hz, 1H), 7.89-7.78 (m, 3H), 7.72-7.60 (m, 4H), 7.06 (s, 2H), 6.30 (dd, J=6.0, 3.5 Hz, 1H), 4.69-4.66 (m, 1H), 4.39-4.37 (m, 1H), 4.24 (s, 2H), 3.92-3.84 (m, 2H), 3.80 (s, 6H), 3.67 (s, 3H).
EXAMPLE 103 (25) 4-(4-(t-Butyloxycarbonyl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3239] 2260
[3240] Free Compound:
[3241] TLC: Rf 0.49 (hexane:ethyl acetate=1:2);
[3242] NMR (CDCl3): &dgr; 7.66-7.52 (m, 6H), 7.48-7.43 (m, 2H), 6.18 (dd, J=9.0, 1.0 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 3.89 (dd, J=15.0, 1.0 Hz, 1H), 3.72 (dd, J=15.0, 9.0 Hz, 1H), 3.49-3.35 (m, 4H), 3.45 (d, J=14.3 Hz, 1H), 2.52-2.45 (m, 2H), 2.36-2.29 (m, 2H), 1.46 (s, 9H).
[3243] Hydrochloride:
[3244] TLC: Rf 0.49 (hexane:ethyl acetate=1:2);
[3245] NMR (CD3OD): &dgr; 8.11 (d, J=7.2 Hz, 1H), 7.92-7.83 (m, 2H), 7.77-7.73 (m, 3H), 7.60-7.55 (m, 2H), 6.03 (dd, J=8.7, 1.0 Hz, 1H), 5.01 (d, J=14.3 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.22 (br, 2H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.84 (dd, J=15.3,1.0 Hz, 1H), 3.65-3.25 (br, 6H), 1.47 (s, 9H).
EXAMPLE 103 (26) 4-(2-Diisopropylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3246] 2261
[3247] TLC: Rf 0.43(methanol:ethyl acetate:triethylamine=2:8:0.5);
[3248] NMR (CD3OD+D2O): &dgr; 8.18 (d, J=7.5 Hz, 1H), 7.97-7.76 (m, 5H), 7.70-7.60 (m, 2H), 6.20-6.12 (m, 1H), 4.85 (d, J=13.8 Hz, 1H); 4.67 (d, J=13.8 Hz, 1H), 4.01-3.50 (m, 8H), 1.44(d, J=6.3 Hz, 12H).
EXAMPLE 103 (27) 4-(2-(Morpholin-4-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride[3249] 2262
[3250] TLC: Rf 0.37(methanol:ethyl acetate:triethylamine=2:8:0.5);
[3251] NMR (CD3OD+D2O): &dgr; 8.18 (d, J=7.5 Hz, 1H), 7.97-7.76 (m, 5H), 7.69-7.60 (m, 2H), 6.17-6.10 (m, 1H), 4.86 (d, J=13.8 Hz, 1H), 4.69 (d, J=13.8 Hz, 1H), 4.05-3.90 (m, 5H), 3.89-3.71 (m, 3H), 3.67-3.53 (m, 2H), 3.5 1-3.33 (m, 4H).
EXAMPLE 103 (28) 4-(N-2-(Piperidin-1-yl)ethyl-N-propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3252] 2263
[3253] Free Compound:
[3254] TLC: Rf 0.51 (ethyl acetate:triethylamine 9:1);
[3255] NMR (CDCl3): &dgr; 7.68 (d, J=7.2 Hz, 1H), 7.64-7.46 (m, 5H), 7.44-7.39 (m, 2H), 6.29 (dd, J=9.3, 1.2 Hz, 1H), 4.69 (d, J=14.4 Hz, 1H), 3.90 (dd, J=15.0, 1.2 Hz, 1H), 3.72 (dd, J=15.0, 9.3 Hz, 1H), 3.58 (d, J=14.4 Hz, 1H), 2.70-2.30 (m, 10H), 1.57-1.38 (m, 8H), 0.79 (t, J=7.2 Hz, 3H).
Hydrochloride:[3256] TLC: Rf 0.51 (ethyl acetate:triethylamine=9:1);
[3257] NMR (CD3OD+pyridine-d5): &dgr; 7.93 (d, J=7.2 Hz, 1H), 7.74-7.68 (m, 4H), 7.61-7.52 (m, 3H), 6.01 (dd, J=8.7,1.2 Hz, 1H), 4.38 (d, J=14.7 Hz, 1H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.89 (dd, J=15.3, 1.2 Hz, 1H), 3.85 (d, J=14.7 Hz, 1H), 3.27-3.22 (m, 2H), 3.14 (br, 4H), 2.97-2.81 (m, 2H), 2.61-2.45 (m, 2H), 1.85-1.77 (m, 4H), 1.65-1.53 (m, 4H), 0.89 (t, J=7.3 Hz, 3H).
EXAMPLE 103 (29) 4-(N-2-(Piperidin-1-yl)ethyl-N-isopropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3258] 2264
[3259] Free Compound:
[3260] TLC: Rf 0.48 (ethyl acetate:triethylamine=9:1);
[3261] NMR (CDCl3): &dgr; 7.77 (d, J=7.2 Hz, 1H), 7.65-7.47 (m, 5H), 7.45-7.40 (m, 2H), 6.09 (d, J=9.0, 1.0 Hz, 1H), 4.54 (d, J=15.0 Hz, 1H), 3.88 (dd, J=15.0, 1.0 Hz, 1H), 3.74 (d, J=15.0 Hz, 1H), 3.73 (dd, J=15.0, 9.0 Hz, 1H), 2.84 (sept, J=6.6 Hz, 1H), 2.57-2.51 (m, 2H), 2.38-2.17 (m, 6H), 1.55-1.48 (m, 4H), 1.42-1.35 (m, 2H), 1.06 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H).
[3262] Hydrochloride:
[3263] TLC: Rf 0.48 (ethyl acetate:triethylamine=9:1);
[3264] NMR (CD3OD+pyridine-d5): &dgr; 7.99 (d, J=7.5 Hz, 1H), 7.75-7.70 (m, 4H), 7.61-7.54 (m, 3H), 5.93 (dd, J=8.7, 1.5 Hz, 1H), 4.27 (d, J=15.6 Hz, 1H), 3.99 (dd, J=15.3, 8.7 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 3.88 (dd, J=15.3, 1.5 Hz, 1H), 3.20-2.80 (m, 9H), 1.82-1.75 (m, 4H), 1.63-1.58 (m, 2H), 1.17-1.14 (m, 6H).
EXAMPLE 103 (30) 4-(3,4-Dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3265] 2265
[3266] Free Compound:
[3267] TLC: Rf 0.19 (ethyl acetate);
[3268] NMR (CDCl3): &dgr; 7.76 (dd, J=7.2, 1.0 Hz, 1H), 7.65-7.51 (m, 5H), 7.46-7.41 (m, 2H), 6.84-6.82 (m, 3H), 5.79 (d, J=9.3 Hz, 1H), 4.47 (d, J=14.0 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H), 3.87 (s, 6H), 3.85 (d, J=15.0 Hz, 1H), 3.82 (d, J=13.2 Hz, 1H), 3.73 (d, J=13.2 Hz, 1H), 3.66 (dd, J=15.0, 9.3 Hz, 1H).
[3269] Hydrochloride:
[3270] TLC: Rf 0.19 (ethyl acetate);
[3271] NMR (DMSO-d6): &dgr; 10.00-9.70 (br, 2H), 8.38-8.28 (m, 1H), 8.06-7.94 (m, 3H), 7.88-7.76 (m, 4H), 7.56 (d, J=1.4 Hz, 1H), 7.27 (dd, J=8.4, 1.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.43-6.38 (m, 1H), 4.80 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.40 (s, 2H), 4.13-4.00 (m, 2H), 3.94 (s, 6H).
EXAMPLE 103 (31) 4-(3-(2-Methylpiperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3272] 2266
[3273] TLC: Rf 0.33 (ethyl acetate:methanol:triethylamine=8:2:0.5);
[3274] NMR (CD3OD): &dgr; 8.18 (d, J=7.2 Hz, 1H), 7.92-7.73 (m, 5H), 7.67-7.57 (m, 2H), 6.22-6.23 (m, 1H), 4.80 (d, J=13.5 Hz, 1H), 4.62 (d, J=13.5 Hz, 1H), 3.98-3.91 (m, 1H), 3.83-3.74 (m, 1H), 3.64-2.98 (m, 7H), 2.37-2.17 (m, 2H), 2.07-1.52 (m, 6H), 1.41 (d, J=6.3 Hz, 3H).
EXAMPLE 103 (32) 4-(4-(Piperidin-1-yl)piperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3275] 2267
[3276] TLC: Rf 0.41 (ethyl acetate methanol:triethylamine=8:2:0.5);
[3277] NMR (D2O): &dgr; 8.17-8.08 (m, 1H), 8.03-7.94 (m, 2H), 7.91-7.82 (m, 1H), 7.79-7.73 (m, 2H), 7.72-7.62 (m, 2H), 4.71 (d, J=14.4 Hz, 1H), 4.65 (d, J=14.4 Hz, 1H), 4.21-4.05 (m, 2H), 3.87-3.75 (m, 1H), 3.69-3.48 (m, 4H), 3.38-2.98 (m, 4H), 2.52-2.32 (m, 2H), 2.19-1.93 (m, 4H), 1.91-1.65 (m, 3H), 1.59-1.40 (m, 1H).
EXAMPLE 103 (33) 4-(3-(Piperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3278] 2268
[3279] TLC: Rf 0.25 (methanol:ethyl acetate:triethylamine=2:8:0.5);
[3280] NMR (CD3OD+D2O) &dgr; 8.16 (d, J=7.2 Hz, 1H), 7.95-7.74 (m, 5H), 7.69-7.59 (m, 2H), 6.17-6.08 (m, 1H), 4.78 (d, J=14.1 Hz, 1H), 4.62 (d, J=14.1 Hz, 1H), 4.02-3.88 (m, 1H), 3.85-3.73 (m, 1H), 3.73-2.76 (m, 8H), 2.3 8-2.21 (m, 2H), 2.14-1.44 (m, 6H).
EXAMPLE 103 (34) 4-(3-Bromobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.hydrochloride[3281] 2269
[3282] TLC: Rf 0.50 (ethyl acetate:triethylamine 6:0.5);
[3283] NMR (DMSO-d6): &dgr; 9.83 (brs, 1H), 9.56 (brs, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.90-7.70 (m, 6H), 7.68-7.58 (m, 4H), 7.41 (t, J=7.5 Hz, 1H), 6.41-6.28 (m, 1H), 4.80-4.60 (m, 1H), 4.52-4.22 (m, 3H), 3.96-3.80 (m, 2H).
EXAMPLE 103 (35) 4-(4-Nitrobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene hydrochloride[3284] 2270
[3285] TLC: Rf 0.34 (ethyl acetate:triethylamine=6:0.5);
[3286] NMR (DMSO-d6): &dgr; 10.05 (brs, 1H), 9.79 (brs, 1H), 8.29 (d, J=8.1 Hz, 2H), 8.18 (d, J=6.6 Hz, 1H), 7.94-7.70 (m, 7H), 7.67-7.57 (m, 2H), 6.48-6.33 (m, 1H), 4.83-4.64 (m, 1H), 4.59-4.35 (m, 3H), 3.95-3.81 (m, 2H).
EXAMPLE 103 (36) 4-(4-Aminosulfonylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3287] 2271
[3288] Free Compound:
[3289] TLC: Rf 0.40 (ethyl acetate:methanol=9:1);
[3290] NMR (DMSO-d6): &dgr; 7.93 (dd, J=7.0, 1.5 Hz, 1H), 7.79-7.66 (m, 7H), 7.63-7.58 (m, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.31 (s, 2H), 5.93 (dd, J=8.3, 1.5 Hz, 1H), 4.07 (d, J=14.1 Hz,1H), 3.95 (dd, J=15.0, 8.3 Hz, 1H), 3.87 (dd, J=15.0, 1.5 Hz, 1H), 3.82 (d, J=14.1 Hz, 1H), 3.75 (s, 2H), 2.86 (br, 1H).
[3291] Hydrochloride:
[3292] TLC: Rf 0.40 (ethyl acetate:methanol=9:1);
[3293] NMR (DMSO-d6): &dgr; 9.80 (br, 1H), 9.52 (br, 1H), 8.15 (d, J=7.0 Hz, 1H), 7.89-7.74 (m, 9H), 7.67-7.62 (m, 2H), 7.44 (s, 2H), 6.37-6.32 (m, 1H), 4.78-4.70 (m, 1H), 4.47-4.41 (m, 1H), 4.41 (s, 2H), 3.96-3.84 (m, 2H).
EXAMPLE 103 (37) 4-(Piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3294] 2272
[3295] TLC: Rf 0.10 (ethyl acetate:methanol triethylamine=8:2:1);
[3296] NMR (CD3OD+D2O): &dgr; 7.96 (d, J=7.8 Hz, 1H), 7.80-7.67 (m, SH), 7.61-7.56 (m, 2H), 6.16 (dd, J=9.0, 1.3 Hz, 1H), 4.60 (d, J=14.5 Hz, 1H), 4.01 (dd, J=15.4, 9.0 Hz, 1H), 3.95 (d, J=14.5 Hz, 1H), 3.89 (dd, J=15.4, 1.3 Hz, 1H), 3.37-3.33 (m, 4H), 2.98-2.90 (m, 4H).
EXAMPLE 103 (38) 4-(2,4,6-Trimethoxybenzyl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3297] 2273
[3298] Free Compound:
[3299] TLC: Rf 0.38 (ethyl acetate:methanol=9:1);
[3300] NMR (CDCl3): &dgr; 7.69 (dd, J=7.0,1.5Hz, 1H), 7.64-7.49 (m, 5H), 7.45-7.40 (m, 2H), 6.19 (dd, J=9.0,1.0 Hz, 1H), 6.12 (s, 2H), 4.50 (d, J=14.3 Hz, 1H), 3.88 (d, J=14.3 Hz, 1H), 3.85 (dd, J=15.0,1.0 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 3.73 (d, J=12.6 Hz, 1H), 3.65 (d, J=12.6 Hz, 1H), 3.64 (dd, J=15.0, 9.0 Hz, 1H).
[3301] Hydrochloride:
[3302] TLC: Rf 0.38 (ethyl acetate:methanol=9:1);
[3303] NMR (DMSO-d6): &dgr; 9.11 (br, 1H), 8.94 (br, 1H), 8.16-8.13 (m, 1H), 7.88-7.87 (m, 2H), 7.84-7.79 (m, 1H), 7.71-7.61 (m, 4H), 6.31 (s, 2H), 5.92 (dd, J=8.0,1.8 Hz, 1H), 4.66-4.62 (m, 1H), 4.39-4.34 (m, 1H), 4.18-4 .13 (m, 1H), 3.97-3.91 (m, 1H), 3.92 (dd, J=15.3, 8.0 Hz, 1H), 3.83 (dd, J=15.3, 1.8 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 6H).
EXAMPLE 103 (39) 4-(Piperidin-1-yl)carbonylmethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3304] 2274
Free Compound:[3305] TLC: Rf 0.42 (ethyl acetate:methanol:triethylamine=8:1:1);
[3306] NMR (CDCl3): &dgr; 7.75.(dd, J=6.9, 2.1 Hz, 1H), 7.66-7.60 (m, 3H), 7.58-7.53 (m, 2H), 7.48-7.43 (m, 2H), 6.13 (dd, J=9.0, 1.2 Hz, 1H), 4.61 (d, J=13.8 Hz, 1H), 3.97 (d, J=13.8Hz, 1H), 3.87 (dd, J=15.0,1.2Hz, 1H), 3.75 (dd, J=15.0,9.0Hz, 1H), 3.58 (t, J=5.2 Hz, 2H), 3.50 (d, J=16.0 Hz, 1H), 3.41 (d, J=16.0 Hz, 1H), 3.30 (t, J=5.2 Hz, 2H), 1.69-1.55 (m, 6H).
[3307] Hydrochloride:
[3308] TLC: Rf 0.42 (ethyl acetate:methanol: triethylamine=8:1:1);
[3309] NMR (DMSO-d6): &dgr; 9.63 (br, 1H), 9.18 (br, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.93-7.80 (m, 5H), 7.70-7.64 (m, 2H), 6.28 (dd, J=6.0, 4.0 Hz, 1H), 4.83 (d, J=13.2 Hz, 1H), 4.32 (d, J=13.2 Hz, 1H), 4.28-4.16 (m, 2H), 3.85 (dd, J=15.3, 6.0 Hz, 1H), 3.80 (dd, J=15.3, 4.0 Hz, 1H), 3.54-3.50 (m, 2H), 3.37-3.32 (m, 2H), 1.64-1.49 (m, 6H).
EXAMPLE 103 (40) 4-(Pyrrolidin-1-yl)ethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene 2hydrochloride[3310] 2275
[3311] TLC: Rf 0.22(methanol:ethyl acetate:triethylamine=2:8:0.5);
[3312] NMR (CD3OD+D2O): 8.16 (d, J=7.5 Hz, 1H), 7.94-7.75 (m, 5H), 7.68-7.58 (m, 2H), 6.15-6.08 (m, 1H), 4.81 (d, J=13.8 Hz, 1H), 4.63 (d, J=13.8 Hz, 1H), 4.01-3.88 (m, 1H), 3.86-3.76 (m, 1H), 3.75-3.62 (m, 4H), 3.6 2-3.38 (m, 4H), 2.20-2.06 (m, 4H).
EXAMPLE 103 (41) 4-(4-(1,3-Dioxaindan-5-ylmethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene-2hydrochloride[3313] 2276
[3314] TLC: Rf 0.51 (ethyl acetate:triethylamine=6:0.5);
[3315] NMR (CD3OD+D2O): &dgr; 7.90 (d, J=7.5 Hz, 1H), 7.79-7.52 (m, 7H), 7.04-6.96 (m, 2H), 6.95-6.87 (m, 1H), 6.15-6.07 (m, 1H), 6.01 (s, 2H), 4.45 (d, J=14.4 Hz, 1H), 4.25 (s, 2H), 4.01 (dd, J=15.6, 8.7 Hz,1H), 3.90 (dd, J=15.6, 1.2 Hz, 1H), 3.77 (d, J=14.4 Hz, 1H), 3.50-3.10 (br, 4H), 2.98-2.63 (br, 4H).
EXAMPLE 104 4-Cyano-6,7-dihydrobenzo[b]thiophene[3316] 2277
[3317] To a suspension of zinc iodide (6.2 g) in acetonitrile (200 ml) were added 4-keto-4,5,6,7-tetrahydrothianaphthene (20 g) and trimethylsilylcyanide (18 ml) successively. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The residue was dissolved in pyridine (65 ml), followed by adding phosphryl chloride (15 ml) dropwise at room temperature. The mixture was refluxed for 30 minutes. The reaction mixture was cooled with ice and thereto was added dropwise isopropanol. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The extract was washed by hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated to give the title compound (17 g) having the following physical data.
[3318] TLC: Rf 0.45 (hexane:ethyl acetate=3:1);
[3319] NMR (CDCl3): &dgr; 7.12 (d, J=5.4 Hz, 1H), 7.07 (d, J=5.4 Hz, 1H), 6.62 (t, J=4.8 Hz, 1H), 2.93 (t, J=9.0 Hz, 2H), 2.60 (t, J=9.0, 4.8 Hz, 2H).
EXAMPLE 105 4-Cyanobenzo[b]thiophene[3320] 2278
[3321] To a solution of the compound prepared in Example 104 (17 g) in benzene (200 ml), was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (30 g). The mixture was refluxed for 1.5 hours. The mixture was filtered. The filtrate was concentrated. The residue was extracted with a mixed solvent (hexane:ethyl acetate=1:1). The extract was washed by an aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatopgaphy on silica gel (hexane:ethyl acetate=100:1) to give the title compound (14.5 g) having the following physical data.
[3322] TLC: Rf 0.40 (hexane:ethyl acetate=4:1);
[3323] NMR (CDCl3): &dgr; 7.45 (t, J=7.5Hz, 1H), 7.60 (d, J=5.0 Hz, 1H), 7.70 (d, J=5.0 Hz, 1H), 7.75 (d, J=7.5Hz, 1H), 8.10 (d, J=7.5Hz, 1H).
EXAMPLE 106 4-Carboxybenzo[b]thiophene[3324] 2279
[3325] 1) To a suspension of the compound prepared in Example 105 (14.5 g) in ethyleneglycol (50 ml) was added 85% potassium hydroxide (19 g). The mixture was stirred at 1 80“C for 2 hours. The reaction mixture was poured into hydrochloric acid, and the acidic mixture was extracted with ethyl acetate. The extract was washed by water and a saturated aqueous solution of sodium chloride sucessively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (12.2 g) having the following physical data.
[3326] The above title compound may be prepared by the following method. 2) A mixture of the compound prepared in Example 104 (1.61 g), nitrobenzene (2.46 g), ethyleneglycol (10 ml) and 10% palladium carbon (161 mg) was stirred at 200° C. for 3 hours and at 1 80“C for 17 hours. To the reaction mixture, sodium hydroxide was added at 150° C. The mixture was stirred at 180° C. for 1 hour. The reaction mixture was cooled to room temperature. Thereto were added water (10 ml) and activated charcoal. The mixture was filtrated. The filtrate was washed by ethyl acetate (20 ml). To aqueous layer was added concentrated hydrochloric acid (2.5 ml). The mixture was extracted with ethyl acetate, washed by water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile (25 ml) to give the title compound (1.46 g).
[3327] TLC: Rf 0.10 (hexane:ethyl acetate=4:1);
[3328] NMR (CDCl3): &dgr; 8.32 (dd, J=5.6, 1.0 Hz, 1H), 8.27 (dd, J=7.6, —1.0 Hz, 1H), 8.18-8.11 (m, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.51-7.41 (m, 1H).
EXAMPLE 107 4-Carboxy-1,1-dioxidebenzo[b]thiophene[3329] 2280
[3330] To a suspension of the compound prepared in Example 106 (35 g) in methanol (720 ml), was added a suspension of OXONE@ (362 g) in pure water (720 ml) at room temperature. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was filtered. The filtrate was concentrated. The residue was extracted with ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane, followed by drying to give the compound of the present invention (30 g) having the following physical data.
[3331] TLC: Rf 0.18 (ethyl acetate);
[3332] NMR (CDCl3): &dgr; 8.28 (d, J=7.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H).
[3333] Examples relates to different method for preparation of the compounds of the present invention
[3334] The compounds prepared in Examples 35 (49)˜(61), Example 70, Example 94, Examples 103˜103 (29) may be prepared by the same procedure as described hereinafter in Example 108 or Example 109.
[3335] 1) For example, the compound described in Example 35 (50) may be prepared by the following procedure.
EXAMPLE 108 4-(Pyridin-3-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene.2hydrochloride[3336] 2281
[3337] Under an atmosphere of argon, to a solution of the compound prepared in Example 82 in dimethylformamide (5 ml) was added a solution of 3-(aminomethyl)pyridine (73 &mgr;l) in dimethylformamide (1 ml), followed by adding 5% palladium-carbon (50 mg). Then, an atmosphere was replaced by hydrogen. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered. The filtrate was concentrated. The obtained residue was purified with column chromatography on silica gel (chloroform methanol 25:1) followed by converting into hydrochloride by addition of 4N hydrochloride/ethyl acetate and recrystallization using ethanol to give the compound of the present invention (231 mg).
[3338] A free compound of the compound described in Example 35 (52) may be prepared by the following procedure.
EXAMPLE 109 4-(N,N-Bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene[3339] 2282
[3340] To a suspension of the compound prepared in Example 82 (168 mg) in methylene chloride (2 ml) were added diethanolamine (53 &mgr;l), sodium borocyanohydride (63 mg), concentrated hydrochloric acid (2 drops) and methanol (0.5 ml). The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water, and extracted with a mixed solvent (methylene chloride and methanol). The organic layer was washed by a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography on silica gel to give the compound of the present invention (50 mg).
[3341] 2) The compound prepared in Example 81 (1) may be prepared by the same procedure as described in Example 27 using the compound prepared in Example 107 instead of 5-methyl-1,1-dioxidebenzo[b]thiophene, and if necesary, by converting into a corresponding free compound by a known method.
[3342] 3) The compounds prepared in Examples 35˜35 (32), Examples 45 (1)˜45 (2), Example 70, Example 71 and Example 87 may be prepared by the same procedure as described in Example 100.
[3343] For example, the compound prepared in Example 35 (11) may be prepared by the same procedure as described in Example 100 using the compound (free compound or sodium salt) prepared in Example 81 (1), and 2-(piperidin-1-yl)ethylamine instead of furan-2-ylmethylamine.
FORMULATION EXAMPLE Formulation Example 1[3344] The following components were admixed in a conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient. 79 4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1- 5.0 g dioxidebenzo[b]thiophene Carboxymethylcellulose calcium (disintegrating agent) 0.2 g Magnesium stearate (lubricating agent) 0.1 g Microcrystalline cellulose 4.7 g
Formulation Example 2[3345] The following components were admixed in a conventional method, and the solution was sterilized in a conventional method, placed 5 ml portions into ampoules and freeze-dried in a conventional method to obtain 100 ampoules each containing 20 mg of active ingredient. 80 4-(Pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1- 2.0 g dioxidebenzo[b]thiophene Mannitol 20 g DIstilled water 500 ml
Claims
1. An inhibitor of producing interleukin-6 and/or interieukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I)
- 2283
- [wherein is a single or double bond,
- Y is
- 2284
- or
- (ii) hydrogen
- (with a proviso that when is a double bond, Y is hydrogen, and when is a single bond, Y is
- 2285
- m and n are each independently 0 or an integer of 1-2,
- p is 0 or an integer of 1-4,
- q is 0 or an integer of 1-5,
- Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene,
- 2286
- is
- (i) benzene ring or
- (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s),
- 2287
- is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- each R1 of (R1)p is independently,
- (i) C1-8 alkyl,
- (ii) C2-8 alkenyl,
- (iii) C2-8 alkynyl,
- (iv) nitro,
- (v) cyano,
- (vi) halogen,
- (vii) Cyc1,
- (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or
- (ix) —A1—A2—A3,
- A1 is
- (i) single bond,
- (ii) C1-8 alkylene,
- (iii) C2-8 alkenylene or
- (iv) C2-8 alkynylene,
- A2 is
- (i) —O—,
- (ii) —NR3—
- (iii) —C(O)—,
- (iv) —CH(OH)—,
- (v) —C(O)NR4—,
- (vi) —NR5C(O)—,
- (vii) —C(O)O—,
- (viii) —OC(O)—,
- (ix) —SO2NR6—,
- (x) —NR7SO2—,
- (xi) —C(O)NR9O—,
- (xii) —OC(O)NR10—,
- (xiii) —NR11C(O)NR12—,
- (xiv) —NR13C(O)O— or
- (xv) —OC(O)O—
- (wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, —OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
- A3 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) C2-8 alkynyl,
- (v) Cyc1 or
- (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
- (a) halogen,
- (b) cyano,
- (c) —P(O)(R15)2,
- (d) —Si(R16)3,
- (e) Cyc1,
- (f) —C(O)R17,
- (g) —OR18,
- (h) —NR19R20,
- (i) —SR21;
- plural R15s are each independently, hydroxy or C1-8 alkoxy,
- plural R16s are each independently C1-8 alkyl,
- R17 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) hydroxy,
- (iv) C1-8 alkoxy,
- (v) Cyc1 or
- (vi) —NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
- R18 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) Cyc1 or
- (v) C1-8 alkyl substituted with Cyc1, Si(R2)3 (wherein plural R26s are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
- R9 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) phenyl or
- (iv) C1-8 alkyl substituted with phenyl,
- R20 is
- (i) hydrogen,
- (ii) C1-8 alkyl or
- (iii) —C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
- (iv) Cyc1 or
- (v) C1-8 alkyl substituted with Cyc1 or cyano,
- R21 is
- (i) hydrogen,
- (ii) C1-8 alkyl or
- (iii) Cyc1,
- Cyc1 is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) —OR31, (xiv) —SR32, (xv) —NR33R34, (xvi) —SO2NR35R36, (xvii) —C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or —C(O)—Cyc2,
- R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
- R33 is hydrogen or C1-8 alkyl,
- R34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
- R35 is hydrogen or C1-8 alkyl,
- R36 is hydrogen, C1-8 alkyl or Cyc2,
- R37 is hydrogen, C1-8 alkyl, —OR38, —NR39R40, CyC2, or C1-8 alkyl substituted with Cyc2 or —C(O)—Cyc2,
- R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
- CyC2 is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) —OR41, (xi) —SR42, (xii) —NR43R44, (xiii) —SO2NR45R44, (xiv) —C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
- R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
- R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
- each R2 of (R2)q is independently,
- (i) C1-8 alkyl,
- (ii) C2-8 alkenyl,
- (iii) C2-8 alkynyl,
- (iv) —OR48,
- (v) —NR49R50,
- (vi) —C(O)R51,
- (vii) nitro,
- (viii) cyano,
- (ix) halogen or
- (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR, —NR49R50, —C(O)R51, halogen or Cyc3,
- R48 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) C2-8 alkynyl,
- (v) Cyc3 or
- (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR52, —NR53R54, —C(O)R55 or Cyc3,
- R49 and R50 are each independently, hydrogen, C1-8 alkyl or —COR59,
- R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR60R61,
- R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
- R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3,
- R55 is hydroxy, C1-8 alkoxy, or —NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3,
- R59 is C1-8 alkyl or C1-8 alkoxy,
- R60 and R61 are each independently, hydrogen or C1-8 alkyl,
- Cyc3is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) —NR62R63, (ix) —COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR62R63 or —COOR64,
- R62 and R63 are each independently, hydrogen or C1-8 alkyl,
- R64 is hydrogen or C1-8 alkyl,
- with the proviso that when A2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or
- (xv) —OC(O)O—, then A3 is not hydrogen.],
- an N-oxide derivative thereof or a non-toxic salt thereof.
2. An agent for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, gammopathy, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmune diseases, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, infectious diseases containing a fused thiophene derivative of the formula (I) depicted in claim 1, an N-oxide derivative thereof or a non-toxic salt thereof as an active ingredient.
3. An inhibitor of producing interleukin-6 and/or interleukin-12 according to claim 1, comprising a compound which is
- (1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (8) 5,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
- (11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-dioxidebenzo[b]thiophene,
- (12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
- (13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino) ethyl)-1-dioxidebenzo[b]thiophene,
- (14) 5-(2-hydroxyethyl)-1,1-dioxidebenzo[b]thiopherie,
- (15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
- (16) 7-bromo-5-methyl -methyl-1,1-dioxidebenzo[b]thiophene,
- (17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
- (18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
- (19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
- (20) 4-bromo-5-methyl- -methyl-1,1-dioxidebenzo[b]thiophene,
- (21) 6-amino-1,1-dioxidebenzo[b]thiophene,
- (22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
- (23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
- (24) 1,1-dioxidethieno[2,3-b]pyridine,
- (25) 1,1-dioxidethieno[3,2-b]pyridine,
- (26) 1,1-dioxidethieno[2,3-c]pyridine,
- (27) 5-amino-1,1-dioxidebenzo[b]thiophene,
- (28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
- (29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene,
- (30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
- (31) 1,1-dioxidebenzo[b]thiophene,
- (32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine,
- (33) 5-((E)-2-(ethoxycarbonyl)ethenyl)-4-methoxybenzo[b]thiophene,
- (34) 5-(2-(ethoxycarbonyl)ethyl-4-methoxybenzo[b]thiophene,
- (35) 5-methoxycarbonyl-4-ethoxybenzo[b]thiophene,
- (36) 5-carboxy-4-ethoxybenzo[b]thiophene,
- (37) 5-benzyloxycarbonyl-4-ethoxybenzo[b]thiophene,
- (38) 5-hydroxy-4-formylbenzo[b]thiophene,
- (39) 5-benzyloxy-4-formylbenzo[b]thiophene,
- (40) 5-benzyloxy-4-hydroxymethylbenzo[b]thiophene or
- (41) 4-t-butoxycarbonylaminobenzo[b]thiophene,
- or an N-oxide derivative thereof, or a non-toxic salt thereof as active ingredient.
4. A fused thiophene derivative of formula (IA)
- 2288
- [wherein is a single or double bond,
- Y is (i)
- 2289
- or
- (ii) hydrogen
- (with a proviso that when is a double bond, Y is hydrogen, and when is a single bond, Y is
- 2290
- m and n are each independently 0 or an integer of 1-2,
- p is 0 or an integer of 1-4,
- q is 0 or an integer of 1-5,
- Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene,
- 2291
- is
- (i) benzene ring or
- (ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s),
- 2292
- is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- each R1 of (R1)p is independently,
- (i) C1-8 alkyl,
- (ii) C2-8 alkenyl,
- (iii) C2-8 alkynyl,
- (iv) nitro,
- (v) cyano,
- (vi) halogen,
- (vii) Cyc1,
- (viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or
- (ix) —A1—A2—A3,
- A1 is
- (i) single bond,
- (ii) C1-8 alkylene,
- (iii) C2-8 alkenylene or
- (iv) C2-8 alkynylene,
- A2 is
- (i) —O—,
- (ii) —NR3—
- (iii) —C(O)—,
- (iv) —CH(OH)—,
- (v) —C(O)NR4—,
- (vi) —NR5C(O)—,
- (vii) —C(O)O—,
- (viii) —OC(O)—,
- (ix) —SO2NR6—,
- (x) —NR7SO2—,
- (xi) —C(O)NR9O—,
- (xii) —OC(O)NR10,
- (xiii) —NR11C(O)NR12—,
- (xiv) —NR13C(O)O— or
- (xv) —OC(O)O—
- (wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, —OR4 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
- A3 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) C2-8 alkynyl,
- (v) Cyc1 or
- (vi) C1-8 alkyl, C2-8 alkenyl or
- C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
- (a) halogen,
- (b) cyano,
- (c) —P(O)(R15)2,
- (d) —Si(R16)3,
- (e) Cyc1,
- (f) —C(O)R17,
- (g) —OR18,
- (h) —NR19R20,
- (i) —SR21;
- plural R15s are each independently, hydroxy or C1-8 alkoxy,
- plural R16s are each independently C1-8 alkyl,
- R17 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) hydroxy,
- (iv) C1-8 alkoxy,
- (v) Cyc1 or
- (vi) —NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R22 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
- R18 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) Cyc1 or
- (v) C1-8 alkyl substituted with Cyc1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or —OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
- R19 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) phenyl or
- (iv) C1-8 alkyl substituted with phenyl,
- R20 is
- (i) hydrogen,
- (ii) C1-8 alkyl or
- (iii) —C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
- (iv) Cyc1 or
- (v) C1-8 alkyl substituted with Cyc1 or cyano,
- R21 is
- (i) hydrogen,
- (ii) C1-8 alkyl or
- (iii) Cyc1,
- Cyc1 is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) —OR3, (xiv) —SR32, (xv) —NR33R34, (xvi) —SO2NR35R36, (xvii) —C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or —C(O)—Cyc2,
- R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
- R33 is hydrogen or C1-8 alkyl,
- R34 is hydrogen, C1-8 alkyl or —C(O)-Cyc2,
- R35 is hydrogen or C1-8 alkyl,
- R36 is hydrogen, C1-8 alkyl or Cyc2,
- R37 is hydrogen, C1-8 alkyl, —OR3, —NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or —C(O)-Cyc2,
- R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
- Cyc2 is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) —OR4, (xi) —SR42, (xii) —NR4R44, (xiii) —SO2NR45R46, (xiv) —C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
- R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
- R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
- each R2 of (R2)q is independently,
- (i) C1-8 alkyl,
- (ii) C2-8 alkenyl,
- (iii) C2-8 alkynyl,
- (iv) —OR48,
- (v) —NR49R50,
- (vi) —C(O)R51,
- (vii) nitro,
- (viii) cyano,
- (ix) halogen or
- (x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with —OR48, —NR49R50, —C(O)R51, halogen or Cyc3,
- R48 is
- (i) hydrogen,
- (ii) C1-8 alkyl,
- (iii) C2-8 alkenyl,
- (iv) C2-8 alkynyl,
- (v) Cyc3 or
- (vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, —OR52, —NR53R54, —C(O)R55 or CyC3,
- R49 and R50 are each independently, hydrogen, C1-8 alkyl or —COR59,
- R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or —NR60R61,
- R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
- R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or —C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3),
- R59 is hydroxy, C1-8 alkoxy, or —NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3),
- R59 is C1-8 alkyl or C1-8 alkoxy,
- R60 and R61 are each independently, hydrogen or C1-8 alkyl,
- Cyc3 is
- (i) C3-15 mono-, bi- or tricyclic carbo ring or
- (ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 14 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
- the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) —NR62R6, (ix) —COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, —NR62R63 or —COOR64,
- R62 and R63 are each independently, hydrogen or C1-8 alkyl,
- R64 is hydrogen or C1-8 alkyl,
- with the proviso that when
- (1) when A2 is (vi) —NR5C(O)—, (x) —NR7SO2—, (xiv) —NR13C(O)O— or (xv) —OC(O)O—, then A3 is not hydrogen,
- (2) when is a double bond and Y is hydrogen, then n is 1 or 2,
- (3) when is a single bond, Y is
- 2293
- n is 2, m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
- (4) when is a single bond, Y is
- 2294
- n is 2, m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, and q is an integer of 1-5, then R2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen,
- (5) when is a double bond, Y is hydrogen, n is 2, p is 1 and ring A is benzene ring, then R1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
- (6) when is a double bond, Y is hydrogen, n is 2, p is 2 and ring A is benzene ring and one R1 is phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino or 4-methylphenylsulfonylamino, then the other R1 is not C1-8 alkyl,
- (7) when is a double bond, Y is hydrogen, n is 2, p is 2-3, ring A is benzene ring, one R1 is hydroxy, C1-8 alkoxy, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl, then the other R1 is neither halogen nor C1-8 alkyl,
- (8) when is a double bond, Y is hydrogen, n is 2, p is 3-4 and ring A is benzene ring, then two or three R1 are not t-butyl at the same time, and
- (9) the following compounds (1)-(32) are excluded:
- (1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (8) 5,7-dimethyl-1,1-dioxidebenzo[b[thiophene,
- (9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
- (10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
- (11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-ioxidebenzo[b]thiophene,
- (12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
- (13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[bjthiophene,
- (14) 5-(2-hydroxyethyl)-1,1-di oxidebenzo[b]thiophene,
- (15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
- (16) 7-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
- (17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
- (18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
- (19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
- (20) 4-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
- (21) 6-amino-1,1-dioxidebenzo[b]thiophene,
- (22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
- (23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
- (24) 1,1-dioxidethieno[2,3-b]pyridine,
- (25) 1,1-dioxidethieno[3,2-b]pyridine,
- (26) 1,1-dioxidethieno[2,3-c]pyridine,
- (27) 5-amino-1,1-dioxidebenzo[b]thiophene,
- (28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
- (29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1-dioxidebenzo[b]thiophene,
- (30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
- (31) 1,1-dioxidebenzo[b]thiophene or (32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine.], an N-oxide derivative thereof or a non-toxic salt thereof.
5. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein is a double bond, an N-oxide derivative thereof, or a non-toxic salt thereof.
6. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein is a single bond, an N-oxide derivative thereof or a non-toxic salt thereof.
7. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2295
- is benzene, an N-oxide derivative thereof or a non-toxic salt thereof.
8. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2296
- is 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), an N-oxide derivative thereof or a non-toxic salt thereof.
9. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2297
- is a C3-15 mono-, bi- or tricyclic carbo ring, an N-oxide derivative thereof, or a non-toxic salt thereof.
10. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2298
- is a 4-membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
11. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2299
- is 5-10 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
12. A fused thiophene derivative of the formula (IA) depicted in claim 4, wherein
- 2300
- is 11-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, an N-oxide derivative thereof, or a non-toxic salt thereof.
13. A compound according to claim 4, which is
- (1) 3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (2) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (3) 3-(4-methylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (4) 3-(4-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (5) 3-(4-chlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (6) 3-(4-fluorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (7) 3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (8) 3-(3-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (9) 3-(2-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (10) 3-(pyridin-4-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (11) 3-(pyrimidin-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (12) 3-(thiazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (13) 3-(3-methylfuran-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (14) 3-(3-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (15) 3-(2-methoxycarbonylphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (16) 3-cyclohexylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (17) 3-(naphthalen-1-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (18) 3-(2-methoxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (19) 3-(1-methylimidazol-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (20) 3-phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (21) 3-(thiophen-2-yl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (22) 3-(2-methoxycarbonylphenyl)sulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (23) 3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (24) 3-(thiophen-2-yl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (25) 3-(4-methylphenyl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (26) 3-(4-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (27) 3-(4-chlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (28) 3-(4-fluorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (29) 3-(4-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (30) 3-(3-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dloxidebenZo[b]thiophene,
- (31) 3-(2-hydroxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (32) 3-(pyridin-4-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (33) 3-(pyrimidin-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (34) 3-(thiazol-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (35) 3-(3-methylfuran-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (36) 3-(3-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (37) 3-(2-methoxycarbonylphenyl) sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (38) 3-cyclohexylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
- (39) 3-(naphthalen-1-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (40) 3-(2-methoxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (41) 3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (42) 3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (43) 3-(4-(2-(morpholin-4-yl)ethoxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (44) 3-(3-benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (45) 3-(2-benzyloxyphenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (46) 3-(4-(pyridin-2-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (47) 3-(4-(pyridin-3-ylmethyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (48) 3-(4-pyridin-4-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (49) 3-(4-(3-hydroxypropyloxy) phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (50) 3-(3-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (51) 3-(3-(3-hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (52) 3-(2-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (53) 3-(2-(3-hydroxypropyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (54) 3-(4-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (55) 3-(3-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (56) 3-(4-(pyridin-2-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (57) 3-(4-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (58) 3-(4-(pyridin-4-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (59) 3-(4-(3-hydroxypropyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (60) 3-(3-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (61) 3-(3-(3-hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (62) 3-(2-(pyridin-3-ylmethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (63) 3-(2-(3-hydroxypropyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (64) 3-(4-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (65) 3-(3-(2-(t-butoxycarbonylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (66) 3-(4-(2-aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (67) 3-(3-(2-aminoethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[bjthiophene,
- (68) 3-(4-(2-(N,N-dimethylamino)ethyloxyphenyl)sulfonyl-2,3dihydro-1,1-dioxidebenzo[b]thiophene,
- (69) 3-(3-(2-(N,N-dimethylamino)ethyloxy)phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (70) 5-nitro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (71) 6-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (72) 4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene, (73) 5-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (74) 7-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (75) 4-chloro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (76) 5-(t-butoxycarbonylamino) methyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (77) 4,7-dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (78) 4,6-dimethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (79) 4-ethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (80) 4-methoxy-5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (81) 4-bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (82) 4-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (83) 5-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (84) 6-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (85) 7-hydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (86) 3-phenylthio-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine,
- (87) 4,7-dihydroxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (88) 5-nitro-3-phenyisulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene,
- (89) 6-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (90) 4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (91) 5-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (92) 7-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (93) 4-chloro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (94) 4-(t-butoxycarbonylamino) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (95) 4,7-dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (96) 4,6-dimethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (97) 4-ethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (98) 4-methoxy-5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (99) 4-bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (100) 4-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (101) 5-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene
- (102) 6-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (103) 7-hydroxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (104) 3-phenylsulfonyl-2,3-dihydro-1,1-dioxidethieno[2,3-b]pyridine,
- (105) 5-amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (106) 5-acetylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (107) 4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (108) 4-(N,N-dimethylamino) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (109) 4-methoxy-5-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (110) 4-methoxy-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (111 ) 4-methoxy-3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (112) 4-(4-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (113) 4-(3-phenyloxypropyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (114) 4-benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (115) 4-(3-benzyloxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (116) 4-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (117) 4-(quinolin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (118) 4-(pyridin-2-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (119) 4-(pyridin-4-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (120) 4-(3-(pyridin-3-yl)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (121) 4-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (122) 5-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (123) 5-(2-phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (124) 5-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (125) 5-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (126) 5-(3-(pyridin-3-yl) propyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (127) 6-(3-phenyloxypropyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (128) 6-benzyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (129) 6-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (130) 6-(2-(morpholin-4-yl) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (131) 6-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (132) 6-(pyridin-3-ylmethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (133) 6-(3-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (134) 6-(3-bromopropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (135) 7-pentoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (136) 7-(2-phenyloxyethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (137) 7-(3-hydroxypropyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (138) 7-(pyridin-3-ylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (139) 4-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (140) 5-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (141) 6-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (142) 7-(t-butoxycarbonylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (143) 4-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (144) 4-(3-(t-butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (145) 5-(2-(t-butoxycarbonylamino) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[bjthiophene,
- (146) 6-(3-(t-butoxycarbonylamino)propyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (147) 6-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (148) 7-(2-(t-butoxycarbonylamino) ethyl) oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (149) 4-(N-(t-butoxycarbonyl) piperidin-4-yl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (150) 4,7-bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (151) 4-(3-nitrophenylmethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (152) 4,7-bis(pyridin-3-ylmethyloxy)-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (153) 4-(3-hydroxypropyl)oxy-3-phenylsulfinyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (154) 4-(4-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (155) 4-(3-phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (156) 4-benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (157) 4-(3-benzyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (158) 4-(pyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (159) 4-(N-oxidequinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (160) 4-(pyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (161) 4-(N-oxidepyridin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (162) 4-(pyridin-4-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (163) 4-(3-(pyridin-3-yl) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (164) 4-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (165) 5-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (166) 5-(2-phenyloxyethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (167) 5-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (168) 5-(pyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (169) 5-(3-(pyridin-3-yl)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (170) 6-(3-phenyloxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (171) 6-benzyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (172) 6-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (173) 6-(2-(morpholin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (174) 6-(3-hydroxypropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (175) 6-(pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (176) 6-(3-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (177) 6-(3-bromopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (178) 7-pentoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (179) 7-(2-phenyloxyethyl)oxy-3-phenylsuffonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (180) 7-(3-hydroxypropyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (181) 7-(pyridin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (182) 7-(N-oxidepyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (183) 4-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (184) 5-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (185) 6-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (186) 7-(t-butoxycarbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (187) 4-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (188) 4-(3-(t-butoxycarbonylamino) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (189) 5-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (190) 6-(3-(t-butoxycarbonylamino) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (191) 6-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (192) 7-(2-(t-butoxycarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (193) 4-(N-(t-butoxycarbonyl) piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (194) 4,7-bis[(2-(t-butoxycarbonylamino)ethyl)oxy]-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (195) 4-(3-nitrophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (196) 4-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (197) 5-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (198) 6-carboxymethoxy-3-phenylsutfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (199) 7-carboxymethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (200) 4-(N-(pyridin-3-ylmethyl) carbamoylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (201) 4-((2-(N,N-dimethylamino)ethylamino)carbonylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (202) 4-(N-benzyl-2-(N′,N′-dimethylamino)ethylamino)carbonymethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (203) 4-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (204) 4-(3-aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (205) 5-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (206) 6-(3-aminopropyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (207) 6-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (208) 7-(2-aminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (209) 4-(piperidin-4-yl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (210) 4,7-bis[(2-aminoethyl)oxy] -3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (211) 4-(2-(N,N-dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (212) 4-(3-(N,N-dimethylamino)propyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (213) 4-(3-(N-cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (214) 5-(2-(N,N-dimethylamino)ethyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (215) 6-(3-(N,N-dimethylamino)propyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (216) 6-(3-(N-cyanomethyl-N-methylamino)propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (217) 6-(2-(N,N-dimethylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (218) 7-(2-(N,N-dimethylaminoethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (219) 4-(3-aminophenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (220) 4-(3-(pyridin-3-ylcarbonylamino)phenylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (221) 4-(2-(pyridin-3-ylcarbonylamino)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (222) 5-methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (223) 5-(4-chlorophenylcarbonyl)amino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (224) 4-cyano-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (225) 6-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (226) 4,7-dimethoxy-3-phenylsulfonyl-2;3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (227) 4,7-bis(3-hydroxypropyl)oxy-3-phenyIsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (228) 4-(pyridin-3-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (229) 4-(4-benzylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (230) 4-(N-(2-(pyridin-3-yl) ethyl)-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (231) 4-(2-(2-hydroxyethoxy)ethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (232) 4-(2,4-dimethoxyphenylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (233) 4-(1-benzylpiperidin-4-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (234) 4-(pyridin-4-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (235) 4-(2-t-butoxycarbonylethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (236) 4-(thiophen-2-ylmethyl)carbamoyl-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (237) 4-benzylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (238) 4-(pyridin-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (239) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (240) 4-((1S)-1-t-butoxycarbonyl-2-methylpropyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (241) 4-(2-fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (242) 4-(3-fluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (243) 4-(3-methylphenylmethyl)carbamoyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (244) 4-(2-methoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (245) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (246) 4-(3,4-dimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (247) 4-(2,5-difluorophenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (248) 4-(3,4,5-trimethoxyphenylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (249) 4-(benzimidazol-2-ylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (250) 4-(3,5-difluorophenylmethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (251) 4-(N-benzyl-N-methylcarbamoyl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (252) 4-(4-nitrophenymethyl)carbamoyl-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (253) 5-(2-hydroxyethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (254) 5-(pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (255) 5-(2-dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (256) 5-dimethylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (257) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (258) 5-(2,3-dihydroindol-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (259) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (260) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (261) 4-(pyridin-3-ylcarbonyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (262) 4-(3-(pyrrol-1-yl) propyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (263) 4-(quinolin-2-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (264) 4-(2-(pyrrol-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (265) 4-(2-(4-methylthiazol-5-yl)ethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (266) 4-(3-(pyridin-4-yl) propyl)oxy-3-phenylsuffonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (267) 4-(1-t-butoxycarbonylpiperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (268) 4-(2-(pyrrolidin-1-yl)ethyl)oxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (269) 4-(2-(piperidin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (270) 4-(2-(2-acetyloxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (271) 4-(2-(4-benzylpiperazin-1-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (272) 4-diethylcarbamoylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (273) 4-cyanomethyloxy-3-phenyl sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (274) 5-(pyridin-3-yloxy)methyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (275) 5-(2-(t-butoxycarbonylamino)ethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (276) 5-((2E)-3-ethoxycarbonyl-2-propenyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (277) 4-(2,4-dimethoxyphenylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (278) 4-(pyridin-3-ylmethyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (279) 4-(2-dimethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (280) 4-(N,N-bis(2-hydroxyethyl)amino)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (281) 4-(2-(2-hydroxyethoky)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (282) 4-(4-benzylpiperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (283) 4-(4-(pyridin-2-yl)piperazi n-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (284) 4-(4-ethoxycarbonylpiperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (285) 4-(4-(2-hydroxyethyl)piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (286) 4-(4-(pyridin-4-yl)piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (287) 4-benzylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (288) 4-(1-benzylpiperidin-4-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (289) 4-(morpholin-4-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (290) 4-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (291) 4-benzyloxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (292) 4-(pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (293) 6-(pyridin-3-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (294) 4-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (295) 6-bromo-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (296) 6-amino-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (297) 5-methyicarbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (298) 4-dimethylxarbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (299) 4-carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (300) 4-(2-(pyridin-4-yl)ethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (301) 4-(2-(pyridin-3-yl)ethyl)oxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (302) 4-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (303) 6-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (304) 6-cyanomethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (305) 5-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (306) 7-ethoxycarbonylmethyloxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (307) 5-benzyloxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (308) 5-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (309) 7-methoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (310) 7-ethoxycarbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (311) 5-t-butoxycarbonyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (312) 5-(2-(ethoxycarbonyl)ethyl)-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (313) 4-(furan-2-ylmethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (314) 5-(4,4-dimethyl-4,5-dihydroxazol-2-yl) -3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (315) 3-benzylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (316) 3-(3,4-dichlorophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (317) 3-(4-nitrophenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (318) 5-hydroxymethyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (319) 4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (320) 6-fl uoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (321) 4-fluoro-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (322) 5-methylcarbamoyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (323) 4-dimethylcarbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (324) 4-carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (325) 4-(2-(pyridin-4-yl)ethyl)oxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (326) 4-(2-(pyridin-3-yl)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (327) 4-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (328) 6-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (329) 6-cyanomethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (330) 5-ethoxycarbonylmethyloxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (331) 7-ethoxycarbonylmethyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (332) 5-benzyloxycarbonyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (333) 5-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (334) 7-methoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (335) 7-ethoxycarbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (336) 5-t-butoxycarbonyl-4-methoxy-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (337) 5-(2-ethoxycarbonylethyl)-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (338) 3-benzylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (339) 3-(3,4-dichlorophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (340) 3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (341) 5-hydroxymethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (342) 4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (343) 6-fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (344) 4-fluoro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (345) 5-benzylozycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (346) 5-benzyloxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (347) 5-benzyloxycarbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (348) 5-benzyloxycarbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (349) 5-carboxy-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (350) 5-carboxy-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (351) 5-carboxy-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (352) 5-carboxy-4-octyloxy-3-phenylsuldonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (353) 5-methoxycarbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (354) 5-methoxycarbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (355) 5-methoxycarbonyl-4butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (356) 5-methoxycarbonyl-4-octyloxy-3-phenylsufonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (357) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (358) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (359) 5-(dimethylaminoethylcarbamoyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (360) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (361) 5-(2,3-dihydroindol-1-yl)carbonyl-4-ethoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (362) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (363) 5-(4-(2-chlorophenyl)piperazin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (364) 5-(2-dimethylaminoethyl)carbamoyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (365) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (366) 5-(2,3-dihydroindol-1-yl)carbonyl-4-hexyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo [b]thiophene,
- (367) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl) carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (368) 5-(4-(2-chlorophenyl) piperazin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (369) 5-(2-dimethylaminoethyl)carbamoyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (370) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (371) 5-(2,3-dihydroindol-1-yl) carbonyl-4-butoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (372) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (373) 5-(4-(2-chlorophenyl) piperazin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (374) 5-(2-dimethylaminoethyl)carbamoyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (375) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (376) 5-(2,3-dihydroindol-1-yl)carbonyl-4-octyloxy-3-phenylsulfonyl-2,3-dihydro-1,1-di oxidebenzo[b]thiophene,
- (377) 5-benzyloxy-4-hydroxymethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (378) 5-benzyloxy-4-bromomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (379) 5-benzyloxy-4-aminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (380) 5-benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (381) 5-benzyloxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (382) 5-benzyloxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (383) 5-hydroxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (384) 5-methoxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (385) 5-(3-phenylpropyl) oxy-4-t-butoxycarbonylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (386) 5-methoxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (387) 5-(3-phenylpropyl)oxy-4-aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (388) 5-benzyloxy-4-hydroxymethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (389) 5-benzyloxy-4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (390) 5-benzyloxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (391) 5-hydroxy-4-(pyridin-3-ylmethyl)carbamoyl-3-phenylsuifonyi-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (392) 4,7-dimethoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (393) 6-bromo-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (394) 4-(piperidin-3-ylmethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (395) 5-(2-aminoethyl)oxy-4-nitro-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (396) 4-(2-(2-hydroxyethoxy)ethyl)oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (397) 5-carboxy-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (398) 4-carboxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (399) 4-formyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (400) 5-(4-phenylbutyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (401) 5-(pyridin-3-ylmethyl)aminomethyl-4-methoxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (402) 6-dimethylamino-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (403) 4-(2-dimethylaminoethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (404) 4,7-bis(pyridin-3-ylmethyloxy)-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (405) 4-(N-oxidepyridin-3-ylmethyl) oxy-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (406) 4-(2-(N-oxidepyridin-4-yl)ethyl)oxy-3-phenylsulfonyl-2,3-di hydro-1,1-dioxidebenzo[b]thiophene,
- (407) 4-methoxy-3-(4-hydroxyphenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (408) 4-methoxy-3-(4-(pyridin-3-ylmethyloxy)phenyl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (409) 4-methoxy-3-(4-(pyridin-3-ylmethyloxy) phenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (410) 5-(2-dimethylaminoethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (411) 5-(pyridin-3-ylmethyl)carbamoyl-4-methoxy-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (412) 4-(2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (413) 4-(furan-2-ylmethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (414) 4-(2,4,6-trimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (415) 4-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl-3-phenylsuIfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (416) 4-((3S)-1-benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (417) 4-(2-(pyrrolidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (418) 4-(2-diethylaminoethyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (419) 4-(2-(N-ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (420) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (421) 4-(3-(imidazol-1-yl) propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (422) 4-((3R)-1-benzylpyrrolidin-3-yl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (423) 4-(3-(pyrrolidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (424) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (425) 4-(3,5-dimethoxybenzyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (426) 4-(3-(piperidin-1-yl)propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (427) 4-(2-diisopropylamino)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (428) 4-(2-(morpholin-4-yl)ethyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (429) 4-(N-2-(piperidin-1-yl)ethyl-N-propyl)carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (430) 4-(N-2-(piperidin-1-yl)ethyl-N-isopropyl) carbamoyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (431) 4-(4-benzoylpiperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (432) 4-(4-(4-ethylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (433) 4-(4-(4-phenylbenzyl)piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (434) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (435) 4-(4-benzyloxycarbonylpiperazin-1-yl) carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (436) 4-(4-(2-methylphenyl) piperazin-1-yl)carbonyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (437) 4-(4-(4-methoxyphenyl) piperazin-1-yl) carbonyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (438) 4-(2-(pyridin-2-yl)ethyl) oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene,
- (439) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-phenylthio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (440) 4-(2-(piperidin-1-yl)ethyl)carbamoyl-3-(4-nitrophenyl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (441) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (442) 4-(2-(N-ethyl-N-3-methylphenyl)aminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (443) 4-(N-benzyl-N-ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (444) 4-(2-diethylaminoethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (445) 4-(4-methylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (446) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (447) 4-(2-methoxybenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (448) 4-(3-phenylpropyi)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (449) 4-(3,5-dimethoxybenzyl)aminomethyl-3-phenyisulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (450) 4-((3R)-1-benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (451) 4-((3S)-1-benzylpyrrolidin-3-yl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (452) 4-(2-phenylethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (453) 4-(N-benzyl-N-methyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (454) 4-(3-(2-oxopyrrolidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (455) 4-(4-aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (456) 4-(4-((2E)-3-phenyl-2-propenyl) piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (457) 4-(2-aminobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (458) 4-(4-benzylpiperidin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (459) 4-(4-chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (460) 4-(3-chlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (461) 4-(3-methoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (462) 4-(3,4-dichlorobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (463) 4-(1,3-dioxaindan-5-ylmethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (464) 4-(2,3-dimethoxybenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (465) 4-(3,4,5-trimethoxybenzyl)aminomethyl3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (466) 4-(4-(t-butyloxycarbonyl) piperazin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (467) 4-(2-diisopropylamino) ethyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (468) 4-(2-(morpholin-4-yl) ethyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (469) 4-(N-2-(piperidin-1-yl) ethyl-N-propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (470) 4-(N-2-(piperidin-1-yl)ethyl-N-isopropyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (471) 4-(3,4-dimethoxybenzyl) aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (472) 4-(3-(2-methylpiperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (473) 4-(4-(piperidin-1-yl)piperidin-1-yl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (474) 4-(3-(piperidin-1-yl)propyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (475) 4-(3-bromobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (476) 4-(4-nitrobenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (477) 4-(4-aminosulfonylbenzyl)aminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (478) 4-(piperazin-1-yl)methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (479) 4-(2,4,6-trimethoxybenzyl) methyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (480) 4-(piperidin-1-yl)carbonylmethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (481) 4-(pyrrolidin-1-yl)ethylaminomethyl-3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
- (482) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl) methyl-1,1-dioxidebenzo[b]thiophene, or
- an N-oxide derivative thereof or a non-toxic salt thereof.
14. A compound ccording to claim 4, which is
- (1) 4-(pyridin-3-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (2) 4-(4-benzyl piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (3) 4-(N-(2-(pyridi n-3-yl)ethyl)-N-methylcarbamoyl) -1,1-dioxidebenzo[b]th iophene,
- (4) 4-(2-(2-hydroxyethoxy)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (5) 4-(2,4-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (6) 4-(1-benzylpiperidin-4-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (7) 4-(pyridin-4-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (8) 4-(2-t-butoxycarbonylethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (9) 4-(thiophen-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (10) 4-benzylcarbamoyl-1,1-dioxidebenzo[b]thiophene,
- (11) 4-(pyridin-2-ylmethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (12) 4-(2-t(piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thlophene,
- (13) 4-((1 S)-1-t-butoxycarbonyl-2-methylpropyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (14) 4-(2-fluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (15) 4-(3-fluorophenylmethyl)carbamoyl-1,1-di oxidebenzo[b]thiophene,
- (16) 4-(3-methylphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (17) 4-(2-methoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (18) 4-(2,3-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (19) 4-(3,4-dimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (20) 4-(2,5-difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[bjthiophene,
- (21) 4-(3,4,5-trimethoxyphenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (22) 4-(benzimidazol-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (23) 4-(3,5-difluorophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (24) 4-(N-benzyl-N-methylcarbamoyl)-1,1-dioxidebenzo[b]thiophene,
- (25) 4-(4-nitrophenylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (26) 5-(2-hydroxyethyl)carbamoyl-1,1-di oxidebenzo[b]thiophene,
- (27) 5-(pyridin-3-ylmethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (28) 5-(2-dimethylaminoethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (29) 5-dimethylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (30) 5-(2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (31) 5-(2,3-dihydroindol-1-yl) carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (32) 5-(4-(2-chlorophenyl)piperazin-1-yl) carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (33) 5-(4-(2-(2-trifluoromethylphenyl)ethyl)piperazin-1-yl)carbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (34) 4-(pyridin-3-ylcarbonyl) aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (35) 4-(3-(pyrrol-1-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (36) 4-(quinolin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (37) 4-(2-(pyrrol-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (38) 4-(2-(4-methylthiazol-5-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (39) 4-(3-(pyridin-4-yl) propyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (40) 4-(1-t-butoxycarbonylpiperidin-3-ylmethyl)ox-1,1-dioxidebenzo[b]thiophene,
- (41) 4-(2-(pyrrolidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (42) 4-(2-(piperidin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (43) 4-(2-(2-acetyloxyethoxy)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (44) 4-(2-(4-ebnzylpiperazin-1-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (45) 4-diethylcarbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (46) 4-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
- (47) 5-(pyridin-3-yloxy)methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (48) 5-(2-t-butoxycarbonylaminoethyl)oxy-4-nitro-1,1-dioxidebenzo[b]thiophene,
- (49) 5-((2E)-3-ethoxycarbonyl-2-propenyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (50) 4-(2,4-dimethoxyphenylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (51) 4-(pyridin-3-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (52) 4-(2-(dimethylamino)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (53) 4-(N,N-bis(2-hydroxyethyl) amino)methyl-1,1-dioxidebenzo[b]thiophene,
- (54) 4-(2-(2-hydroxyethoxy)ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (55) 4-(4-benzylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (56) 4-(4-(pyridin-2-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (57) 4-(4-ethoxycarbonylpiperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (58) 4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (59) 4-(4-(pyridin-4-yl)piperazin-1-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (60) 4-benzylaminomethyl-1,1-dioxidebenzo[b]thiophene,
- (61) 4-(1-benzylpiperidin-4-yl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (62) 4-(morpholin-4-yl)methyl-1,1-dioxidebenzo[b]thiophene,
- (63) 4-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (64) 4-benzyloxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (65) 4-(pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene,
- (66) 6-(pyridin-3-yl)-1,1-dioxidebenzo[b]thiophene,
- (67) 4-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene,
- (68) 5-methylcarbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (69) 4-dimethylcarbamoyl-1,1-dioxidebenzo[b]thiophene,
- (70) 4-carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (71) 4-(furan-2-ylmethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (72) 4-(2-(pyridin-4-yl)ethyl) oxy-1,1-dioxidebenzo[b]thiophene,
- (73) 4-(2-(pyridin-3-yl)ethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (74) 4-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (75) 6-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (76) 6-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
- (77) 5-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (78) 7-ethoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (79) 5-benzyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (80) 5-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (81) 7-methoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (82) 7-ethoxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (83) 5-t-butoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thi ophene,
- (84) 5-(2-(ethoxycarbonyl)ethyl)-4-methoxy-1,1-di oxidebenzo[b]thiophene,
- (85) 5-(4,4-dimethyl-4,5-dihydroxazol-2-yl)-1,1-dioxidebenzo[b]thiophene,
- (86) 5-benzyloxycarbonyl-4-ethoxy-1,1-dioxidebenzo[b]thiophene,
- (87) 5-benzyloxycarbonyl-4-hexyloxy-1,1-dioxidebenzo[b]thiophene,
- (88) 5-benzyloxycarbonyl-4-butoxy-11-dioxidebenzo[b]thiophene,
- (89) 5-benzyloxycarbonyl-4-octyloxy-1,1-di oxidebenzo[b]thiophene,
- (90) 5-benzyloxy-4-hydroxymethyl-1,1-dioxidebenzo[b]thiophene,
- (91) 4-(1,1-dimethyl-2-hydroxyethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (92) 4-(2-hydroxyethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (93) 4-(4-(2-hydroxyethyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (94) 4-(N-methyl-N-methoxycarbamoyl)-1,1-dioxidebenzo[b]thiophene,
- (95) 4-(4-(thiazol-2-ylsulfamoyl)phenyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (96) 4-((1R) -1-t-butoxycarbonyl-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (97) 6-(1-benzylpiperidin-4-yl)carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (98) 6-(2-diethylaminoethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (99) 6-(pyridin-3-ylmethyl) carbamoyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (100) 5-(6-dimethylaminohexyl)oxycarbonyl-1,1-dioxidebenzo[b]thiophene,
- (101) 4-(4-t-butoxycarbonylpiperazin-1-yl)carbonyl-11-dioxidebenzo[b]thiophene,
- (102) 4-(piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (103) 4-(4-(4-methoxyphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (104) 4-(4-(4-phenylphenylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (105) 4-(4-(naphthalen-1-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (106) 4-(4-(4-ethylphenylmethyl) piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (107) 4-(4-(naphthalen-2-ylcarbonylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (108) 4-(4-(pyridin-2-ylmethyl) piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (109) 4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (110) 4-(4-benzoylpiperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (111) 4-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (112) 4-(4-benzylcarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (113) 4-(2-(pyrrolidin-1-yl) ethyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (114) 4-(3-(pyrrolidin-1-yl) propyl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (115) 4-(4-(2-methylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (116) 4-(4-(3-methylphenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (117) 4-(4-(2-fluorophenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (118) 4-(4-(4-fluorophenyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (119) 4-(4-(4-methoxyphenyl) piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (120) 4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (121) 4-((3R)-1-benzylpyrrolidin-3-yl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (122) 4-((3S)-1-benzylpyrrolidin-3-yl) carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (123) 5-acetylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (124) 5-cyanomethyloxy-1,1-dioxidebenzo[b]thiophene,
- (125) 5-t-butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (126) 5-(3-(ethoxycarbonyl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (127) 5-(4-(ethoxycarbonyl)butyl) oxy-1,1-dioxidebenzo[b]thiophene,
- (128) 4-(pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (129) 4-(pyridin-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (130) 4-(4-trifluoromethylphenylmethyl)oxy-3-phenylthio-1,1-dioxidebenzo[b]thiophene,
- (131) 4-(3,5-dimethylisoxazol-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (132) 4-(4-methoxycarbonylphenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (133) 4-(benzotriazol-1-ylmethyl)oxy-11-dioxidebenzo[b]thiophene,
- (134) 4-(2,6-dimethylphenyl) carbamoylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (135) 4-trimethylsilylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (136) 4-(pyridin-2-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (137) 4-(2-(pyridin-3-ylcarbonyl)aminoethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (138) 4-(3-(pyridin-3-yl)propyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (139) 4-(2-(pyridin-2-yl) ethyl) oxy-1,1-dioxidebenzo[b]thiophene,
- (140) 4-(1-t-butoxycarbonylpiperidin-4-yl)oxy-1,1-dioxidebenzo[b]thiophene,
- (141) 4-(5-methyl-1-tritylimidazol-4-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (142) 4-(1,2,4-oxadiazol-3-yl methyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (143) 6-(pyridin-3-ylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (144) 6-(3-nitrophenylmethyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (145) 6-(3-(t-butoxycarbonylamino) propyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (146) 7-t-butoxycarbonylmethyloxy-1,1-dioxidebenzo[b]thiophene,
- (147) 6-(pyridin-3-yloxy) methyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (148) 4,7-bis(3-hydroxypropyl)-1,1-dioxidebenzo[b]thiophene,
- (149) 5-carboxy-4-ethoxy-1,1-dioxidebenzo[b]thiophene,
- (150) 5-carboxy-4-butoxy-1,1-dioxidebenzo[b]thiophene,
- (151) 5-carboxy-4-hexyloxy-1,1-dioxidebenzo[b]thiophene,
- (152) 5-carboxy-4-octyloxy-1,1-dioxidebenzo[b]thiophene,
- (153) 5-ethoxycarbonyl-4-hydroxy-1,1-dioxidebenzo[b]thiophene,
- (154) 5-ethoxycarbony-4-metoxy-1,1-dioxidebenzo[b]thiophene,
- (155) 5-isopropyloxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (156) 5-(2-methylpropyl)oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (157) 6-meth oxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (158) 6-methoxymethoxycarbonyl-4-methoxy-1,1-dioxidebenzo[b]thiophene,
- (159) 4-(N-(pyridin-2-ylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene,
- (160) 4-(pyridin-2-ylmethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (161) 4-(N-(2,4-dimethoxyphenylmethyl)-N-(1,1-dioxidebenzo[b]thiophen-4-ylmethyl)amino)methyl-1,1-dioxidebenzo[b]thiophene,
- (162) 5-acetyloxy-4-nitro-1,1-dioxidebenzo[b]thiophene,
- (163) 4-(4,5-dihydroxazol-2-yl) -1,1-dioxidebenzo[b]thiophene,
- (164) 5-(4,5-dihydroxazol-2-yl) -1,1-dioxidebenzo[b]thiophene,
- (165) 5-carboxymethyloxy-1,1-dioxidebenzo[b]thiophene,
- (166) 7-carboxymethyloxy-1,1-dioxidebenzo[b]thiophene,
- (167) 4-((1S)-1-carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (168) 4-((1R)-1-carboxy-2-methylpropyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (169) 5-(3-carboxypropyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (170) 5-((2E)-3-carboxy-2-propenyl)oxy-1,1-dioxidebenzo[b]thiophene,
- (171) 4-2-(piperidin-1-yl) ethyl)aminomethyl-1,1-dioxidebenzo[b]thiophene,
- (172) 4-t-butoxycarbonylamino-1,1-dioxidebenzo[b]thiophene,
- (173) 4-amino-1,1-dioxidebenzo[b]thiophene,
- (174) 4-(4-fluorobenzylamino)-1,1-dioxidebenzo[b]thiophene,
- (175) 4-(pyridin-3-ylcarbonyl)amino-1,1-dioxidebenzo[b]thiophene,
- (176) 4-(3-chlorobenzoyl)amino-1,1-dioxidebenzo[b]thiophene,
- (177) 4-benzylcarbonylamino-1,1-dioxidebenzo[b]thiophene,
- (178) 4-(dimethylaminoacetyl)amino-1,1-dioxidebenzo[b]thiophene,
- (179) 4-acetylamino-1,1-dioxidebenzo[b]thiophene,
- (180) 4-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (181) 4-(2-diethylaminoethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (182) 4-(2-(N-ethyl-N-(3-methylphenyl)amino)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (183) 4-(2,4,6-trimethoxybenzyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (184) 4-(4-(2-hydroxyethyl)piperazin-1-yl) carbonyl-1,1-dioxidebenzo[b]thiophene,
- (185) 4-(4-benzyloxycarbonylpiperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (186) 4-(N-ethyl-N-2-(piperidin-1-yl)ethyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (187) 4-(3-(imidazol-1-yl)propyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (188) 4-(N-2-(piperidin-1-yl)ethyl-N-methyl)carbamoyl-1,1-dioxidebenzo[b]thiophene,
- (189) 4-(4-(1,3-dioxaindan-5-ylmethyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene,
- (190) 4-(4-((2E)-3-phenyl-2-propenyl)piperazin-1-yl)carbonyl-1,1-dioxidebenzo[b]thiophene, or
- an N-oxide derivative thereof or a non-toxic salt thereof.
15. A pharmaceutical composition comprising a fused thiophene derivative of the formula (IA) depicted in claim 4, an N-oxide derivative thereof or a non-toxic salt thereof as an active ingredient.
16. A method for preparation of a compound of the formula (XI)
- 2301
- which is characterized by cyanization of a compound of the formula (XII)
- 2302
- to obtain a compound of the formula (XIII)
- 2303
- then by subjecting to dehydration of the said compound of the formula (XIII) to obtain a compound of the formula (XIV)
- 2304
- and then followed by subjecting to hydrolysis of the said compound of the formula (XIV).
Type: Application
Filed: Apr 23, 2002
Publication Date: Apr 17, 2003
Inventors: Mikio Konishi (Osaka), Nobuo Katsube (Osaka), Mitoshi Konno (Osaka), Tadamitsu Kishimoto (Osaka)
Application Number: 10127409
International Classification: C07D333/76; C07D333/78; A61K031/519; A61K031/4743;
