Aromatic sulfone hydroxamic acid metalloprotease inhibitor
A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor. A contemplated compound corresponds in structure to formula B, below, 1
[0001] This is a continuation-in-part of application Ser. No. 09/311,837 filed on May 14, 1999 that was a continuation-in-part of application Ser. No. 09/256,948 filed on Feb. 24, 1999, that was a continuation-in-part of application Ser. No. 09/74497 filed on Nov. 13, 1998.
TECHNICAL FIELD[0002] This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors.
BACKGROUND OF THE INVENTION[0003] Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. Th se biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
[0004] Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
[0005] Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).
[0006] The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
[0007] The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
[0008] Metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-&agr;, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells.
[0009] TNF-&agr; convertase is a metalloprotease involved in the formation of soluble TNF-&agr;. Inhibition of TNF-&agr; convertase (TACE) inhibits production of active TNF-&agr;. Compounds that inhibit both MMPs activity and TNF-&agr; production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-&agr; convertase inhibiting agents.
[0010] MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (&bgr;-Amyloid Precursor Protein) to the amyloid plaque and inactivation of &agr;1-protease inhibitor (&agr;1-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as &agr;1-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
[0011] Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
[0012] Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), &agr;2-macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
[0013] Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
[0014] One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
[0015] Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
[0016] International application WO 98/38163, published on Sep. 3, 1998 disclose a large group of hydroxamate inhibitors of MMPs and TACE. The compounds of WO 98/38163 contain one or two substituents adjacent to the hydroxamate functionality and a substituent that can be an aromatic sulfonyl group adjacent to those one or two substituents.
[0017] International application WO 98/37877, published on Sep. 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring.
[0018] Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1.
SUMMARY OF THE INVENTION[0019] The present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By “substantially less” it is meant that a contemplated compound exhibits an IC50 value ratio against one or more of MMP-2, MMP-9 or MMP-13 as compared to its IC50 value against MMP-1, e.g., IC50 MMP-2:IC50 MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter. The invention also contemplates particular compounds that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor as active ingredient. Similarly contemplated are particular compounds such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient. The invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.
[0020] Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof: 2
[0021] wherein
[0022] R1 and R2 are both hydrido or R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
[0023] R3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. When R3 is a substituted aryl or heteroaryl radical, a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.
[0024] The substituent bonded to the aryl or heteroaryl radical of which the R3 radical is comprised itself can be substituted with one or more substituents; i.e., the substituting substituent is optionally substituted. When that aryl or heteroaryl radical is substituted, and the substituting moiety (group, substituent, or radical) is itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
[0025] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino
[0026] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,
[0027] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group
[0028] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
[0029] Preferably, the R3 substituent is Ph-Q-A-R-E-Y wherein Ph is phenyl substituted at the 4-position relative to the depicted SO2 group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms, one of which is bonded the depicted phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y.
[0030] A compound of formula I is a compound of more general formula A, wherein R3, R1 and R2 are as defined before and R20 is defined below. 3
[0031] The substituent R20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl., benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur. When used in a contemplated process or method, R20 is —NH—O—R22, as defined above.
[0032] In preferred practice, R1 and R2 together with the atoms to which they are bonded form a 6-membered ring.
[0033] An R3 radical preferably has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], more preferably greater than about that of a hexyl group [a —(CH2)5CH3 chain], and most preferably greater than an octyl group [a —(CH2)7CH3 chain]. An R3 radical preferably has a length that is less than that of an icosyl group [a —(CH2)19CH3 chain], and more preferably a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). A preferred R3 group contains two or more 5- or 6-membered rings. A contemplated R3 group, when rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three-dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two phenyl rings.
[0034] It is also preferred that a R3 radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C3-C14 alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group. The substituent of the 5- or 6-membered aryl or heteroaryl group can itself be substituted as discussed before.
[0035] A preferred compound for use in a contemplated process has a structure that corresponds to formula II, below, or a pharmaceutically acceptable salt thereof: 4
[0036] wherein
[0037] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
[0038] m is zero, 1 or 2;
[0039] n is zero, 1 or 2;
[0040] p is zero, 1 or 2;
[0041] the sum of m+n+p=1, 2, 3 or 4;
[0042] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
[0043] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
[0044] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of 5
[0045] wherein wavy lines are bonds to the atoms of the depicted ring;
[0046] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, Cs-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
[0047] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
[0048] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
[0049] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
[0050] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
[0051] G-A-R-E-Y is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:
[0052] G is an aryl or heteroaryl group;
[0053] A is selected from the group consisting of
[0054] (1) —O—;
[0055] (2) —S—;
[0056] (3) —NR17—;
[0057] (4) —CO—N(R17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;
[0058] (5) —CO—O— or —O—CO—;
[0059] (6) —O—CO—O—;
[0060] (7) —HC═CH—;
[0061] (8) —NH—CO—NH—;
[0062] (9) —C≡C—;
[0063] (10) —NH—CO—O— or —O—CO—NH—;
[0064] (11) —N═N—;
[0065] (12) —NH—NH—; and
[0066] (13) —CS—N(R18)— or —N(R18)—CS—, wherein
[0067] R18 is hydrogen C1-C4-alkyl, or phenyl; or
[0068] (14) A is absent and G is bonded directly to R;
[0069] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
[0070] E is selected from the group consisting of
[0071] (1) —CO(R19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;
[0072] (2) —CONH— or —HNCO—; and
[0073] (3) —CO—;
[0074] (4) —SO2—R19— or —R19—SO2—;
[0075] (5) —SO2—;
[0076] (6) —NH—SO2— or —SO2—NH—;
[0077] (7) —S—;
[0078] (8) —NH—CO—O— or —O—CO—NH—; or
[0079] (9) E is absent and R is bonded directly to Y; and
[0080] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
[0081] A particularly preferred compound for use in a contemplated process corresponds in structure to formula III, below, or a pharmaceutically acceptable salt thereof: 6
[0082] wherein
[0083] m, n, p, X, Z. Y and R14 are as defined above for formula II, and the R3 radical that is defined below is a sub-set of the previously discussed G-A-R-E-Y substituents.
[0084] Thus, R3 is a radical that is comprised of a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and a 4-benzyloxyphenoxy group.
[0085] A more particularly preferred compound for use in a contemplated process has a structure that corresponds to formula IV, below, or a pharmaceutically acceptable salt thereof: 7
[0086] wherein R3 is as defined above for formula I, more preferably as defined for formula II (wherein this R3 group is the G-A-R-E-Y substituent), and more preferably still as defined for formula III, and
[0087] Z is selected group the group consisting of O, S, NR6, SO, SO2, and NSO2R7,
[0088] wherein R6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and
[0089] R7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group.
[0090] A still more preferred group of compounds for use in a contemplated process correspond in structure to formula V, below, or a pharmaceutically acceptable salt thereof: 8
[0091] wherein
[0092] Z is as previously defined in formula IV;
[0093] W and Q are independently oxygen (O), NR6 or sulfur (S), and R6 is as defined in formula IV; and
[0094] q is zero or one such that when q is zero, the trifluoromethyl group is bonded directly to the depicted phenyl ring.
[0095] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B (including formulas B, B-A, B-1, B-1A, B-2, B-2A, B-3 and B-3A), formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q is a substituent of the depicted phenyl ring and can itself be substituted. Substituent Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one additional nitrogen atom. The substituents of Q such as A-R-E-Y, R-E-Y and E-Y are as defined before, and such a substituent is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. The remaining members of such a Q-beraing substituent (e.g., A-R-E-Y) are defined herein for the substituent G-A-R-E-Y. In addition, R20, X, Y, Z, m, n, and p of the ring system and g are as before described, with Z preferably being O or NR6. 9 10
[0096] The compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, are more particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII. In those latter formulas, Z is as before described, with Z preferably being O or NR6, and substituent Q is a 6-membered ring, as is shown. The A moiety of the Q ring substituent -A-R-E-Y (e.g. of formula B or B-1) is preferably absent in some embodiments, as in the compounds of formulas XI through XII, whereas both moieties A and R of that substituent group are absent in compounds of formulas 1× through X. The moieties A, R, E and Y of the substituent group -A-R-E-Y are as defined for the substituent group -G-A-R-E-Y. 11
[0097] When used in a contemplated in a before-described process, a compound of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, a R20 group is preferably —NH—O—R22 as defined above, and such a compound can also be present as a pharmaceutically acceptable salt. In addition, when so used, g is 2 in formulas B, VIC, VIC-1, VIC-2 and VII. The compounds of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII and their pharmaceutically acceptable salts are contemplated compounds of this invention.
[0098] The present invention also contemplates a precursor or intermediate compound that is useful in preparing a compound of formulas I-X. Such an intermediate compound corresponds in structure to formula VI, below: 12
[0099] wherein m, n, p, X, Z and Y are as defined above for formula II, g is zero, 1 or 2 and R24 is R3 as defined in formulas I, III or IV, is the substituent G-A-R-E-Y of formula II (formula VIA) or is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D. 13
[0100] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl.
[0101] R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
[0102] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII 14
[0103] wherein m, n, p, g, X, Z, Y, D and R20 are as defined above for formula VI.
[0104] Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
[0105] More particularly, a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease.
[0106] An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.
[0107] Yet another advantage of the invention is the provision of a process for preparing such compounds.
[0108] Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
[0109] A further advantage of the invention is the provision of a process for preparing such compositions.
[0110] Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
DETAILED DESCRIPTION OF THE INVENTION[0111] In accordance with the present invention, it has been discovered that certain aromatic sulfone hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (“MMPs”) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain aromatic sulfone hydroxamates are effective for inhibition of one or more enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply; i.e., angiogenesis.
[0112] Moreover, it has been discovered that these aromatic sulfone hydroxamates are selective in the inhibition of one or more of MMP-2, MMP-9 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated aromatic sulfone hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for one or more of MMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1.
[0113] There is thus a substantial difference in the activity of a compound used in a contemplated process toward one or more of MMP-2, MMP-9 and MMP-13 and MMP-1. This substantial difference is assayed using the in vitro inhibition assay discussed in the examples. A substantial difference in activity corresponds to a compound exhibiting an IC50 value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1 times that of the compound against MMP-1, and more preferably 0.01 times that against MMP-1 and most preferably 0.001 times that against MMP-1, or more. Indeed, some compounds exhibit selectivity differences measured by IC50 values that exceed the bounds of the assay at the number 100,000-fold. These selectivities are illustrated in the Inhibition Tables hereinafter.
[0114] Put differently, a contemplated compound can inhibit the activity of MMP-2 compared to MMP-9 or MMP-13 and MMP-1. Similarly, a contemplated compound can inhibit the activity of MMP-13 and MMP-2, while exhibiting less inhibition against MMP-1 and MMP-9. In addition, a contemplated compound can inhibit the activity of a MMP enzyme, while having less of an effect on tumor necrosis factor release.
[0115] The advantages of the selectivity of a contemplated compound can be appreciated, without wishing to be bound by theory, by considering the therapeutic uses the compounds. For example, inhibition of MMP-1 is suggested to be undesirable due to its role as a housekeeping enzyme, helping to maintain normal connective tissue turnover and repair. Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 has been suggested to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 compared with inhibition MMP-1 is highly desirable because a MMP-13 inhibitor can have a positive effect on disease progression in a patient in addition to having an anti-inflammatory effect.
[0116] Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis. A profile of selective inhibition of MMP-2 and MMP-9 relative to MMP-1 can provide a therapeutic advantage.
[0117] Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered.
[0118] The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF cad be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.
[0119] A contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor. A compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes. Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently-responsible to take drug at the required intervals. This is true even if the person is being treated with more than one drug for one or more diseases. On the other hand, IV drug administration is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled. A contemplated inhibitor can also be formulated for IM administration if desired. This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.
[0120] Thus, in one embodiment, the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity. A contemplated aromatic sulfone hydroxamate inhibitor compound useful in such a process inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinbelow. An aromatic sulfone hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below: 15
[0121] wherein
[0122] In one embodiment, R1 and R2 are both hydrido. In another embodiment, R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
[0123] It is preferred that R1 and R2 together with the atoms to which they are bonded form a five-to eight-membered ring that contains one or two heteroatoms in the ring, although R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms. The heterocyclic ring can itself also be substituted with up to six C1-C6-alkyl groups or groups that comprise a another 5- to 8-membered carbocyclic or heterocyclic ring, an amino group, or contain one or two oxo (carbonyl) groups.
[0124] R3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. That R3 radical is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.
[0125] The substituent of which R3 is comprised itself is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
[0126] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino
[0127] wherein the carboxamido nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,
[0128] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl-group
[0129] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. A compound of formula I can also be used in the form of a pharmaceutically acceptable salt.
[0130] The R3 radical has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], is more preferably greater than about the length of a hexyl group [a —(CH2)5CH3 chain), and most preferably is greater than about the length of an octyl group [a —(CH2)7CH3 chain]. A R3 group has a length that is less than that of an icosyl group [eicosyl; a —(CH2)19CH3 chain), and more preferably, a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). When rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, a contemplated R3 radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
[0131] A compound of formula I is a compound of more general formula A, wherein R3, R1 and R2 are as defined before and R20 is defined below. 16
[0132] The substituent R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is 0 (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d)—NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
[0133] Several exemplary R1 and R2 groups that together form a contemplated heterocyclic ring are shown in the Tables that follow hereinafter, as well as in the descriptions of those 5- to 8-membered rings and the specific Examples, as are several contemplated aromatic sulfone hydroxamic acid compounds.
[0134] In more preferred practice, R1 and R2 of formula I or formula A together with the atom to which they are bonded form a 5- to 8-membered ring that contains one, two or three heteroatoms. Most preferably, that ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO2 group is bonded. Other preferred compounds for use in a contemplated process correspond in structure to one or more of formulas II, III, IV or V, which are discussed hereinafter.
[0135] In one embodiment, a preferred compound used in a contemplated process has a structure that corresponds to formula II, below: 17
[0136] wherein
[0137] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
[0138] m is zero, 1 or 2;
[0139] n is zero, 1 or 2;
[0140] p is zero, 1 or 2;
[0141] the sum of m+n+p=1, 2, 3 or 4;
[0142] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
[0143] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
[0144] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of 18
[0145] wherein wavy lines are bonds to the atoms of the depicted ring;
[0146] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl; NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
[0147] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
[0148] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
[0149] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
[0150] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
[0151] G-A-R-E-Y is a substituent that preferably as a length greater than that of a pentyl group, and ore preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:
[0152] G is an aryl or heteroaryl group;
[0153] A is selected from the group consisting of
[0154] (1) —O—;
[0155] (2) —S—;
[0156] (3) —NR17—;
[0157] (4) —CO—N(R17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;
[0158] (5) —CO—O— or —O—CO—;
[0159] (6) —O—CO—O—;
[0160] (7) —HC═CH—;
[0161] (8) —NH—CO—NH—;
[0162] (9) —C≡C—;
[0163] (10) —NH—CO—O— or —O—CO—NH—;
[0164] (11) —N═N—;
[0165] (12) —NH—NH—; and
[0166] (13) —CS—N(R18)— or —N(R18)—CS—, wherein
[0167] R18 is hydrogen C1-C4-alkyl, or phenyl; or
[0168] (14) A is absent and G is bonded directly to R;
[0169] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
[0170] E is selected from the group consisting of
[0171] (1) —CO(R19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;
[0172] (2) —CONH— or —HNCO—; and
[0173] (3) —CO—;
[0174] (4) —SO2—R19— or —R19—SO2—;
[0175] (5) —SO2—;
[0176] (6) —NH—SO2— or —SO2—NH—;
[0177] (7) —S—;
[0178] (8) —NH—CO—O— or —O—CO—NH—; or
[0179] (9) E is absent and R is bonded directly to Y; and
[0180] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.
[0181] The substituent -G-A-R-E-Y preferably contains two to four carbocyclic or heterocyclic rings, including the aryl or heteroaryl group, G. More preferably, each of those rings is 6-membered. Additional separate preferences for a compound of formula II include: (a) that A is —O— or —S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent, and (d) Y is selected from the group consisting of hydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthio group.
[0182] A more preferred compound for use in a contemplated process has a structure that corresponds to formula III, below: 19
[0183] wherein R3 is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chloro-phenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluoro-phenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoro-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy, 4-(trifluoromethyl-thio)thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methyl-phenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and a 4-benzyloxyphenoxy group;
[0184] R14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and a C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
[0185] m is zero, 1 or 2;
[0186] n is zero, 1 or 2;
[0187] p is zero, 1 or 2;
[0188] the sum of m+n+p 1, 2, 3 or 4;
[0189] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
[0190] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
[0191] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of 20
[0192] wherein wavy lines are bonds to the atoms of the depicted ring;
[0193] R6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6 alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
[0194] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
[0195] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
[0196] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl; and
[0197] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group. Again, the use of a compound of formula III as a pharmaceutically acceptable salt is also contemplated.
[0198] Preferences related to a compound of formula III that also apply to a compound of formula II include the following, which are independently preferred: (a) the sum of m+n+p=1 or 2, and more preferably 2; (b) Z is O, S or NR6; (c) R6 is selected from the group consisting of C3-C6-cycloalkyl, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C6-alkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, aminosulfonyl, heteroaryl-C1-C6-alkyl, aryloxycarbonyl, and C1-C6-alkoxycarbonyl; and (d) m=n=zero, p=1, and Y is NR6. Another preference for a compound of both of formulas II and III is that R14 be hydrido, or that W of the C(W)R15 pro-drug form be 0 and R15 be a C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, or aryloxy group.
[0199] A still more preferred compound for use in a contemplated process corresponds in structure to formula IV, below: 21
[0200] Here, R3 is as defined above as to formulas I, III and more preferably as defined as to formula II (wherein the R3 radical is the substituent G-A-R-E-Y). Most preferably, R3 is as defined in formula III.
[0201] Z is selected group the group consisting of O, S, NR6, SO, SO2, and NSO2R7,
[0202] wherein R6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and
[0203] R7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group. Most preferably, Z is O or NR6. Here too, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.
[0204] A still more preferred group of contemplated compounds for use in a contemplated process correspond in structure to formula V, below; 22
[0205] wherein
[0206] Z is as previously defined for formula IV;
[0207] W and Q are independently oxygen (O), NR6 or sulfur (S), and R6 is as defined in formula IV; and
[0208] q is zero or one such that when q is zero, Q is absent and the trifluoromethyl group is bonded directly to the depicted phenyl ring. Here again, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.
[0209] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B, formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one nitrogen atom in addition to that depicted. The members of substituent -A-R-E-Y (or —R-E-Y or -E-Y) are as defined elsewhere in the definition of the members of the substituent -G-A-R-E-Y. Furthermore, substituent -A-R-E-Y (or substituent —R-E-Y or -E-Y) is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. Still fruther, R20, X, Y, Z, m, n, and p of the ring system and g are as before described. 23 24
[0210] More particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII, are the compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, wherein Z is as before described and the members of substituent group -E-Y and —R-E-Y are as defined for the substituent group -G-A-R-E-Y. 25 26
[0211] The use of a compound of formulas A and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2 and X, or a pharmaceutically acceptable salt of one of those compounds is contemplated in a before-described process. In addition, the compounds of those formulas and their pharmaceutically acceptable salts are contemplated compounds of this invention.
[0212] Particularly preferred compounds within the group defined by formula B have the structural formulas shown below: 27
[0213] Several particularly preferred compounds whose structures correspond to formulas I through XII are illustrated in the Tables and examples provided hereinafter.
[0214] As was noted before, the compounds of formulas I-XII, and their pharmaceutically acceptable salts are themselves contemplated compounds of the invention.
[0215] In preferred practice, an SO2-linked R3 radical is an aryl or heteroaryl group that is a 5- or 6-membered single-ring that is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group having a chain length of 3 to about 16 carbon atoms (and more preferably a length of up to about 14 carbon atoms), a phenoxy group, a thiophenoxy (C6H5—S—] group, a phenylazo [C6H5—N2—] group, a N-piperidyl [C5H10N—] group, a N-piperazyl [NC4H9N—] group or a benzamido [—NHC(O)C6H5] group. The SO2-linked single-ringed aryl or heteroaryl R3 group here is substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring.
[0216] The SO2-linked aryl or heteroaryl group of a R3 radical is preferably itself substituted at the 4-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring. A particularly preferred substituent is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or can itself be substituted.
[0217] The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding as compared to formalized ring numbering positions used in heteroaryl nomenclature, as is discussed further hereinbelow. Here, single atoms such as halogen moieties (fluoro, chloro, bromo, or iodo) or substituents that contain one to a chain length of about five atoms other than hydrogen such as phenyl, C1-C4 alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carboxyethyl groups are preferred, although longer substituents can be accommodated up to a total length of an icosyl group.
[0218] Exemplary particularly preferred substituted SO2-linked R3 radicals include 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl.
[0219] Inasmuch as a contemplated SO2-linked aryl or heteroaryl radical of an R3 group is itself preferably substituted with a 6-membered ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO2-linked aryl or heteroaryl radical. Although ortho, meta and para positional nomenclature is normally not used with aliphatic ring systems, it is believed more readily understood for describing the present compounds when used in conjunction with the numerical system for the first ring bonded to the SO2-group. When a R3 radical is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
[0220] Thus, the 1-position of an above-discussed SO2-linked aryl or heteroaryl group is the position at which the SO2-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
[0221] When examined along its longest chain of atoms, an R3 radical including its own substituent has a total length that is greater than a saturated chain of five carbon atoms (a pentyl group), and preferably has a length greater than that of a saturated chain of six carbon atoms (a hexyl group); i.e., a length of about a heptyl chain or longer. An R3 radical also has a length that is less than that of a saturated chain of about 20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)] and more preferably about 18 carbon atoms (a stearyl group). Most preferably, the length of R3 is about that of an 8 to about 12 carbon atom chain, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
[0222] Looked at more generally, and aside from specific moieties from which it is constructed, an R3 radical (group or moiety) has a length that is greater than that of a pentyl group. Such an R3 radical also has a length that is less than that of an icosyl (didecyl) group. That is to say that R3 is a radical having a minimal length longer that a saturated five carbon chain, and preferably greater than a hexyl group, but is shorter than the length of a saturated twenty carbon atom chain, and preferably shorter than an eighteen carbon chain. Most preferably, R3 has a length greater than that of an octyl group and less than that of a lauryl group.
[0223] More specifically, an R3 group has a minimal length of a hexyl group only when that substituent is comprised of two rings that can be fused or simply covalently linked together by exocyclic bonding. When R3 does not contain two linked or fused rings, e.g., where a R3 radical includes an alkyl or second, third or fourth ring substituent, R3 has a length that is greater than that of a hexyl group. Exemplary of such two ring R3 groups are a 2-naphthyl group or a 2-quinolinyl group (each with a six carbon chain length) and 8-purinyl (with a five carbon atom chain length). Without wishing to be bound by theory, it is believed that the presence of multiple rings in R3 enhances selectivity of the enzyme activity inhibitor profile.
[0224] The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms around a ring where necessary. Each atom in the chain, e.g. carbon, oxygen, sulfur or nitrogen, is presumed to be carbon for ease in calculation.
[0225] Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a desired, usually staggered, chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a phenyl or pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using such a measurement mode.
[0226] In addition, a R3 group when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring or the SO2-bonded position and substituent-bonded 3- or 4-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
[0227] Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R3 group when examined using the above rotational width criterion as well as the before-discussed criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too wide upon rotation and is excluded from being an R3 group.
[0228] As a consequence of these length and width requirements, R3 radicals such as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl are particularly preferred R3 radicals. Those substituents can themselves also be substituted in the second ring from the SO2 group at the meta- or para-position or both with a single atom or a substituent containing a longest chain length that is preferably of up to five atoms, excluding hydrogen.
[0229] Without wishing to be bound by theory, the length of a R3 radical substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. The length of the R3 radical group also appears to play a role in the selective activity of an inhibitor compound against particular MMP enzymes.
[0230] In particularly preferred practice, R3 is a PhR23 group, wherein Ph is phenyl. The phenyl ring (Ph) of a PhR23 group is substituted at its para-position (4-position) by an R23 group that can be another single-ringed aryl or heteroaryl group, a piperidyl group, a piperazinyl group, a phenoxy group, a thiophenoxy [C6H5—S—) group, a phenylazo [C6H5—N2—] group or a benzamido [—NHC(O)C6H5] group.
[0231] In one embodiment of a particularly preferred aromatic sulfone hydroxamate inhibitor compound, an R23 substituent is phenoxy and is itself substituted at its own para-position with a moiety that is selected from the group consisting of a halogen, a C1-C4 alkoxy group, a C1-C4 alkyl group, a dimethylamino group, a carboxyl C1-C3 alkylene group, a C1-C4 alkoxy carbonyl C1-C3 alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group and a carboxamido C1-C3 alkylene group, or is substituted at the meta- and para-positions by a methylenedioxy group. It is to be understood that any R23 substituent can be substituted with a moiety from the above list. Such substitution at the para-position is preferred.
[0232] The present invention also contemplates a compound that corresponds in structure to formula VI, below, that is useful in preparing a compound of formulas I-V, as well as as an active MMP-inhibiting compound and as a pro-drug form of an inhibitor. 28
[0233] wherein g is zero, 1 or 2;
[0234] R20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 7-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;
[0235] m is zero, 1 or 2;
[0236] n is zero, 1 or 2;
[0237] p is zero, 1 or 2;
[0238] the sum of m+n+p=1, 2, 3 or 4;
[0239] (a) one of X, Y and Z is selected from the group consisting of C(O), NR6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
[0240] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
[0241] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of 29
[0242] wherein wavy lines are bonds to the atoms of the depicted ring;
[0243] R6 and R6 are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
[0244] R7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
[0245] R8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
[0246] R12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
[0247] R13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
[0248] R24 is R3 as defined in formulas I, III, IV or is the substituent G-A-R-E-Y of formula II (formula VIA). Alternatively, R24 is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D. 30
[0249] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl. Additional coupling substituents include, without limitation, a hydroxyl group and an amino group that can be coupled with carbonyl-containing moieties to form esters, urethanes, carbonates, amides and ureas. Similarly, a carboxyl coupling substituent can be used to form an ester, thioester or amide. Thus, a coupling substituent is useful in converting a coupling substituent-containing aryl or heteroaryl group into a substituent such as a G-A-R-E-Y substituent discussed hereinabove by the formation of a covalent bond.
[0250] A compound of formula VI can be coupled with another moiety at the R3′ coupling substituent to form a compound whose newly formed R3 group is that of formulas I, III, IV or -G-A-R-E-Y. Exemplary of such couplings are the nucleophilic displacement to form ethers and thioethers, as well as the formation of ester, amide, urea, carbonate, urethane and the like linkages.
[0251] More particularly, where a R20 group is —O—R21, with R21 being selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, a precursor carboxylic acid or ester compound is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several examples hereinafter.
[0252] Where a R20 group is —NH—O—R22, wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group, an o-nitrophenyl group, or a peptide synthesis resin and the like, a synthetic intermediate is typically defined. In these compounds, a trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, ar-C1-C6-alkyl or a mixture thereof, such as a trimethylsilyl, dimethylisopropylsilyl, triethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York (1991).
[0253] A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, MO. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37(44):8048-8048(1996).
[0254] A 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group. A contemplated THP-protected hydroxamate compound of formula VII can be prepared by reacting the carboxylic acid precursor compound of formula VII [where R20 is —O—R21 and R21 is a hydrido group] in water with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol. An illustrative THP-protected compound corresponds in structure to formula VIIB, below, wherein m, n, p, g, X, Z. Y, and D are as defined previously.
[0255] Where R20 is —NR26R27, and R26 and R27 are as defined before, an amide compound is defined that can be used as a precursor intermediate and surprisingly as a MMP inhibitor compound. R26 and R27 are both preferably hydrido.
[0256] Where a R group is —NH—O—R14, and R14 is hydrido, or a pharmaceutically acceptable cation, an active hydroxamic acid or hydroxamate is defined. Where a R20 group is —NH—O—R14, and R14 is a C(W)R25 group as defined before, a pro-drug form of the hydroxamic acid is defined that can form a hydroxamic acid or hydroxamate form of the inhibitor in situ.
[0257] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII, below 31
[0258] wherein m, n, p, g, X, Z, Y, D and R20 are as defined above for formula VI. 32
[0259] In regard to a compound of each of formulas VI and VII, the subscript letter “g” is used to show the oxidation state of the sulfur atom. Where g is zero, the sulfur is unoxidized, and the compound depicted is typically the sulfide reaction product of a sulfur-containing synthon as is illustrated in the examples hereinafter. Where g is 1, the sulfur is oxidized to a sulfoxide, whereas when g is 2, the sulfur is oxidized to a sulfone as is also illustrated hereinafter. A compound of formulas VI or VII wherein g is zero or 1 as itself typically an intermediate in the formation of a similar compound wherein g is 2 and the intermediate is a preferred sulfone.
[0260] A preferred intermediate corresponds in structure to formula VIIA, below, wherein R20, X, Y, Z, m, n, p and D are as defined previously. 33
[0261] In the written descriptions of molecules and groups, molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like. A specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C6H5—CH2—CH2—O—CH2—O—(C═O)— wherein C6H5— is phenyl. It is also to be noted that a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl. Such combinations are used herein in the description of the processes, compounds and compositions of this invention and further examples are described below. The following list is not intended to be exhaustive or drawn out but provide illustrative examples of words or phrases (terms) that are used herein.
[0262] As utilized herein, the term “alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
[0263] The term “alkenyl”, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
[0264] The term “alkynyl”, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
[0265] The term “carbonyl” or “oxo”, alone or in combination, means a —C(═O)— group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group —C(OH)2—.
[0266] The term “thiol” or “sulfhydryl”, alone or in combination, means a —SH group. The term “thio” or “thia”, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
[0267] The term “amino”, alone or in combination, means an amine or —NH2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine —N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a —N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
[0268] Amines, amino groups and amides are compounds that can be designated as primary (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IV°) means a nitrogen with four substituents [—N+(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [—N+(substituent)3—O−]; i.e., the charges are internally compensated.
[0269] The term “cyano”, alone or in combination, means a —C-triple bond-N (—C≡N) group. The term “azido”, alone or in combination, means a —N-triple bond-N (—N≡N) group. The term “hydroxyl”, alone or in combination, means a —OH group. The term “nitro”, alone or in combination, means a —NO2 group. The term “azo”, alone or in combination, means a —N═N-group wherein the bonds at the terminal positions can be independently substituted.
[0270] The term “hydrazino”, alone or in combination, means a —NH—NH— group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
[0271] The term “sulfonyl”, alone or in combination, means a —SO2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfoxido”, alone or in combination, means a —SO— group wherein the remaining two bonds (valences) can be independently substituted.
[0272] The term “sulfone”, alone or in combination, means a —SO2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfenamide”, alone or in combination, means a —SON═ group wherein the remaining three depicted bonds (valences) can be independently substituted. The term “sulfide”, alone or in combination, means a —S— group wherein the remaining two bonds (valences) can be independently substituted.
[0273] The term “alkoxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
[0274] The term “cycloalkyl”, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term “cycloalkylalkyl” means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
[0275] A heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxy-carbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., —NH—) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., ═N—) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [═N(O)-] group.
[0276] The term “aryl”, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.
[0277] The term “heteroaryl”, alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, &bgr;-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals.
[0278] When an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoro-methoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
[0279] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino
[0280] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,
[0281] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group
[0282] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
[0283] The term “aralkyl”, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
[0284] The term “aralkoxycarbonyl”, alone or in combination, means a radical of the formula aralkyl-O—C(O)— in which the term “aralkyl” has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
[0285] The term “aryloxy” means a radical of the formula aryl-O— in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical.
[0286] The terms “heteroaralkyl” and “heteroaryloxy” mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.
[0287] The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
[0288] The term “cycloalkylcarbonyl” means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.
[0289] The terms “aralkanoyl” or “aralkylcarbonyl” mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.
[0290] The terms “aroyl” or “arylcarbonyl” means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
[0291] The term “cycloalkylalkoxycarbonyl” means an acyl group of the formula cycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance given above. The term “aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term “heterocyclooxycarbonyl” means an acyl group having the formula heterocyclo-O—CO— wherein heterocyclo is as defined above.
[0292] The term “heterocycloalkanoyl” is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term “heterocycloalkoxycarbonyl” means an acyl radical of the formula heterocyclo-substituted alkane-O—CO— wherein heterocyclo has the significance given above. The term “heteroaryloxycarbonyl” means an acyl radical represented by the formula heteroaryl-O—CO— wherein heteroaryl has the significance given above.
[0293] The term “aminocarbonyl” (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (—NH2) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.
[0294] The term “aminoalkanoyl” means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
[0295] The term “halogen” means fluoride, chloride, bromide or iodide. The term “haloalkyl” means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
[0296] The term “perfluoroalkyl” means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
[0297] The term “perfluoroalkoxy” alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F3C—O—), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.
[0298] The term “perfluoroalkylthio” alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F3C—S—), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
[0299] The term “aromatic ring” in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.
[0300] The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
[0301] “M” utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.
[0302] Preparation of Useful Compounds
[0303] Schemes A through C and Schemes 1 through 19 hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I, II, III, IV and V and similar cyclic inhibitors. In addition, the preparation of compounds of formula VI and formula VII is illustrated. Compounds of formula VI and formula VII can be used as intermediates in the preparation of the compounds of formulas I, II, III, IV and V or pro-drugs or MMP inhibitors.
[0304] In Schemes A through C, the symbol J independently represents R20 or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like. The n is 0, 1 or 2 and is preferred to be 1 or 2 in Scheme C. The n of these schemes corresponds to g in formulas VI and VII., and is zero, 1 or 2. The symbol m is 1 or 2. The symbol r is independently 1, 2 or 3. The symbol P represents a protecting group that can also be a member of the group R6. In Scheme A, for simplicity and clarity of illustration positional isomers are illustrated with a bond through the ring in standard fashion. Later Schemes typically only show one positional isomer but positional isomers are represented by these structures and reactions in a manner consistent with Formula I, II, III, IV, V, VI, VII above. Similarly, the symbol B represents O, S, SO, SO2 and NR6. The symbols C and C′ independently are electrophilic groups or groups capable of participating in a condensation reaction. Here to it should be noted that the six-membered ring is shown for illustrative purposes but the procedures and/or reagents are applicable to and represent combinations the permit the preparation of 5- to 8-membered rings.
[0305] The structures in Schemes 1 through 19 are also shown with compounds that represent the other compounds of this invention. The aromatic ring in Scheme C is aryl and heteroaryl. The moieties of -A-R-E-Y are as defined before. Reactions illustrated involving a spiroheterocyclic nitrogen atom may not be applicable to those compounds with sulfur or oxygen. 34
[0306] Scheme A shows in step 1 the reduction of a heteraryl compound to a carboxyl derivative. Generally, the first product is a hydrogen-containing amine heterocycle when the starting material is aromatic or an R6-containing heterocycle when a partially unsaturated heterocycle is the starting material.
[0307] Compound 2 can be treated in several ways depending on the needs of the chemist. In Step 2, the nitrogen can be protected by preparing, for example, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative. Such acylations can be carried out by methods well known in the art, especially the art of amino acid and peptide synthesis. The process of acylation with activated carboxyl group- or activated sulfonyl group-containing reagents to prepare contemplated compounds is carried out in the same manner. Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative. These acylations can be run in the presence of base including mild bases such as triethylamine or N-ethylmorpholine if desired. The preparation of some activated ester reagents and their use to prepare other compounds useful in this invention is discussed below. It should be recalled that the groups constituting P and serving as a selectively removable protecting group can also be included as part of the group R6.
[0308] Step 4 of Scheme A shows the alkylation or acylation of Compound 2 to produce compound 5. The process of acylation and alkylation are as discussed herein. In Step 5, the group J can be changed if desired. An example of such a change is exchange of an ester for a THP-protected hydroxamate conversion of a THP-protected hydroxamate inot a hydroxamate or conversion of an acid into a protected hydroxamate or the like.
[0309] Steps 3, 7 and 8 show the preparation of sulfur-containing derivatives of the contemplated compounds or intermediates to those compounds. The starting material for the above steps (e.g., compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to the carbonyl function. This anion can be reacted with a sulfur electrophile to produce a sulfone, sulfoxide or sulfide. Such electrophiles can be of the form of, for example, R24S—SR24, R24SO2C1, R24SC1, R24SOC1, R24S(O)—SR24 and the like where R24 is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R3′, that can be used to prepare one of the R24-containing groups. Preparation of the anion requires a base and a strong base may be required such as one of the metal amides, hydrides or alkyls discussed herein. The solvents are nonprotic, and dipolar aprotic solvents are preferred along with an inert atmosphere. Subsequent schemes usually utilize R3 for the R24 group for ease of illustration.
[0310] It should be noted that these processes produce sulfides (thio ethers), sulfoxides or sulfones depending on starting material. In addition, the sulfides can be oxidized to sulfoxides or sulfones, and the sulfoxides can be oxidized to their corresponding sulfone derivatives. The choice of position in the synthetic sequence to change the oxidation state of sulfur as well as the decision to change oxidation state is under the control of the chemist skilled in the art. Methods of oxidizing sulfur are discussed hereinbelow.
[0311] Scheme A, Steps 6, 9, 10 and 12 independently illustrate the interconversion of groups within J. Examples of such interconversions include exchange of an ester for hydroxamic acid or hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl derivative or into a hydroxamic acid or hydroxamic acid derivative (pro-drug or protected derivative), or removal of a protecting group from a hydroxamate derivative. The preparation of activated carbonyl compounds their reaction with nucleophiles such as hydroxamic acid, protected hydroxamates or hydroxamic acid pro-drugs is discussed below as is the conversion of protected hydroxamic acid derivatives into hydroxamic acids. The preparation of, for example, hydroxybenzotriazole/carbodiimide, derived products is discussed herein. The preparation or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides and the like are synthetic methods very well known in the art, and are not discussed in detail herein. Step 6 illustrates the conversion of compound 4 into compound 9, without first being converted into compound 7. 35
[0312] Scheme B illustrates an alternate method of preparing contemplated compounds. The reagent shown above the arrow in Step 1 is a reagent with two active groups in addition to the heteroatoms (B) noted before. Here again, the particular reagent illustrated was selected to permit a clear illustration of the reaction, but it is also intended to represent reagents that permit the preparation of the heteroatom position, and 5-, 7- and 8-membered ring size compounds. These reagents are readily selected by those skilled in the art.
[0313] C and C′ in this Step 1 reagent are independently an electophile or a group convertible into an electrophile. Such groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and the like. This reagent is reacted with a nucleophilic anion of a sulfur containing carbonyl compound such as compound 1. The anion is formed by deprotonation of compound 1 and examples of bases suitable for such a deprotonation are discussed below. Treatment with the above electrophilic reagent is carried out under alkylating conditions well known in the art and discussed herein. The product of this reaction can be either Compound 2 or Compound 3; i.e., the reaction can be carried out as a pot or two step process as required.
[0314] Step 3 illustrates the interconversion of J groups if desired as discussed above for Scheme A. Step 4 uses reagent where C, for example, represents a nucleophile as discussed above and C′ represents an electrophile or a nucleophile such as hydroxyl, thiol or R6-amino. It is noted that Cl can be, independently, a nucleophile or an electrophile when m is 2; i.e., the C′ groups are not required to be the same when m is 2. When m is 2, treatment with a second mole of base provides the skilled chemist an alternative preparation of Compound 5. When C′ is hydroxyl, thiol, or R6-amino and m is 2, the person skilled in the art can condense Compound 4 with, for example, an aldehyde or ketone, under reductive conditions or with subsequent reduction to form a contemplated compound. As above, the compound where m is 2 can be made in one step (one pot process) or two steps, thus permitting the chemist the choice of having the reagent(s) be the same (one pot) or different (two step).
[0315] Scheme B also illustrates the interconversions of the groups within J, the oxidation state of the sulfur and groups on nitrogen; i.e., R6 groups, to provide the contemplated compounds. These methods and processes are discussed above for the reactions of Scheme A. 36
[0316] Scheme C illustrates the nucleophilic displacement of a group D as defined herein. This reaction is carried out in a similar manner to the displacement reactions discussed herein. The choice of oxidation state of the sulfur is made by the person skilled in the art, but sulfoxide or sulfone groups are preferred, and the sulfone is most preferred. The displacement can be carried out either before or after the methylene next to the carbonyl group is reacted to form a Spiro heterocyclic group.
[0317] Steps 1, 2 and 3 also illustrate that although the nucleophilic displacement can be carried out with one nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and as shown herein to provide the group -A-R-E-Y as defined hereinbefore.
[0318] A non-limiting illustration of such a process is provided when D is fluoride. The fluoride leaving group can be directly displaced with the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to provide a contemplated compound. This is a one pot process from Compound 4. Other compounds included in -A-R-E-Y can be prepared by displacing the fluoride leaving group with ammonia to provide an amine, which can then be acylated by methods discussed wherein with, for example, 4-trifluoromethylbenzoyl chloride, to form another contemplated product compound.
[0319] The R6 function can be changed and/or further modified in compounds or at steps in the Schemes as desired or required by the person skilled in the art to prepare the contemplated compounds. Interconversion of dual purpose functional groups such as short or long term protecting groups into other R6 groups has been mentioned. Many other routine and/or useful conversions, including the preparation of synthetic intermediates, are very well known in the art. A few non-limiting examples of such conversions or reactions include: reductions; nucleophilic displacement/substitution reactions; exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, mixed anhydrides and the like; electrophilic displacement/substitution reactions; oxidations; ring/chain conversions, ring opening reactions, condensation reactions including those involving sulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced by either or both of those groups. The selection of preparative methods or conversion methods of the contemplated compounds and the order of the reaction(s) is made by the skilled person. It is expected that should a particular sequence or method prove to be undesirable that an alternative will be selected and used. Included is the choice of preparing/adding the groups in a single step using a convergent inhibitor strategy or preparing the final R6 group following a stepwise strategy.
[0320] Thus, in general, the choices of starting material and reaction conditions can vary as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required. Conditions are also selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually be minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.
[0321] These reactions can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolysis, can be carried out under laboratory air. In addition, some processes of these syntheses can be carried out in a pressure apparatus at pressures above, equal to or below atmospheric pressure. The use of such an apparatus aids in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like, and can also help prevent the leakage of air or humidity into a reaction in progress. This discussion is not intended to be exhaustive as it is readily noted that additional or alternative methods, conditions, reactions or systems can be identified and used by a chemist of ordinary skill.
[0322] The illustrated reactions are usually carried out at a temperature of between −25° C. to solvent reflux under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents. Reactions can be carried out at lower temperatures such as dry ice/acetone or liquid nitrogen temperature if desired to carry out such reactions as metalations or anion formations using strong bases.
[0323] In some cases, amines such as triethylamine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents. In some instances, in these reactions and other reactions in these Schemes, protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person can maintain or retain include, amines, other hydroxyls, thiols, acids and the like. Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups. The preparation of such protected compounds as well as their removal is well known in the art. The protecting groups can also be used as substituents in the contemplated compounds whose utility is as a drug rather than as a synthetic intermediate.
[0324] Many reactions or processes involve bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethyl-morpholiniumhydroxide, N,N,N′,N′-tetramethylpiperazinium hydroxide, and N-ethyl-N′-hexylpiperidinium hydroxide and the like.
[0325] Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadmium reagents such as dimethylcadmium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases can be reacted with acids to form contemplated pharmaceutically acceptable salts. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions.
[0326] Generally, reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making contemplated products and the like.
[0327] The preparation of compounds contemplated herein can require the oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones. Reagents for this process can include, in a non-limiting example, peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hypochlorite, sodium hydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like with the weaker agents being most useful for the preparation of sulfones and sulfoxides. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.
[0328] The oxidation can be carried out at temperature of about −780 to about 50° degrees Centigrade, and normally selected from a range −10° C. to about 40° C. Sulfoxides are best prepared using one equivalent of oxidizing agent. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. It should be noted that the oxidation of sulfides to sulfones can be carried out in one step or two steps via the sulfoxide as desired by the chemist.
[0329] Reduction is a well known process in the art with a useful method being hydrogenation. In such cases (catalytic reduction), there can be a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred or very high pressures in special hydrogenation equipment well known in the art.
[0330] Reductive alkylation of amines or active methylene compounds is also a useful method of preparing compounds. Such alkylations can be carried out under reductive hydrogenation conditions as presented above using, for example, aldehydes or ketones. Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminumhydride, borane, sodium borohydride, di-isobutylaluminum hydride and the like are also useful as reagents for reductive alkylation. Acyl groups can be reduced in a similar manner to produce substituted amines.
[0331] Alternative methods of alkylating carbon or nitrogen are direct alkylation. Such an alkylation, as is well known in the art, can be carried by treatment of an activated carbon containing at least one hydrogen with base to form the corresponding anion, adding an electrophilic reagent and permitting the SN2 reaction to proceed. An amine to be alkylated is treated similarly except that deprotonation may not be required. Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like.
[0332] Bases and solvents for alkylation reactions are those discussed above. Preferred are bases that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyl lithium. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.
[0333] Acids are used in many reactions during various syntheses. For example, removal of the THP protecting group to produce the hydroxamic acid. The acid can be a mono-, di- or tri-protic organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like. Acids in a protic can also be used to hydrolyze esters, amides and the like as well as catalyze exchange reactions.
[0334] Conversion of a carboxylic acid protected as an ester or amide into a hydroxamic acid or hydroxamic acid derivative such as an O-arylalkylether or O-cycloalkoxyalkylether group is useful. In the case where hydroxylamine is used, treatment of an ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents, usually protic or partially protic, such as those listed above can provide a hydroxamic acid directly. This exchange process can be further catalyzed by the addition of additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds such as shown in Schemes A, B and C that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products. Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
[0335] In the case where R20 is hydroxyl; i.e., where the intermediate is a carboxylic acid, standard coupling reactions can be used. For example, the acid can be converted into an acid chloride, mixed anhydride or activated ester such as hydroxybenzotriazole and treated with hydroxylamine or a protected hydroxylamine in the presence of a non-competitive base to the nitrogen acylated compound. This is the same product as discussed above. Couplings of this nature are well known in the art and especially the art related to peptide and amino acid chemistry.
[0336] An amide of this invention, whether used as a drug or as a protecting group, is prepared by treatment of an acid halide, anhydride, mixed anhydride or active ester with a primary amine, secondary amine or ammonia, or their equivalent. These standard coupling reactions are well known in the art and are discussed elsewhere herein. An alternative method of preparation of amides is by the exchange of, for example, an alkoxycarbonyl (ester) or aminecarbonyl (amide) group for an amine or different amine as required. Ester exchange processes are especially useful when less hindered amines, including ammonia, are used to make the corresponding amides of this invention.
[0337] Further, amides can be prepared from hydroxamic acids or protected hydroxamic acid compounds by catalytic reductions or in vivo or in vitro enzymatic processes. For example, catalytic reduction of O-benzylhydroxamic acid compounds is known to produce varying ratios of amide and hydroxamic acid depending upon the catalyst used as well as other reaction conditions such as solvent, temperature, hydrogen gas pressure and the like.
[0338] Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures. A compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation. An isomer can exist in equilibrium with another isomer in a mammal or a test system. Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, as is well known in the art. All isomers are included as compounds of this invention.
[0339] The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, are applicable to the preparation of the corresponding compounds that are contemplated. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
[0340] Table 1 through Table 165, below, show several contemplated aromatic sulfone hydroxamic acid inhibitor compounds or structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1 and R2 and R3, are as shown in each Table, and are typically not those used before. One or two bonds (wavy lines) are shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 2, R1 and R2 together with the atoms to which they are bonded is the variable group with the structural entities that can substitute for R1 and R2 together shown in the balance of that table. 1 TABLE 1 56 1 57 7 58 2 59 8 60 3 61 9 62 4 63 10 64 5 65 11 66 6 67 12 68
[0341] 2 TABLE 2 II 69 1 70 2 71 3 72 4 73 5 74 6 75 7 76 8 77 9 78 10 79 11 80 12 81
[0342] 3 TABLE 3 82 1 83 2 84 3 85 4 86 5 87 6 88 7 89 8 90 9 91 10 92 11 93 12 94 13 95 14 96 15 97 16 98 17 99 18 100
[0343] 4 TABLE 4 101 1 102 2 103 3 104 4 105 5 106 6 107 7 108 8 109 9 110 10 111 11 112 12 113 13 114 14 115 15 116 16 117 17 118 18 119 19 120 20 121 21 122
[0344] 5 TABLE 5 123 1 124 2 125 3 126 4 127 5 128 6 129 7 130 8 131 9 132 10 133 11 134 12 135 13 136 14 137 15 138 16 139 17 140 18 141 19 142 20 143 21 144 22 145
[0345] 6 TABLE 6 146 1 147 2 148 3 149 4 150 5 151 6 152 7 153 8 154 9 155 10 156 11 157 12 158 13 159 14 160 15 161 16 162 17 163 18 164 19 165 20 166 21 167 22 168 23 169 24 170 25 171 26 172 27 173 28 174 29 175 30 176
[0346] 7 TABLE 7 177 1 178 2 179 3 180 4 181 5 182 6 183 7 184 8 185 9 186 10 187 11 188 12 189 13 190 14 191 15 192 16 193 17 194 18 195 19 196 20 197 21 198
[0347] 8 TABLE 8 199 1 200 2 201 3 202 4 203 5 204 6 205 7 206 8 207 9 208 10 209 11 210
[0348] 9 TABLE 9 211 1 212 2 213 3 214 4 215 5 216 6 217 7 218 8 219 9 220 10 221 11 222 12 223 13 224 14 225 15 226 16 227 17 228 18 229 19 230 20 231 21 232
[0349] 10 TABLE 10 233 1 234 2 235 3 236 4 237 5 238 6 239 7 240 8 241 9 242 10 243 11 244 12 245 13 246 14 247 15 248 16 249 17 250 18 251
[0350] 11 TABLE 11 252 253 1 254 2 255 3 256 4 257 5 258 6 259 7 260 8 261 9 262 10 263 11 264 12 265 13 266 14 267 15 268 16 269 17 270 18 271 19 272 20 273 21 274
[0351] 12 TABLE 12 275 276 1 277 2 278 3 279 4 280 5 281 6 282 7 283 8 284 9 285 10 286 11 287 12 288 13 289 14 290 15 291 16 292 17 293 18 294 19 295 20 296 21 297 22 298
[0352] 13 TABLE 13 299 300 1 301 2 302 3 303 4 304 5 305 6 306 7 307 8 308 9 309 10 310 11 311 12 312 13 313 14 314 15 315 16 316 17 317 18 318 19 319 20 320 21 321 22 322 23 323 24 324 25 325 26 326 27 327 28 328 29 329 30 330
[0353] 14 TABLE 14 331 332 1 333 2 334 3 335 4 336 5 337 6 338 7 339 8 340 9 341 10 342 11 343 12 344 13 345 14 346 15 347 16 348 17 349 18 350 19 351 20 352 21 353
[0354] 15 TABLE 15 354 355 1 356 2 357 3 358 4 359 5 360 6 361 7 362 8 363 9 364 10 365 11 366
[0355] 16 TABLE 16 367 368 1 369 2 370 3 371 4 372 5 373 6 374 7 375 8 376 9 377 10 378 11 379 12 380 13 381 14 382 15 383 16 384 17 385 18 386 19 387 20 388 21 389
[0356] 17 TABLE 17 390 391 1 392 2 393 3 394 4 395 5 396 6 397 7 398 8 399 9 400 10 401 11 402 12 403 13 404 14 405 15 406 16 407 17 408 18 409
[0357] 18 TABLE 18 410 411 1 412 2 413 3 414 4 415 5 416 6 417 7 418 8 419 9 420 10 421 11 422 12 423 13 424 14 425 15 426 16 427 17 428 18 429 19 430 20 431 21 432
[0358] 19 TABLE 19 433 434 1 435 2 436 3 437 4 438 5 439 6 440 7 441 8 442 9 443 10 444 11 445 12 446 13 447 14 448 15 449 16 450 17 451 18 452 19 453 20 454 21 455 22 456
[0359] 20 TABLE 20 457 458 1 459 2 460 3 461 4 462 5 463 6 464 7 465 8 466 9 467 10 468 11 469 12 470 13 471 14 472 15 473 16 474 17 475 18 476 19 477 20 478 21 479 22 480 23 481 24 482 25 483 26 484 27 485 28 486 29 487 30 488
[0360] 21 TABLE 21 489 1 490 2 491 3 492 4 493 5 494 6 495 7 496 8 497 9 498 10 499 11 500 12 501 13 502 14 503 15 504 16 505 17 506 18 507 19 508 20 509 21 510
[0361] 22 TABLE 22 511 1 512 2 513 3 514 4 515 5 516 6 517 7 518 8 519 9 520 10 521 11 522
[0362] 23 TABLE 23 523 1 524 2 525 3 526 4 527 5 528 6 529 7 530 8 531 9 532 10 533 11 534 12 535 13 536 14 537 15 538 16 539 17 540 18 541 19 542 20 543 21 544
[0363] 24 TABLE 24 545 1 546 2 547 3 548 4 549 5 550 6 551 7 552 8 553 9 554 10 555 11 556 12 557 13 558 14 559 15 560 16 561 17 562 18 563
[0364] 25 TABLE 25 564 1 565 2 566 3 567 4 568 5 569 6 570 7 571 8 572 9 573 10 574 11 575 12 576 13 577 14 578 15 579 16 580 17 581 18 582 19 583 20 584 21 585
[0365] 26 TABLE 26 586 1 587 2 588 3 589 4 590 5 591 6 592 7 593 8 594 9 595 10 596 11 597 12 598 13 599 14 600 15 601 16 602 17 603 18 604 19 605 20 606 21 607 22 608
[0366] 27 TABLE 27 609 1 610 2 611 3 612 4 613 5 614 6 615 7 616 8 617 9 618 10 619 11 620 12 621 13 622 14 623 15 624 16 625 17 626 18 627 19 628 20 629 21 630 22 631 23 632 24 633 25 634 26 635 27 636 28 637 29 638 30 639
[0367] 28 TABLE 28 640 1 641 2 642 3 643 4 644 5 645 6 646 7 647 8 648 9 649 10 650 11 651 12 652 13 653 14 654 15 655 16 656 17 657 18 658 19 659 20 660 21 661
[0368] 29 TABLE 29 662 1 663 2 664 3 665 4 666 5 667 6 668 7 669 8 670 9 671 10 672 11 673
[0369] 30 TABLE 30 674 1 675 2 676 3 677 4 678 5 679 6 680 7 681 8 682 9 683 10 684 11 685 12 686 13 687 14 688 15 689 16 690 17 691 18 692
[0370] 31 TABLE 31 693 1 694 2 695 3 696 4 697 5 698 6 699 7 700 8 701 9 702 10 703 11 704 12 705 13 706 14 707 15 708 16 709 17 710 18 711 19 712 20 713 21 714
[0371] 32 TABLE 32 715 1 716 2 717 3 718 4 719 5 720 6 721 7 722 8 723 9 724 10 725 11 726 12 727 13 728 14 729 15 730 16 731 17 732 18 733 19 734 20 735 21 736 22 737
[0372] 33 TABLE 33 738 1 739 2 740 3 741 4 742 5 743 6 744 7 745 8 746 9 747 10 748 11 749 12 750 13 751 14 752 15 753 16 754 17 755 18 756 19 757 20 758 21 759 22 760 23 761 24 762 25 763 26 764 27 765 28 766 29 767 30 768
[0373] 34 TABLE 34 769 1 770 2 771 3 772 4 773 5 774 6 775 7 776 8 777 9 778 10 779 11 780 12 781 13 782 14 783 15 784 16 785 17 786 18 787 19 788 20 789 21 790
[0374] 35 TABLE 35 791 1 792 2 793 3 794 4 795 5 796 6 797 7 798 8 799 9 800 10 801 11 802
[0375] 36 TABLE 36 803 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 21 824
[0376] 37 TABLE 37 825 1 826 2 827 3 828 4 829 5 830 6 831 7 832 8 833 9 834 10 835 11 836 12 837 13 838 14 839 15 840 16 841 17 842 18 843
[0377] 38 TABLE 38 844 1 845 2 846 3 847 4 848 5 849 6 850 7 851 8 852 9 853 10 854 11 855 12 856 13 857 14 858 15 859 16 860 17 861 18 862 19 863 20 864 21 865
[0378] 39 TABLE 39 866 1 867 2 868 3 869 4 870 5 871 6 872 7 873 8 874 9 875 10 876 11 877 12 878 13 879 14 880 15 881 16 882 17 883 18 884 19 885 20 886 21 887 22 888
[0379] 40 TABLE 40 889 1 890 2 891 3 892 4 893 5 894 6 895 7 896 8 897 9 898 10 899 11 900 12 901 13 902 14 903 15 904 16 905 17 906 18 907 19 908 20 909 21 910 22 911 23 912 24 913 25 914 26 915 27 916 28 917 29 918 30 919
[0380] 41 TABLE 41 920 1 921 2 922 3 923 4 924 5 925 6 926 7 927 8 928 9 929 10 930 11 931 12 932 13 933 14 934 15 935 16 936 17 937 18 938 19 939 20 940 21 941
[0381] 42 TABLE 42 942 1 943 2 944 3 945 4 946 5 947 6 948 7 949 8 950 9 951 10 952 11 953
[0382] 43 TABLE 43 954 1 955 2 956 3 957 4 958 5 959 6 960 7 961 8 962 9 963 10 964 11 965 12 966 13 967 14 968 15 969 16 970 17 971 18 972 19 973 20 974 21 975
[0383] 44 TABLE 44 976 1 977 2 978 3 979 4 980 5 981 6 982 7 983 8 984 9 985 10 986 11 987 12 988 13 989 14 990 15 991 16 992 17 993 18 994
[0384] 45 TABLE 45 995 1 996 2 997 3 998 4 999 5 1000 6 1001 7 1002 8 1003 9 1004 10 1005 11 1006 12 1007 13 1008 14 1009 15 1010 16 1011 17 1012 18 1013 19 1014 20 1015 21 1016
[0385] 46 TABLE 46 1017 1 1018 2 1019 3 1020 4 1021 5 1022 6 1023 7 1024 8 1025 9 1026 10 1027 11 1028 12 1029 13 1030 14 1031 15 1032 16 1033 17 1034 18 1035 19 1036 20 1037 21 1038 22 1039
[0386] 47 TABLE 47 1040 1 1041 2 1042 3 1043 4 1044 5 1045 6 1046 7 1047 8 1048 9 1049 10 1050 11 1051 12 1052 13 1053 14 1054 15 1055 16 1056 17 1057 18 1058 19 1059 20 1060 21 1061 22 1062 23 1063 24 1064 25 1065 26 1066 27 1067 28 1068 29 1069 30 1070
[0387] 48 TABLE 48 1071 1 1072 2 1073 3 1074 4 1075 5 1076 6 1077 7 1078 8 1079 9 1080 10 1081 11 1082 12 1083 13 1084 14 1085 15 1086 16 1087 17 1088 18 1089 19 1090 20 1091 21 1092
[0388] 49 TABLE 49 1093 1 1094 2 1095 3 1096 4 1097 5 1098 6 1099 7 1100 8 1101 9 1102 10 1103 11 1104
[0389] 50 TABLE 50 1105 1 1106 2 1107 3 1108 4 1109 5 1110 6 1111 7 1112 8 1113 9 1114 10 1115 11 1116 12 1117 13 1118 14 1119 15 1120 16 1121 17 1122 18 1123 19 1124 20 1125 21 1126
[0390] 51 TABLE 51 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145
[0391] 52 TABLE 52 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167
[0392] 53 TABLE 53 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190
[0393] 54 TABLE 54 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221
[0394] 55 TABLE 55 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243
[0395] 56 TABLE 56 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255
[0396] 57 TABLE 57 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277
[0397] 58 TABLE 58 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296
[0398] 59 TABLE 59 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318
[0399] 60 TABLE 60 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340 1341
[0400] 61 TABLE 61 1342 1343 1 1344 2 1345 3 1346 4 1347 5 1348 6 1349 7 1350 8 1351 9 1352 10 1353 11 1354 12 1355 13 1356 14 1357 15 1358 16 1359 17 1360 18 1361 19 1362 20 1363 21 1364 22 1365 23 1366 24 1367 25 1368 26 1369 27 1370 28 1371 29 1372 30 1373
[0401] 62 TABLE 62 1374 1375 1 1376 2 1377 3 1378 4 1379 5 1380 6 1381 7 1382 8 1383 9 1384 10 1385 11 1386 12 1387 13 1388 14 1389 15 1390 16 1391 17 1392 18 1393 19 1394 20 1395 21 1396
[0402] 63 TABLE 63 1397 1398 1 1399 2 1400 3 1401 4 1402 5 1403 6 1404 7 1405 8 1406 9 1407 10 1408 11 1409
[0403] 64 TABLE 64 1410 1411 1 1412 2 1413 3 1414 4 1415 5 1416 6 1417 7 1418 8 1419 9 1420 10 1421 11 1422 12 1423 13 1424 14 1425 15 1426 16 1427 17 1428 18 1429 19 1430 20 1431 21 1432
[0404] 65 TABLE 65 1433 1434 1 1435 2 1436 3 1437 4 1438 5 1439 6 1440 7 1441 8 1442 9 1443 10 1444 11 1445 12 1446 13 1447 14 1448 15 1449 16 1450 17 1451 18 1452
[0405] 66 TABLE 66 1453 1454 1 1455 2 1456 3 1457 4 1458 5 1459 6 1460 7 1461 8 1462 9 1463 10 1464 11 1465 12 1466 13 1467 14 1468 15 1469 16 1470 17 1471 18 1472 19 1473 20 1474 21 1475
[0406] 67 TABLE 67 1476 1477 1 1478 2 1479 3 1480 4 1481 5 1482 6 1483 7 1484 8 1485 9 1486 10 1487 11 1488 12 1489 13 1490 14 1491 15 1492 16 1493 17 1494 18 1495 19 1496 20 1497 21 1498 22 1499
[0407] 68 TABLE 68 1500 1501 1 1502 2 1503 3 1504 4 1505 5 1506 6 1507 7 1508 8 1509 9 1510 10 1511 11 1512 12 1513 13 1514 14 1515 15 1516 16 1517 17 1518 18 1519 19 1520 20 1521 21 1522 22 1523 23 1524 24 1525 25 1526 26 1527 27 1528 28 1529 29 1530 30 1531
[0408] 69 TABLE 69 1532 1533 1 1534 2 1535 3 1536 4 1537 5 1538 6 1539 7 1540 8 1541 9 1542 10 1543 11 1544 12 1545 13 1546 14 1547 15 1548 16 1549 17 1550 18 1551 19 1552 20 1553 21 1554
[0409] 70 TABLE 70 1555 1556 1 1557 2 1558 3 1559 4 1560 5 1561 6 1562 7 1563 8 1564 9 1565 10 1566 11 1567
[0410] 71 TABLE 71 1568 1 1569 2 1570 3 1571 4 1572 5 1573 6 1574 7 1575 8 1576 9 1577 10 1578 11 1579 12 1580 13 1581 14 1582 15 1583 16 1584 17 1585 18 1586 19 1587 20 1588 21 1589
[0411] 72 TABLE 72 1590 1 1591 2 1592 3 1593 4 1594 5 1595 6 1596 7 1597 8 1598 9 1599 10 1600 11 1601 12 1602 13 1603 14 1604 15 1605 16 1606 17 1607 18 1608
[0412] 73 TABLE 73 1609 1 1610 2 1611 3 1612 4 1613 5 1614 6 1615 7 1616 8 1617 9 1618 10 1619 11 1620 12 1621 13 1622 14 1623 15 1624 16 1625 17 1626 18 1627 19 1628 20 1629 21 1630
[0413] 74 TABLE 74 1631 1 1632 2 1633 3 1634 4 1635 5 1636 6 1637 7 1638 8 1639 9 1640 10 1641 11 1642 12 1643 13 1644 14 1645 15 1646 16 1647 17 1648 18 1649 19 1650 20 1651 21 1652 22 1653
[0414] 75 TABLE 75 1654 1 1655 2 1656 3 1657 4 1658 5 1659 6 1660 7 1661 8 1662 9 1663 10 1664 11 1665 12 1666 13 1667 14 1668 15 1669 16 1670 17 1671 18 1672 19 1673 20 1674 21 1675 22 1676 23 1677 24 1678 25 1679 26 1680 27 1681 28 1682 29 1683 30 1684
[0415] 76 TABLE 76 1685 1 1686 2 1687 3 1688 4 1689 5 1690 6 1691 7 1692 8 1693 9 1694 10 1695 11 1696 12 1697 13 1698 14 1699 15 1700 16 1701 17 1702 18 1703 19 1704 20 1705 21 1706
[0416] 77 TABLE 77 1707 1 1708 2 1709 3 1710 4 1711 5 1712 6 1713 7 1714 8 1715 9 1716 10 1717 11 1718
[0417] 78 TABLE 78 1719 1 1720 2 1721 3 1722 4 1723 5 1724 6 1725 7 1726 8 1727 9 1728 10 1729 11 1730 12 1731 13 1732 14 1733 15 1734 16 1735 17 1736 18 1737 19 1738 20 1739 21 1740
[0418] 79 TABLE 79 1741 1 1742 2 1743 3 1744 4 1745 5 1746 6 1747 7 1748 8 1749 9 1750 10 1751 11 1752 12 1753 13 1754 14 1755 15 1756 16 1757 17 1758 18 1759
[0419] 80 TABLE 80 1760 1 1761 2 1762 3 1763 4 1764 5 1765 6 1766 7 1767 8 1768 9 1769 10 1770 11 1771 12 1772 13 1773 14 1774 15 1775 16 1776 17 1777 18 1778 19 1779 20 1780 21 1781
[0420] 81 TABLE 81 1782 1 1783 2 1784 3 1785 4 1786 5 1787 6 1788 7 1789 8 1790 9 1791 10 1792 11 1793 12 1794 13 1795 14 1796 15 1797 16 1798 17 1799 18 1800 19 1801 20 1802 21 1803 22 1804
[0421] 82 TABLE 82 1805 1 1806 2 1807 3 1808 4 1809 5 1810 6 1811 7 1812 8 1813 9 1814 10 1815 11 1816 12 1817 13 1818 14 1819 15 1820 16 1821 17 1822 18 1823 19 1824 20 1825 21 1826 22 1827 23 1828 24 1829 25 1830 26 1831 27 1832 28 1833 29 1834 30 1835
[0422] 83 TABLE 83 1836 1 1837 2 1838 3 1839 4 1840 5 1841 6 1842 7 1843 8 1844 9 1845 10 1846 11 1847 12 1848 13 1849 14 1850 15 1851 16 1852 17 1853 18 1854 19 1855 20 1856 21 1857
[0423] 84 TABLE 84 1858 1 1859 2 1860 3 1861 4 1862 5 1863 6 1864 7 1865 8 1866 9 1867 10 1868 11 1869
[0424] 85 TABLE 85 1870 1 1871 2 1872 3 1873 4 1874 5 1875 6 1876 7 1877 8 1878 9 1879 10 1880 11 1881 12 1882 13 1883 14 1884 15 1885 16 1886 17 1887 18 1888 19 1889 20 1890 21 1891
[0425] 86 TABLE 86 1892 1 1893 2 1894 3 1895 4 1896 5 1897 6 1898 7 1899 8 1900 9 1901 10 1902 11 1903 12 1904 13 1905 14 1906 15 1907 16 1908 17 1909 18 1910
[0426] 87 TABLE 87 1911 1 1912 2 1913 3 1914 4 1915 5 1916 6 1917 7 1918 8 1919 9 1920 10 1921 11 1922 12 1923 13 1924 14 1925 15 1926 16 1927 17 1928 18 1929 19 1930 20 1931 21 1932
[0427] 88 TABLE 88 1933 1 1934 2 1935 3 1936 4 1937 5 1938 6 1939 7 1940 8 1941 9 1942 10 1943 11 1944 12 1945 13 1946 14 1947 15 1948 16 1949 17 1950 18 1951 19 1952 20 1953 21 1954 22 1955
[0428] 89 TABLE 89 1956 1 1957 2 1958 3 1959 4 1960 5 1961 6 1962 7 1963 8 1964 9 1965 10 1966 11 1967 12 1968 13 1969 14 1970 15 1971 16 1972 17 1973 18 1974 19 1975 20 1976 21 1977 22 1978 23 1979 24 1980 25 1981 26 1982 27 1983 28 1984 29 1985 30 1986
[0429] 90 TABLE 90 1987 1 1988 2 1989 3 1990 4 1991 5 1992 6 1993 7 1994 8 1995 9 1996 10 1997 11 1998 12 1999 13 2000 14 2001 15 2002 16 2003 17 2004 18 2005 19 2006 20 2007 21 2008
[0430] 91 TABLE 91 2009 1 2010 2 2011 3 2012 4 2013 5 2014 6 2015 7 2016 8 2017 9 2018 10 2019 11 2020
[0431] 92 TABLE 92 2021 1 2022 2 2023 3 2024 4 2025 5 2026 6 2027 7 2028 8 2029 9 2030 10 2031 11 2032 12 2033 13 2034 14 2035 15 2036 16 2037 17 2038 18 2039 19 2040 20 2041 21 2042
[0432] 93 TABLE 93 2043 1 2044 2 2045 3 2046 4 2047 5 2048 6 2049 7 2050 8 2051 9 2052 10 2053 11 2054 12 2055 13 2056 14 2057 15 2058 16 2059 17 2060 18 2061
[0433] 94 TABLE 94 2062 1 2063 2 2064 3 2065 4 2066 5 2067 6 2068 7 2069 8 2070 9 2071 10 2072 11 2073 12 2074 13 2075 14 2076 15 2077 16 2078 17 2079 18 2080 19 2081 20 2082 21 2083
[0434] 95 TABLE 95 2084 1 2085 2 2086 3 2087 4 2088 5 2089 6 2090 7 2091 8 2092 9 2093 10 2094 11 2095 12 2096 13 2097 14 2098 15 2099 16 2100 17 2101 18 2102 19 2103 20 2104 21 2105 22 2106
[0435] 96 TABLE 96 2107 1 2108 2 2109 3 2110 4 2111 5 2112 6 2113 7 2114 8 2115 9 2116 10 2117 11 2118 12 2119 13 2120 14 2121 15 2122 16 2123 17 2124 18 2125 19 2126 20 2127 21 2128 22 2129 23 2130 24 2131 25 2132 26 2133 27 2134 28 2135 29 2136 30 2137
[0436] 97 TABLE 97 2138 1 2139 2 2140 3 2141 4 2142 5 2143 6 2144 7 2145 8 2146 9 2147 10 2148 11 2149 12 2150 13 2151 14 2152 15 2153 16 2154 17 2155 18 2156 19 2157 20 2158 21 2159
[0437] 98 TABLE 98 2160 1 2161 2 2162 3 2163 4 2164 5 2165 6 2166 7 2167 8 2168 9 2169 10 2170 11 2171
[0438] 99 TABLE 99 2172 1 2173 2 2174 3 2175 4 2176 5 2177 6 2178 7 2179 8 2180 9 2181 10 2182 11 2183 12 2184 13 2185 14 2186 15 2187 16 2188 17 2189 18 2190 19 2191 20 2192 21 2193
[0439] 100 TABLE 100 2194 1 2195 2 2196 3 2197 4 2198 5 2199 6 2200 7 2201 8 2202 9 2203 10 2204 11 2205 12 2206 13 2207 14 2208 15 2209 16 2210 17 2211 18 2212
[0440] 101 TABLE 101 2213 2214 1 2215 2 2216 3 2217 4 2218 5 2219 6 2220 7 2221 8 2222 9 2223 10 2224 11 2225 12 2226 13 2227 14 2228 15 2229 16 2230 17 2231 18 2232 19 2233 20 2234 21 2235
[0441] 102 TABLE 102 2236 2237 1 2238 2 2239 3 2240 4 2241 5 2242 6 2243 7 2244 8 2245 9 2246 10 2247 11 2248 12 2249 13 2250 14 2251 15 2252 16 2253 17 2254 18 2255 19 2256 20 2257 21 2258 22 2259
[0442] 103 TABLE 103 2260 2261 1 2262 2 2263 3 2264 4 2265 5 2266 6 2267 7 2268 8 2269 9 2270 10 2271 11 2272 12 2273 13 2274 14 2275 15 2276 16 2277 17 2278 18 2279 19 2280 20 2281 21 2282 22 2283 23 2284 24 2285 25 2286 26 2287 27 2288 28 2289 29 2290 30 2291
[0443] 104 TABLE 104 2292 2293 1 2294 2 2295 3 2296 4 2297 5 2298 6 2299 7 2300 8 2301 9 2302 10 2303 11 2304 12 2305 13 2306 14 2307 15 2308 16 2309 17 2310 18 2311 19 2312 20 2313 21 2314
[0444] 105 TABLE 105 2315 2316 1 2317 2 2318 3 2319 4 2320 5 2321 6 2322 7 2323 8 2324 9 2325 10 2326 11 2327
[0445] 106 TABLE 106 2328 2329 1 2330 2 2331 3 2332 4 2333 5 2334 6 2335 7 2336 8 2337 9 2338 10 2339 11 2340 12 2341 13 2342 14 2343 15 2344 16 2345 17 2346 18 2347 19 2348 20 2349 21 2350
[0446] 107 TABLE 107 2351 2352 1 2353 2 2354 3 2355 4 2356 5 2357 6 2358 7 2359 8 2360 9 2361 10 2362 11 2363 12 2364 13 2365 14 2366 15 2367 16 2368 17 2369 18 2370
[0447] 108 TABLE 108 2371 2372 1 2373 2 2374 3 2375 4 2376 5 2377 6 2378 7 2379 8 2380 9 2381 10 2382 11 2383 12 2384 13 2385 14 2386 15 2387 16 2388 17 2389 18 2390 19 2391 20 2392 21 2393
[0448] 109 TABLE 109 2394 2395 1 2396 2 2397 3 2398 4 2399 5 2400 6 2401 7 2402 8 2403 9 2404 10 2405 11 2406 12 2407 13 2408 14 2409 15 2410 16 2411 17 2412 18 2413 19 2414 20 2415 21 2416 22 2417
[0449] 110 TABLE 110 2418 2419 1 2420 2 2421 3 2422 4 2423 5 2424 6 2425 7 2426 8 2427 9 2428 10 2429 11 2430 12 2431 13 2432 14 2433 15 2434 16 2435 17 2436 18 2437 19 2438 20 2439 21 2440 22 2441 23 2442 24 2443 25 2444 26 2445 27 2446 28 2447 29 2448 30 2449
[0450] 111 TABLE 111 2450 1 2451 2 2452 3 2453 4 2454 5 2455 6 2456 7 2457 8 2458 9 2459 10 2460 11 2461 12 2462 13 2463 14 2464 15 2465 16 2466 17 2467 18 2468 19 2469 20 2470 21 2471
[0451] 112 TABLE 112 2472 1 2473 2 2474 3 2475 4 2476 5 2477 6 2478 7 2479 8 2480 9 2481 10 2482 11 2483
[0452] 113 TABLE 113 2484 1 2485 2 2486 3 2487 4 2488 5 2489 6 2490 7 2491 8 2492 9 2493 10 2494 11 2495 12 2496 13 2497 14 2498 15 2499 16 2500 17 2501 18 2502 19 2503 20 2504 21 2505
[0453] 114 TABLE 114 2506 1 2507 2 2508 3 2509 4 2510 5 2511 6 2512 7 2513 8 2514 9 2515 10 2516 11 2517 12 2518 13 2519 14 2520 15 2521 16 2522 17 2523 18 2524
[0454] 115 TABLE 115 2525 1 2526 2 2527 3 2528 4 2529 5 2530 6 2531 7 2532 8 2533 9 2534 10 2535 11 2536 12 2537 13 2538 14 2539 15 2540 16 2541 17 2542 18 2543 19 2544 20 2545 21 2546
[0455] 116 TABLE 116 2547 1 2548 2 2549 3 2550 4 2551 5 2552 6 2553 7 2554 8 2555 9 2556 10 2557 11 2558 12 2559 13 2560 14 2561 15 2562 16 2563 17 2564 18 2565 19 2566 20 2567 21 2568 22 2569
[0456] 117 TABLE 117 2570 1 2571 2 2572 3 2573 4 2574 5 2575 6 2576 7 2577 8 2578 9 2579 10 2580 11 2581 12 2582 13 2583 14 2584 15 2585 16 2586 17 2587 18 2588 19 2589 20 2590 21 2591 22 2592 23 2593 24 2594 25 2595 26 2596 27 2597 28 2598 29 2599 30 2600
[0457] 118 TABLE 118 2601 1 2602 2 2603 3 2604 4 2605 5 2606 6 2607 7 2608 8 2609 9 2610 10 2611 11 2612
[0458] 119 TABLE 119 2613 1 2614 2 2615 3 2616 4 2617 5 2618 6 2619 7 2620 8 2621 9 2622 10 2623 11 2624 12 2625 13 2626 14 2627 15 2628 16 2629 17 2630 18 2631 19 2632 20 2633 21 2634
[0459] 120 TABLE 120 2635 1 2636 2 2637 3 2638 4 2639 5 2640 6 2641 7 2642 8 2643 9 2644 10 2645 11 2646 12 2647 13 2648 14 2649 15 2650 16 2651 17 2652 18 2653
[0460] 121 TABLE 121 2654 1 2655 2 2656 3 2657 4 2658 5 2659 6 2660 7 2661 8 2662 9 2663 10 2664 11 2665 12 2666 13 2667 14 2668 15 2669 16 2670 17 2671 18 2672 19 2673 20 2674 21 2675
[0461] 122 TABLE 122 2676 1 2677 2 2678 3 2679 4 2680 5 2681 6 2682 7 2683 8 2684 9 2685 10 2686 11 2687 12 2688 13 2689 14 2690 15 2691 16 2692 17 2693 18 2694 19 2695 20 2696 21 2697 22 2698
[0462] 123 TABLE 123 2699 1 2700 2 2701 3 2702 4 2703 5 2704 6 2705 7 2706 8 2707 9 2708 10 2709 11 2710 12 2711 13 2712 14 2713 15 2714 16 2715 17 2716 18 2717 19 2718 20 2719 21 2720 22 2721 23 2722 24 2723 25 2724 26 2725 27 2726 28 2727 29 2728 30 2729
[0463] 124 TABLE 124 2730 1 2731 2 2732 3 2733 4 2734 5 2735 6 2736 7 2737 8 2738 9 2739 10 2740 11 2741 12 2742 13 2743 14 2744 15 2745 16 2746 17 2747 18 2748 19 2749 20 2750 21 2751
[0464] 125 TABLE 125 2752 1 2753 2 2754 3 2755 4 2756 5 2757 6 2758 7 2759 8 2760 9 2761 10 2762 11 2763
[0465] 126 TABLE 126 2764 1 2765 2 2766 3 2767 4 2768 5 2769 6 2770 7 2771 8 2772 9 2773 10 2774 11 2775 12 2776 13 2777 14 2778 15 2779 16 2780 17 2781 18 2782 19 2783 20 2784 21 2785
[0466] 127 TABLE 127 2786 1 2787 2 2788 3 2789 4 2790 5 2791 6 2792 7 2793 8 2794 9 2795 10 2796 11 2797 12 2798 13 2799 14 2800 15 2801 16 2802 17 2803 18 2804 19 2805 20 2806 21 2807
[0467] 128 TABLE 128 2808 1 2809 2 2810 3 2811 4 2812 5 2813 6 2814 7 2815 8 2816 9 2817 10 2818 11 2819 12 2820 13 2821 14 2822 15 2823 16 2824 17 2825 18 2826 19 2827 20 2828 21 2829
[0468] 129 TABLE 129 2830 1 2831 14 2832 2 2833 15 2834 3 2835 16 2836 4 2837 17 2838 5 2839 18 2840 6 2841 19 2842 7 2843 20 2844 8 2845 21 2846 9 2847 22 2848 10 2849 23 2850 11 2851 24 2852 12 2853 25 2854 13 2855 26 2856
[0469] 130 TABLE 130 2857 1 2858 14 2859 2 2860 15 2861 3 2862 16 2863 4 2864 17 2865 5 2866 18 2867 6 2868 19 2869 7 2870 20 2871 8 2872 21 2873 9 2874 22 2875 10 2876 23 2877 11 2878 24 2879 12 2880 25 2881 13 2882 26 2883
[0470] 131 TABLE 131 2884 2885 1 2886 14 2887 2 2888 15 2889 3 2890 16 2891 4 2892 17 2893 5 2894 18 2895 6 2896 19 2897 7 2898 20 2899 8 2900 21 2901 9 2902 22 2903 10 2904 23 2905 11 2906 24 2907 12 2908 25 2909 13 2910 26 2911
[0471] 132 TABLE 132 2912 2913 1 2914 14 2915 2 2916 15 2917 3 2918 16 2919 4 2920 17 2921 5 2922 18 2923 6 2924 19 2925 7 2926 20 2927 8 2928 21 2929 9 2930 22 2931 10 2932 23 2933 11 2934 24 2935 12 2936 25 2937 13 2938 26 2939
[0472] 133 TABLE 133 2940 2941 1 2942 14 2943 2 2944 15 2945 3 2946 16 2947 4 2948 17 2949 5 2950 18 2951 6 2952 19 2953 7 2954 20 2955 8 2956 21 2957 9 2958 22 2959 10 2960 23 2961 11 2962 24 2963 12 2964 25 2965 13 2966 26 2967
[0473] 134 TABLE 134 2968 2969 1 2970 14 2971 2 2972 15 2973 3 2974 16 2975 4 2976 17 2977 5 2978 18 2979 6 2980 19 2981 7 2982 20 2983 8 2984 21 2985 9 2986 22 2987 10 2988 23 2989 11 2990 24 2991 12 2992 25 2993 13 2994 26 2995
[0474] 135 TABLE 135 2996 2997 1 2998 2 2999 3 3000 4 3001 5 3002 6 3003 7 3004 8 3005 9 3006 10 3007 11 3008 12 3009 13 3010 14 3011 15 3012 16 3013
[0475] 136 TABLE 136 3014 3015 1 3016 2 3017 3 3018 4 3019 5 3020 6 3021 7 3022 8 3023 9 3024 10 3025 11 3026 12 3027 13 3028 14 3029 15 3030 16 3031
[0476] 137 TABLE 137 3032 3033 1 3034 2 3035 3 3036 4 3037 5 3038 6 3039 7 3040 8 3041 9 3042 10 3043 11 3044 12 3045 13 3046 14 3047 15 3048 16 3049
[0477] 138 TABLE 138 3050 3051 1 3052 2 3053 3 3054 4 3055 5 3056 6 3057 7 3058 8 3059 9 3060 10 3061 11 3062 12 3063 13 3064 14 3065 15 3066 16 3067
[0478] 139 TABLE 139 3068 3069 1 3070 2 3071 3 3072 4 3073 5 3074 6 3075 7 3076 8 3077 9 3078 10 3079 11 3080 12 3081 13 3082 14 3083 15 3084 16 3085
[0479] 140 TABLE 140 3086 3087 1 3088 2 3089 3 3090 4 3091 5 3092 6 3093 7 3094 8 3095 9 3096 10 3097 11 3098 12 3099 13 3100 14 3101 15 3102 16 3103
[0480] 141 TABLE 141 3104 3105 1 3106 2 3107 3 3108 4 3109 5 3110 6 3111 7 3112 8 3113 9 3114 10 3115 11 3116 12 3117 13 3118 14 3119 15 3120 16 3121
[0481] 142 TABLE 142 3122 3123 1 3124 2 3125 3 3126 4 3127 5 3128 6 3129 7 3130 8 3131 9 3132 10 3133 11 3134 12 3135 13 3136 14 3137 15 3138 16 3139
[0482] 143 TABLE 143 3140 3141 1 3142 2 3143 3 3144 4 3145 5 3146 6 3147 7 3148 8 3149 9 3150 10 3151 11 3152 12 3153
[0483] 144 TABLE 144 3154 3155 1 3156 2 3157 3 3158 4 3159 5 3160 6 3161 7 3162 8 3163 9 3164 10 3165 11 3166 12 3167
[0484] 145 TABLE 145 3168 3169 1 3170 2 3171 3 3172 4 3173 5 3174 6 3175 7 3176 8 3177 9 3178 10 3179 11 3180 12 3181
[0485] 146 TABLE 146 3182 3183 1 3184 2 3185 3 3186 4 3187 5 3188 6 3189 7 3190 8 3191 9 3192 10 3193 11 3194 12 3195
[0486] 147 TABLE 147 3196 3197 1 3198 2 3199 3 3200 4 3201 5 3202 6 3203 7 3204 8 3205 9 3206 10 3207 11 3208 12 3209
[0487] 148 TABLE 148 3210 3211 1 3212 2 3213 3 3214 4 3215 5 3216 6 3217 7 3218 8 3219 9 3220 10 3221 11 3222 12 3223
[0488] 149 TABLE 149 3224 3225 1 3226 2 3227 3 3228 4 3229 5 3230 6 3231 7 3232 8 3233 9 3234 10 3235 11 3236 12 3237
[0489] 150 TABLE 150 3238 3239 1 3240 2 3241 3 3242 4 3243 5 3244 6 3245 7 3246 8 3247 9 3248 10 3249 11 3250 12 3251
[0490] 151 TABLE 151 3252 1 3253 22 3254 2 3255 23 3256 3 3257 24 3258 4 3259 25 3260 5 3261 26 3262 6 3263 27 3264 7 3265 28 3266 8 3267 29 3268 9 3269 30 3270 10 3271 31 3272 11 3273 32 3274 12 3275 33 3276 13 3277 34 3278 14 3279 35 3280 15 3281 36 3282 16 3283 37 3284 17 3285 38 3286 18 3287 39 3288 19 3289 40 3290 20 3291 41 3292 21 3293 42 3294
[0491] 152 TABLE 152 3295 43 3296 70 3297 44 3298 71 3299 45 3300 72 3301 46 3302 73 3303 47 3304 74 3305 48 3306 75 3307 49 3308 76 3309 50 3310 78 3311 51 3312 79 3313 52 3314 80 3315 53 3316 81 3317 54 3318 82 3319 55 3320 83 3321 56 3322 84 3323 57 3324 85 3325 58 3326 86 3327 59 3328 87 3329 60 3330 88 3331 61 3332 89 3333 62 3334 90 3335 63 3336 91 3337 64 3338 92 3339 65 3340 93 3341 66 3342 94 3343 67 3344 95 3345 68 3346 96 3347 69 3348
[0492] 153 TABLE 153 3349 97 3350 112 3351 98 3352 113 3353 99 3354 114 3355 100 3356 115 3357 101 3358 116 3359 102 3360 117 3361 103 3362 118 3363 104 3364 119 3365 105 3366 120 3367 106 3368 121 3369 107 3370 122 3371 108 3372 123 3373 109 3374 124 3375 110 3376 125 3377 111 3378 126 3379
[0493] 154 TABLE 154 3380 127 3381 142 3382 128 3383 143 3384 129 3385 144 3386 130 3387 145 3388 131 3389 146 3390 132 3391 147 3392 133 3393 148 3394 134 3395 149 3396 135 3397 150 3398 136 3399 151 3400 137 3401 152 3402 138 3403 153 3404 139 3405 154 3406 140 3407 155 3408 141 3409 156 3410
[0494] 155 TABLE 155 3411 157 3412 165 3413 158 3414 166 3415 159 3416 167 3417 160 3418 168 3419 161 3420 169 3421 162 3422 170 3423 163 3424 171 3425 164 3426 172 3427
[0495] 156 TABLE 156 3428 1 3429 22 3430 2 3431 23 3432 3 3433 24 3434 4 3435 25 3436 5 3437 26 3438 6 3439 27 3440 7 3441 28 3442 8 3443 29 3444 9 3445 30 3446 10 3447 31 3448 11 3449 32 3450 12 3451 33 3452 13 3453 34 3454 14 3455 35 3456 15 3457 36 3458 16 3459 37 3460 17 3461 38 3462 18 3463 39 3464 19 3465 40 3466 20 3467 41 3468 21 3469 42 3470
[0496] 157 TABLE 157 3471 43 3472 70 3473 44 3474 71 3475 45 3476 72 3477 46 3478 73 3479 47 3480 74 3481 48 3482 75 3483 49 3484 76 3485 50 3486 78 3487 51 3488 79 3489 52 3490 80 3491 53 3492 81 3493 54 3494 82 3495 55 3496 83 3497 56 3498 84 3499 57 3500 85 3501 58 3502 86 3503 59 3504 87 3505 60 3506 88 3507 61 3508 89 3509 62 3510 90 3511 63 3512 91 3513 64 3514 92 3515 65 3516 93 3517 66 3518 94 3519 67 3520 95 3521 68 3522 96 3523 69 3524
[0497] 158 TABLE 158 3525 97 3526 112 3527 98 3528 113 3529 99 3530 114 3531 100 3532 115 3533 101 3534 116 3535 102 3536 117 3537 103 3538 118 3539 104 3540 119 3541 105 3542 120 3543 106 3544 121 3545 107 3546 122 3547 108 3548 123 3549 109 3550 124 3551 110 3552 125 3553 111 3554 126 3555
[0498] 159 TABLE 159 3556 127 3557 142 3558 128 3559 143 3560 129 3561 144 3562 130 3563 145 3564 131 3565 146 3566 132 3567 147 3568 133 3569 148 3570 134 3571 149 3572 135 3573 150 3574 136 3575 151 3576 137 3577 152 3578 138 3579 153 3580 139 3581 154 3582 140 3583 155 3584 141 3585 156 3586
[0499] 160 TABLE 160 3587 157 3588 165 3589 158 3590 166 3591 159 3592 167 3593 160 3594 168 3595 161 3596 169 3597 162 3598 170 3599 163 3600 171 3601 164 3602 172 3603
[0500] 161 TABLE 161 3604 1 3605 2 3606 3 3607 4 3608 5 3609 6 3610 7 3611 8 3612 9 3613 10 3614 11 3615 12 3616 13 3617 14 3618 15 3619 16 3620 17 3621 18 3622 19 3623 20 3624 21 3625 22 3626 23 3627 24 3628 25 3629 26 3630 27 3631 28 3632 29 3633 30 3634 31 3635 32 3636 33 3637 34 3638 35 3639 36 3640 37 3641 38 3642 39 3643 40 3644 41 3645 42 3646
[0501] 162 TABLE 162 3647 43 3648 44 3649 45 3650 46 3651 47 3652 48 3653 49 3654 50 3655 51 3656 52 3657 53 3658 54 3659 55 3660 56 3661 57 3662 58 3663 59 3664 60 3665 61 3666 62 3667 63 3668 64 3669 65 3670 66 3671 67 3672 68 3673 69 3674 70 3675 71 3676 72 3677 73 3678 74 3679 75 3680 76 3681 78 3682 79 3683 80 3684 81 3685 82 3686 83 3687 84 3688 85 3689 86 3690 87 3691 88 3692 89 3693 95 3694 90 3695 91 3696 92 3697 93 3698 94 3699 96 3700
[0502] 163 TABLE 163 3701 97 3702 98 3703 99 3704 100 3705 101 3706 102 3707 103 3708 104 3709 105 3710 106 3711 107 3712 108 3713 109 3714 110 3715 111 3716 112 3717 113 3718 114 3719 115 3720 116 3721 117 3722 118 3723 119 3724 120 3725 121 3726 122 3727 123 3728 124 3729 125 3730 126 3731
[0503] 164 TABLE 164 3732 127 3733 128 3734 129 3735 130 3736 131 3737 132 3738 133 3739 134 3740 135 3741 136 3742 137 3743 138 3744 139 3745 140 3746 141 3747 142 3748 143 3749 144 3750 145 3751 146 3752 147 3753 148 3754 149 3755 150 3756 151 3757 152 3758 153 3759 154 3760 155 3761 156 3762
[0504] 165 TABLE 165 3763 157 3764 158 3765 159 3766 160 3767 161 3768 162 3769 163 3770 164 3771 165 3772 166 3773 167 3774 168 3775 169 3776 170 3777 171 3778 172 3779
[0505] Treatment Method
[0506] A contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
[0507] Also contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF-&agr; convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
[0508] In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
[0509] Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
[0510] Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
[0511] In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
[0512] Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should this be desired by the person prescribing the drug.
[0513] The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
[0514] A compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
[0515] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
[0516] Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
[0517] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
[0518] For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from soerile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
[0519] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
[0520] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
BEST MODE FOR CARRYING OUT THE INVENTION[0521] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.
[0522] Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows:
[0523] BOC=t-butoxycarbonyl
[0524] DEAD=diethyl azodicarboxylate
[0525] DMF=dimethylformamide
[0526] DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
[0527] EtOAc=ethyl acetate
[0528] EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride
[0529] Et2O=diethyl ether
[0530] HOBT=1-hydroxybenzotriazole
[0531] MeOH=methanol
[0532] MeCl2=methylene chloride
[0533] MsCl=methanesulfonyl chloride
[0534] NMM=N-methyl morpholine
[0535] THF=tetrahydrofruan
[0536] TsCl=toluenesulfonyl chloride
[0537] THP—O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine
[0538] The preparation of compounds useful in the synthesis of compounds of the invention are provided herein below in Preparative Examples I through XI.
PREPARATIVE EXAMPLE I Preparation of 1,1-dimethylethyl ester 4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylic acid[0539] 166 3780
[0540] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H2O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
[0541] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil.
[0542] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 minutes, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hours the solution was cooled to minus sixty degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
[0543] Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
[0544] Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H2O (3 mL). The solution was heated at sixty-five degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H2O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C23H27NO7S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
[0545] Part F: To a solution of the acid of part G (730-mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional N-hydroxybenzotriazole.H2O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added. After an additional 24 hours of stirring the solution was diluted with H2O and extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the title compound as a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculated for C23H28N2O7S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.
PREPARATIVE EXAMPLE II Preparation of N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride[0546] 3781
[0547] Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
[0548] Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 degrees Celsius for 6 hours. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%).
[0549] Part C: To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50 degrees Celsius was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hours at zero degrees Celsius. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hours. The reaction was quenched with the addition of H2O and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5N KOH, H2O, and saturated NaCl. Chromatography (on silica, hexane/ethyl acetate) provided the sulfide as an oil (18.0 g, 75%).
[0550] Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to zero degrees Celsius was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours. The solution was diluted with H2O and extracted with dichloromethane. The organic layer was washed with 10 percent Na2SO3, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).
[0551] Part E: Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 minutes followed by stirring at ambient temperature for 4 hours. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%).
[0552] Part F: To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hours at ambient temperature. The solution was partitioned between ethyl acetate and H2O, and the organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).
[0553] Part G: To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO3 (2.79 g, 8.56 mmol) and the solution was heated to 70 degrees Celsius for 6 hours. The solution was partitioned between ethyl ether and H2O. The organic layer was washed with H2O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
[0554] Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H2O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).
[0555] Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H2O and ethyl acetate. The organic layer was washed with H2O, saturated NaHCO3 and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).
[0556] Part J: To a solution of the protected hydroxamate of part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 minutes at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH+ calculated for C21H22N2O4S2: 431, found 431.
PREPARATIVE EXAMPLE III Preparation of N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride[0557] 3782
[0558] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H2O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
[0559] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
[0560] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to minus sixty degrees Celsius and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
[0561] Part D: To a solution of the sulfide of
[0562] Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
[0563] Part E: Into a solution of the sulfone of
[0564] Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to zero degrees Celsius was bubbled HCl gas for 5 minutes. Concentration in vacuo followed by trituration with ethyl ether provided the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS(CI) MH+ calculated for C20H23NO5S: 390, found 390.
[0565] Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K2CO3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).
[0566] Part G: To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65 degrees Celsius for 48 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield).
[0567] Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with H2O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the hydroxamate as a white solid (140 mg, 25%). Analytical calculation for C21H22N2O5S: C, 60.85; H, 5.37; N, 6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.
[0568] Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to zero degrees Celsius was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 minutes the solution was concentrated under a stream of N2. Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C21H22N2O5S.HCl.0.3H2O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
PREPARATIVE EXAMPLE IV Preparation of 4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide[0569] 3783
[0570] Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at two degrees Celsius. The reaction was stirred at ambient temperature for forty five minutes at which time the sodium had dissolved. The solution was chilled to five degrees Celsius and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for four hours, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).
[0571] Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone (720 g, 1.17 mol) at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted. After two hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
[0572] Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate/hexanes to give the pyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculated for C13H15O5S1F1: 303, found 303.
[0573] Part D: In dry equipment under nitrogen, the pyran compound from part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) was added at ambient temperature. After ninety minutes, water (100 mL) was added and the solution concentrated in vacuo. The residue was taken up in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH=1. The slurry was extracted with ethyl acetate and the combined extracts washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the solid filtered and dried to give the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES−) M-H calculated for C12H13O5 S1F1: 287.04, found 287.04.
[0574] Part E: In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After three hours at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the title compound as a crystalline solid (9.7 g, 80%). HRMS (ES+) MH+ calculated for C17H22NO6 S1F1: 388.12, found 388.12.
PREPARATIVE EXAMPLE V Preparation of tetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide[0575] 3784
[0576] Part A: To a solution of the title compound of Preparative Example IV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurry was stirred at 95 degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the substituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS (ES+) MH+ calculated for C24H26N1O8S1F3: 546.14, found 546.14.
[0577] Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%). HRMS (ES+) M+NH4+ calculated for C19H18N1O7S1F3: 479.11, found 479.11.
PREPARATIVE EXAMPLE VI Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxy-ethoxy)phenyl]sulfonyl]-4-piperidine carboxamide, monohydrochloride[0578] 3785
[0579] Part A: To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hours. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. The solid was filtered, washed with H2O/diethyl ether to give the desired cyclopropyl amine {ethyl 4-[(4-fluorophenyl-sulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate} as a white solid (11.83 g, 81.5%). MS MH30 calculated for C17H22NO4SF: 356, found: 356.
[0580] Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135 degrees Celsius for 18 hours under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40 degrees Celsius in a vacuum oven. The solid was dissolved into a mixture of water, acetonitrile, and ethanol and then the pH was adjusted to 12 with 1N NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solid was isolated by filtration, washed with water, and dried at 50 degrees Celsius in a vacuum oven to afford the ether as a white solid (1.8 g, 68%): MS+ calcd. for C25H31NO6S 474, found 474. Anal. calcd. for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.
[0581] Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H2O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50 degrees Celsius in a vacuum oven to give a crude white solid acid (2.3 g).
[0582] A mixture of the crude white solid acid (2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogen atmosphere for 2 days. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N NaOH solution, water, and brine, dried over magnesium sulfate, concentrated in vacuo, and purification by flash chromatography (20:80 to 40:60 ethyl acetate/toluene) to afford the protected hydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. for C28H36N2O7S 545, found 545. Anal. calcd. for C28H36N2O7S: C, 61.74; H, 6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.
[0583] Additional compound was isolated by acidifying the aqueous layer to pH of 3, collecting the solid by filtration, and drying to give a white solid (0.80 g).
[0584] Part D: To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hours, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45 degrees Celsius in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C23H28N2O6S 461, found 461. Anal. calcd. for C23H28N2O6S.1.5 HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.
PREPARATIVE EXAMPLE VII Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0585] 3786
[0586] Part A: To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hours. Then, N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).
[0587] Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K2CO3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
[0588] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of white precipitation provided the acid as a white solid (5.64 g, 73.3%).
[0589] Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, H2O and dried over MgSO4. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl-protected hydroxamate as a white foam (6.65 g, quantitative yield).
[0590] Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C22H25N2O7SF3.HCl.0.5H2O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
PREPARATIVE EXAMPLE VIII Preparation of N-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride[0591] 3787
[0592] Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hours then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%).
[0593] Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N2, was added Cs2CO3 (159 g, 0.488 mol). After degassing the resulting mixture with N2 for 5 minutes, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hours and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).
[0594] Part C: To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was washed with saturated NaHCO3 and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The resulting solids were washed with hexanes then dissolved in dichloromethane and filtered through a pad of Celite®, washing with dichloromethane. The filtrate was concentrated in vacuo and recrystallization from ethyl acetate provided the sulfone as a white crystalline solid (4.45 g, 50%).
[0595] Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs2CO3 (19.9 g, 61.2 mmol) and &agr;,&agr;,&agr;-trifluoro-&agr;-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at eighty degrees Celsius for 16 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The resulting residue was treated with H2O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).
[0596] Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded one degree Celsius. The resulting mixture was stirred at zero degrees Celsius for 1 hour then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded four degrees Celsius. After the addition was complete, the mixture was slowly permitted to warm to ambient temperature. Saturated NH4Cl (50 mL) was added and the tetrahydrofuran was removed in vacuo. Water (50 mL) was added to the residue which was then extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Recrystallization from methanol provided the methyl ester as a pale yellow crystalline solid (7.66 g, 80%).
[0597] Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%).
[0598] Part G: To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K2CO3 (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).
[0599] Part H: To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hours, H2O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).
[0600] Part I: To a suspension of the amino acid of
[0601] Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), 0-(tetrahydropuranyl) hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hours additional N-methylmorpholine (0.872 mL, 7.94 mmol), O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3.17 mmol) were added. The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H2O. The organic layers were washed with saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/chloroform) provided the protected hydroxamate as an off-white solid (2.62 g, 77%).
[0602] Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH+ calculated for C25H31O6N3SF3: 558, found 558.
PREPARATIVE EXAMPLE IX Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride[0603] 3788
[0604] Part A: To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K2CO3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H2O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH+ calculated for C24H26NSO6F3: 514.1511. Found 514.1524.
[0605] Part B: To a solution of diaryl ether from Part A (8.4 g, 16.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.54 g, 164 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo to remove most of organic solvents and the aqueous residue was acidified to pH=4.0. The resulting precipitate was filtered to give the desired filtered to give the hydrochloride salt as a white solid (5.01 g, 63%). HRMS MH+ calculated for C22H22NSO6F3: 486.1198, found 486.1200.
[0606] Part C: To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hours. The solution was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel, eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).
[0607] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%). HRMS MH+ calculated for C22H23N2SO6F3: 501.1307, found 501.1324.
PREPARATIVE EXAMPLE X Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0608] 3789
[0609] Part A: To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K2CO3 (12.34 g, 38.0 mmol) and &agr;,&agr;,&agr;-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred ninety degrees Celsius for 28 hours. The solution was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)
[0610] Part B: To a solution of aryl ether from Part A (7.54 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (7.98 g, quantitative). MS MH+ calculated for C22H22NSO5F3: 470, found 470.
[0611] Part C: To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hours. The solution was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).
[0612] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hours, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH+ calculated for C22H23N2SO5F3: 485, found 485.
PREPARATIVE EXAMPLE XI Preparation of Resin II[0613] Step 1: Attachment of Compound of
PREPARATIVE EXAMPLE IV TO RESIN I[0614] A 500 mL round-bottomed flask was charged with of resin I [Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, and the resin slurry slowly stirred. A separate solution of the compound of Part D, Preparative Example IV (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed by addition of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salt had dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction slurry was stirred at room temperature for 24 hours, then the resin was collected in a sintered-disc funnel and washed with N,N-dimethylformamide, methanol, methylene chloride and diethyl ether (3×30 mL each solvent). The resin was dried in vacuo to yield 10.99 g polymer-bound hydroxymate as a tan polymeric solid. Theoretical loading on polymer was 0.91 mmol/g. FTIR microscopy showed bands at 1693 and 3326 cm−1 indicative of the hydroxamate carbonyl and nitrogen-hydrogen stretches, respectively.
[0615] Step 2: Preparation of Resin III:
[0616] Reaction of Resin II With Nucleophiles
[0617] Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel. In the case of phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added. The vial was capped and heated to 70 to 155 degrees Celsius for 24-48 hours, then cooled to room temperature. The resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3×3 mL each solvent).
[0618] Large Scale Preparation of Resin IIIa:
[0619] Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL) was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80 degrees Celsius with a heating mantle for 65 hours. The flask was thereafter cooled to room temperature.
[0620] The resin was collected in a sintered-disk glass funnel and washed with N,N-dimethylformamide, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to provide 5.86 g of resin IIIa as off-white resin beads. The theoretical loading of the polymer was 0.81 mmol/g. TFA cleavage performed on 50 mg of resin IIIa as described in step 3 yielded 10.4 mg of off-white solid spectroscopically indistinguishable from a known sample.
[0621] Step 3: Cleavage of Hydroxamic Acids From The Polymer-Support
[0622] Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hour at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy.
[0623] Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa
[0624] Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hours. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads. FTIR microscopy showed bands at 1732 and 1704 cm−1 and a broad band from 2500-3500 cm−1. The theoretical loading of the polymer-bound acid was 0.84 mmol/g.
EXAMPLE 1 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide[0625] 3790
[0626] Part A: To a solution of the product of Preparative Example II, part D, (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol) and solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).
[0627] Part B: To a solution of the methoxyethyl amine (6.0 g, 16.0 mmol) of part A and powdered K2CO3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
[0628] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitation provided the carboxylic acid as a white solid (5.64 g, 73.3%).
[0629] Part D: To a suspension of the carboxylic acid of part C (200 mg, 0.397 mmol) in methylene chloride (4 mL) was added oxalyl chloride (101 mg, 0.80 mmol). After 15 minutes at ambient temperature the volatiles were removed under vacuum. The solid residue was resuspended in methylene chloride (4 mL) and gaseous ammonia was bubbled through the suspension. Triethylamine (81 mg, 0.80 mmol) was added and the stream of ammonia gas through the reaction was continued for 1 minute. Concentration afforded a solid which was chromatographed (reverse phase C18 silica eluting with a gradient of 30% acetonitrile/water to 100% acetonitrile) to afford the desired primary amide as a colorless powder (6 mg, 3 mg). MS MH+ calculated for C22H25N2 F3O6S: 503, found 503. HRMS M+ calculated for C22H25N2 F3O6S: 503.1464, found 503.1472.
EXAMPLE 2 Preparation of 4-[(4-phenylthiophenyl) sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide[0630] 3791
[0631] A mixture of the acid from Preparative Example II, part H, (1.29 g, 2.85 mMol), N-hydroxybenzotriazole (1.15 g, 8.54 mMol), 4-methylmorpholine (0.94 mL, 14 mMol), concentrated NH4OH (3 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.64 g, 8.54 mMol) in DMF (25 mL) was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, and brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography (on silica, MeOH/CHCl3) afford the title amide as a white solid (0.143 g, 12%). Analytical calculation for C21H22N2O3S2: C, 60.84; H, 5.35; N, 6.76; S, 15.47. Found: C, 60.74; H, 5.31; N, 6.74; S, 15.43.
EXAMPLES 3-58[0632] The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) using parallel synthesis from Resin IVa as described previously in Preparative Example XI the following compounds were prepared: 167 3792 MS Example Amine R (M + H) 3 3,5-Dimethylpiperidine 3793 508 4 N-Methylpropargylamine 3794 464 5 N-Methylallylamine 3795 466 6 1-(1-phenylethyl)- piperazine 3796 585 7 1-(2-phenylethyl)- piperazine 3797 585 8 1-(2-chlorophenyl)- piperazine 3798 591 9 1-(4-methoxyphenyl)-2- methylpiperazine 3799 585 10 1-(5-Chloro-2- methylphenyl)piperazine 3800 605 11 1-(2-methoxyphenyl)- piperazine 3801 587 12 1-Acetylpiperazine 3802 523 13 1-(2,4-Dimethylphenyl)- piperazine 3803 585 14 N-(2-hydroxyethyl)- piperazine 3804 525 15 1-(Ethoxy- carbonylmethyl)- piperazine 3805 567 16 1-(2-Fluorophenyl)- piperazine 3806 575 17 1-(2-Furoyl)-piperazine 3807 575 18 1-(Cyclopentyl)- piperazine 3808 549 19 1-(2-Propyl)-piperazine 3809 523 20 N-(2-(1-Piperazino)- acetyl)pyrrolidine 3810 592 21 1-(3-Dimethyl- aminopropyl)- piperazine 3811 566 22 1-(2-Methoxyethyl)- piperazine 3812 539 23 1-(2-Dimethyl- aminoethyl)- piperazine 3813 552 24 1-(2-Ethoxyphenyl)- piperazine 3814 601 25 1-(4-Fluorphenyl)- piperazine 3815 575 26 1-(2-Pyridyl)-piperazine 3816 558 27 2-(1-piperazinyl)- pyrimidine 3817 559 28 4-Piperazino- acetophenone 3818 599 29 1-(4-Nitrophenyl)- piperazine 3819 602 30 1-(3,5-Dichloropyrid-4- yl)piperazine 3820 626 31 4-(2-Methoxyphenyl)- piperidine 3821 586 32 N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine 3822 670 33 1-[3-(Trifluormethyl)- pyrid-2-yl]- piperazine 3823 626 34 cis-3,5-Dimethyl- morpholine 3824 510 35 N-Propylcyclopropane- methylamine 3825 508 36 1-(2,4-Difluorphenyl)- piperazine 3826 593 37 1-(4-Pyridyl)- piperazine 3827 558 38 1-(4-Trifluoromethyl- phenyl)-piperazine 3828 625 39 1-Allylpiperazine 3829 521 40 1-(2-Pyrazinyl)- piperazine 3830 559 41 1-[3-Chloro-5- (trifluoromethyl)pyrid- 2-yl)]piperazine 3831 660 42 1-(2-(4-Morpholino)- ethyl)piperazine 3832 594 43 3-Chlorophenyl- piperazine 3833 591 44 4-(Hydroxymethyl)- piperidine 3834 510 45 Diisobutylamine 3835 524 46 cis-2,6-Dimethyl- piperazine 3836 509 47 3-Methylpiperidine 3837 494 48 N,N-Diallylamine 3838 492 49 1-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine 3839 627 50 1-[4-(Trifluormethyl)- 2-pyridyl]- piperazine 3840 626 51 N,N,N′-Trimethyl- ethylenediamine 3841 497 52 (4-Ethylaminomethyl)- pyridine 3842 531 53 Methyl-cyclopropylamine 3843 466 54 3,5-Dimethyl-piperidine 3844 508 55 3,5-Dimethyl-piperidine 3845 508 56 Isobutylamine 3846 468 57 Propylamine 3847 454 58 N-Methyl- isobutylamine 3848 482
EXAMPLES 59-78[0633] Step 5: Preparation of Resin V
[0634] Into a fritted reaction vessel was weighed resin IVa (100 mg, 0.083 mmol), and the vessel was capped under nitrogen and cooled to zero degrees Celsius. A 1.0 M solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine in methylene chloride (0.4 mL, 0.4 mmol) was added followed by a 1.0 M solution of N-methylmorpholine in methylene chloride (0.6 mL, 0.6 mmol.) The solutions were stirred for 4 hours at zero degrees Celsius and warmed to ambient temperature. A 0.7 M solution of the appropriate amine to be reacted in methylene chloride (0.4 mL, 0.28 mmol) was added and the reaction mixture stirred for 24 hours. The reaction mixture was stirred for 24 hours, then the resin was drained and washed with 1-methyl-2-pyrrolidinone and methylene chloride (4×3 mL each solvent). The reaction was repeated using the same amounts of reagents described above. The reaction was stirred for 4 hours at zero degrees Celsius after the activating step and ambient temperature for 24 hours following amine solution addition. After 24 hours, the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent).
[0635] The following hydroxamic acids were synthesized using the indicated polymer-bound acid and the indicated amine in Step 5 followed by release from the polymer using Step 3, before: 168 3849 Example Amine R MS (M + H) 59 Aniline 3850 488 60 N-Methylaniline 3851 502 61 4-(Trifluoromethyl)- aniline 3852 556 62 4-Aminopyridine 3853 489 63 2-(Trifluoromethoxy)- aniline 3854 572 64 2-Chloroaniline 3855 522 65 2-Fluoroaniline 3856 506 66 o-Anisole 3857 518 67 2-(Methylamino)- pyridine 3858 503 68 3-(Trifluoromethoxy)- aniline 3859 572 69 3-(Trifluoromethyl)- aniline 3860 556 70 3-Chloroaniline 3861 522 71 3-Fluoroaniline 3862 506 72 m-Anisole 3863 518 73 4-(Trifluoromethoxy)- aniline 3864 572 74 4-Aminopyrmidine 3865 490 75 4-Fluoroaniline 3866 506 76 p-Anisole 3867 518 77 N,N-Dimethyl-1,3- phenylenediamine 3868 531 78 N,N-Dimethyl-p- phenylenediamine 3869 531
EXAMPLES 79-88[0636] Step 12: Further Synthesis of Resin III.
[0637] Into a 8 mL glass vial was placed resin II (200 mg, 0.18 mmol) and cesium carbonate (0.98 g mg, 3 mmol) (no cesium carbonate used with piperidine and pyrrolidine nucleophiles). One mL of a 1.8 M solution of the amine nucleophile to be reacted in 1-methyl-2-pyrrolidinone (1.8 mmol) was added and the vial was capped and heated to 100 degrees Celsius for 30 hours. Then the vessel was cooled to room temperature, and the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent).
[0638] The following hydroxamic acids were synthesized from Resin III using Step 11 with the indicated amines, followed by release from the polymer using the reaction conditions in Step 3. 169 3870 Example Amine R MS (M + H) 79 1-(2-Methoxyphenyl)- piperidine 3871 475 80 4-(4-Methoxybenzoyl)- piperidine 3872 503 81 Pyrrolidine 3873 355 82 1-(4-Methoxyphenyl)-2- piperazine 3874 490 83 1-(2-Fluorophenyl)- piperazine 3875 464 84 1-(2,4- Diemthylphenyl)- piperiazine 3876 474 85 1-(2-Methoxyphenyl- piperazine 3877 476 86 1-(4-Trifluoromethyl- phenyl)piperazine 3878 514 87 1-(2,4- Difluorophenyl)- piperazine 3879 482 88 1-(2-Chlorphenyl)- piperazine 3880 480
EXAMPLE 89 Preparation of N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide[0639] 3881
[0640] To a solution of 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1diemthylethoxy)-carbonyl]piperidinecarboxylic acid (6.25 g, 11.5 mmol) prepared using techniques discussed elsewhere herein was added 50% trifluoroacetic acid solution in dichloromethane (100 mL) and stirred 1 hour at room temperature. The solvent was evaporated to afford 9.91 g of an oil. The oil was dissolved in acetonitrile (50 mL) and water (50 mL). To the solution was added sodium carbonate to a pH-9-10 followed by a solution of N-(9-fluorenylmethoxy-carbonyloxy)succinimide (3.88 g, 11.5 mmol) in acetone (25 mL). The pH value of the solution was adjusted to 9-10 with sodium carbonate. The reaction mixture was stirred 16 hours. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 3. The solution was extracted with dichloromethane (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent evaporated to afford N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (8.15 g) as a yellow oil. MS (ES) m/z 668 (M+H)+.
EXAMPLE 90 Preparation of N-hydroxy-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide[0641] 3882
[0642] Using the method of Example 89, N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(9-fluorenyl-methoxycarbonyl)-4-piperidinecarboxamide was prepared from 4-[[4-(4-trifluoromethylphenoxy)-phenyl]-sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]-piperidinecarboxylic acid, which itself was prepared using techniques discussed elsewhere herein. MS (ES) m/z 652 (M+H)+.
EXAMPLE 91 Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide[0643] 3883
[0644] Step 1: Preparation of Resin MT-I. To a solution of N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide of Example 89 (11.5 mmol) in dimethylformamide (75 mL) were added resin I (Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048) (7.0 g, 7.67 mmol), pyBOP (8.0 g) and N-methylmorpholine (5.05 mL), and the mixture was stirred with an overhead stirrer 4 days. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-I.
[0645] Step 2: Fmoc deprotection of Resin MT-I. Resin MT-I was swelled with dimethylformamide (2×100 mL) and drained. To swollen resin MT-1, was added a 20% solution of piperidine in dimethylformamide (100 mL). After 1 hour, the resin was drained and retreated with 20% piperidine in dimethylformamide (100 mL). After 15 minutes the resin was filtered and washed with dimethylformamide (3×100 mL), methanol (3×100 mL), dichloromethane (3×100 mL) and ether (3×100 mL). The resin was dried in vacuo to afford resin MT-II (7.23 g).
[0646] Step 3: Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide from Resin MT-II. To a suspension of resin MT-II (250 mg) in dichloromethane (2 mL) was added diisopropyl-ethylamine (165 &mgr;L) and benzoyl chloride (110 &mgr;L) and agitated 3 hours. The resin was filtered and washed with dichloromethane (2×10 mL) and methanol (2×10 mL). To the resin was added a solution of 95% trifluoroacetic acid in water and agitated for 1 hour. The resin was drained and washed with methanol (1×2 mL) and dichloromethane (1×2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide (9.8 mg) as a solid. MS (ES) m/z 565 (M+H)+.
EXAMPLE 92 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide[0647] 3884
[0648] N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide was prepared by the method of Example 91 from N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (the product of Example 90). MS (ES) m/z 549 (M+H)+.
EXAMPLE 93 Preparation of N-(2-tetrahydropyranoxy) -4-[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-4-piperidinecarboxamide[0649] 3885
[0650] Step 1: Boc deprotection of ethyl 4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate. To a solution of ethyl 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)-carbonyl]piperidinecarboxylate (12.58 g, 19.1 mmol; see Example 89) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to afford a pale yellow oil.
[0651] Step 2: Cbz protection of step 1. The material from step 1 was dissolved in dichloromethane (200 mL). To this solution was added diisopropyl-ethylamine (33.3 mL) and benzyl chloroformate (5.5 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 1 and extracted with dichloromethane (2×100 mL). The combined organics were washed with 2M aqueous HCl (1×100 mL) and brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.
[0652] Step 3: Hydrolysis of the product of step 2. The material prepared in step 2 was dissolved in tetrahydrofuran (100 mL) and ethanol (50 mL). To this solution was added 1M aqueous sodium hydroxide (50 mL) and 50% aqueous sodium hydroxide (10 mL) and stirred 16 hours. To the solution was added 50% aqueous sodium hydroxide (2 mL) and stirred and additional 24 hours. The tetrahydrofuran and ethanol were evaporated. The pH value of the solution was adjusted to pH about 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.
[0653] Step 4: Cbz deprotection of step 3. The material prepared in step 3 was dissolved in ethanol (100 mL). This solution was added to 10% palladium on carbon (1.0 g). The solution was placed under 45 psi hydrogen. Additional catalyst was added at 6 hours (1.75 g) and 20 hours (1.0 g 4% Pd/C). After 48 hours the reaction mixture was filtered through a plug of Celite. The filtrate was evaporated and triturated with ether to afford N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide (4.47 g) as a white solid. MS (ES) m/z 545 (M+H)+.
EXAMPLE 94 Preparation of N-(2-tetrahydro-pyranoxy)-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-4-piperidine-carboxamide[0654] 3886
[0655] N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide was prepared by the method of Example 93 starting from ethyl 4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate (see Example 90). MS (ES) m/z 529 (M+H)+.
EXAMPLE 95 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(2-fluorophenyl-carbonyl)-4-piperidinecarboxamide[0656] 3887
[0657] To a solution of N-(2-tetrahydropyranoxy)-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 &mgr;L) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.
EXAMPLES 96-124[0658] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent. 170 3888 MS (ES) Example R Acylating Agent m/z 96 3-fluorophenyl 3-fluorobenzoyl 583 (M + H)+ chloride 97 4-fluorophenyl 4-fluorobenzoyl 583 (M + H)+ chloride 98 2-trifluoro- 2-trifluoromethyl- 633 (M + H)+ methylphenyl benzoyl chloride 99 3-trifluoro- 3-trifluoro- 633 (M + H)+ methylphenyl methylbenzoyl chloride 100 phenylmethyl phenylacetyl chloride 579 (M + H)+ 101 2-tolyl 2-toluoyl chloride 579 (M + H)+ 102 4-tolyl 4-toluoyl chloride 579 (M + H)+ 103 4-methoxy- methyl 4- 623 (M + H)+ carbonylphenyl chlorocarbonyl benzoate 104 4-methoxyphenyl 4-anisoyl chloride 595 (M + H)+ 105 2-thienyl 2-thiophenecarbonyl 571 (M + H)+ chloride 106 2-furyl 2-furoyl chloride 555 (M + H)+ 107 3-pyridyl nicotinoyl chloride 566 (M + H)+ 108 4-pyridyl isonicotinoyl 566 (M + H)+ chloride 109 c-propyl cyclopropanecarbonyl 529 (M + H)+ chloride 110 trichloromethyl trichloroacetic 622 (M + H)+ anhydride 111 trifluoromethyl trifluoroacetic 574 (M + H)+ anhydride 112 pentafluorophenyl pentafluorobenzoyl 655 (M + H)+ chloride 113 4-nitrophenyl 4-nitrobenzoyl 610 (M + H)+ chloride 114 4-trifluoro- 4-trifluoromethyl- 633 (M + H)+ methylphenyl benzoyl chloride 115 4-trifluoro- 4-trifluoromethoxy- 649 (M + H)+ methoxyphenyl benzoyl chloride 116 4-methoxy- 4-methoxyphenyl- 609 (M + H)+ phenylmethyl acetyl chloride 117 3-methoxyphenyl 3-anisoyl chloride 595 (M + H)+ 118 2-methoxyphenyl 2-anisoyl chloride 595 (M + H)+ 119 3,5- 3,5-dimethoxybenzoyl 625 (M + H)+ dimethoxyphenyl chloride 120 3,4- 3,4-dimethoxybenzoyl 625 (M + H)+ dimethoxyphenyl chloride 121 2,5- 2,5-difluorobenzoyl 601 (M + H)+ difluorophenyl chloride 122 methoxy- methyl malonyl 561 (M + H)+ carbonylmethyl chloride 123 4-dimethyl- 4-dimethylamino- 608 (M + H)+ aminophenyl benzoyl chloride 124 1,1-dimethylethyl pivaloyl chloride 545 (M + H)+
EXAMPLES 125-138[0659] The following hydroxamic acids were prepared by the method of Example of 95 using the appropriate isocyanate as the acylating agent. 171 3889 Ex- MS (ES) ample RNCO Isocyanate m/z 125 3890 Phenyl isocyanate 580 (M + H) 126 3891 4-Fluorophenyl isocyanate 598 (M + H) 127 3892 4-Methoxybenzyl isocyanate 624 (M + H) 128 3893 Ethyl isocyanate 532 (M + H) 129 3894 3-Trifluoromethyl phenyl isocyanate 648 (M + H) 130 3895 3-Isocyanate propionic acid 576 (M + H) 131 3896 3-Pyridyl isocyanate 581 (M + H) 132 3897 4-Chlorophenyl isocyanate 614 (M + H) 133 3898 3-Fluorophenyl isocyanate 598 (M + H) 134 3899 4-Acetylphenyl isocyanate 622 (M + H) 135 3900 2-Fluorophenyl isocyanate 598 (M + H) 136 3901 4-(Methylthio) phenyl isocyanate 626 (M + H) 137 3902 Benzyl isocyanate 594 (M + H) 138 3903 3-Cyanophenyl isocyanate 605 (M + H)
EXAMPLES 140-143[0660] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent (electophile) and starting from N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94. 172 3904 Ex- am- MS ple R Electrophile (ES) m/z 140 3905 4-trifluoro- methoxybenzoyl chloride 633 (M + H)+ 141 3906 4-trifluoromethyl- phenyl isocyantate 632 (M + H)+ 142 3907 4-trifluoro- methylphenyl thioisocyanate 648 (M + H)+ 143 3908 4-trifluoromethyl- benzenesulfonyl chloride 653 (M + H)+
EXAMPLE 144 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide[0661] 3909
[0662] A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)+.
EXAMPLE 145 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide[0663] 3910
[0664] To a solution of the product of Example 103 (57 mg) dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (1 mL) plus 50% aqueous sodium hydroxide (50 &mgr;L) and the reaction mixture was stirred 2 hours. The pH value of the reaction mixture was adjusted to 1 with 6M hydrochloric acid. The solution was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by RPHPLC to afford the acid N-hydroxy-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide (12.8 mg). MS (ES) m/z 631 (M+NH4)+.
EXAMPLE 146 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide[0665] 3911
[0666] Step 1: Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate. To a solution of methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate (10.0 g, 31 mmol) dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate (2×100 mL). The pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2×100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g).
[0667] Step 2: Loading on resin. The compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL). To this solution were added pyBOP (6.85 g) and N-methylmorpholine (2.9 mL), and the mixture was stirred with overhead stirring 16 hours. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-III (6.79 g).
[0668] Step 3: Aryl fluoride displacement of resin MT-III. A suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hours. The reaction mixture was cooled and the resin filtered. The resin was washed with dimethylformamide (3×5 mL), methanol (3×5 mL), 10% aqueous acetic acid (3×5 mL), methanol (3×5 mL) and dichloromethane (3×5 mL). To the resin was added 95% aqueous trifluoroacetic acid and the reaction mixture was agitated for 1 hour. The resin was drained and washed with dichloromethane (2×1 mL). The solvent was evaporated. The residue was purified by RPHPLC to provide N-hydroxy-4-[[4-(4-methoxy-phenoxy)phenyl]sulfonyl]-4-thianecarboxamide (17.9 mg) as a pale yellow oil.
EXAMPLES 147-151[0669] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate alcohol. 173 3912 Example R Alcohol MS (ES) m/z 147 4-trifluoro- 4-trifluoro- 495 (M + NH4)+ methoxyphenyl methoxyphenol 148 4-isopropyl- 4-isopropylphenol 453 (M + NH4)+ phenyl 149 3-pyridyl 3-hydroxypyridine 395 (M + H)+ 150 3,4-dimethoxy- 3,4-dimethoxyphenol 471 (M + NH4)+ phenyl 151 4-pyridyl 4-hydroxypyridine 395 (M + H)+
EXAMPLES 152-155[0670] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate amine. 174 3913 Example R Amine MS (ES) m/z 152 4-(4-fluoro- 4-(4-fluorobenzoyl)- 507 (M + H)+ benzoyl)piperidyl piperidine 153 4-(2-methoxy- 4-(2-methoxyphenyl)- 491 (M + H)+ phenyl)piperidyl piperidine 154 3914 N-cyclopropyl-meth- yl-N-methyl-4-pipe- ridine carboxamide 496 (M + H)+ 155 pyrrolidinyl pyrrolidine 371 (M + H)+
Example 156 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide[0671] 3915
[0672] Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III (2.0 g, 1.72 mmol), m-perbenzoic chloroperbenzoic acid (4.37 g) and dichloromethane 25 mL) was stirred at room temperature for 20 hours. The resin was filtered and washed with dichloromethane (3×25 mL), dimethylformamide (3×25 mL), methanol (3×25 mL), 1M aqueous sodium bicarbonate (2×25 mL), methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-IV (2.16 g).
[0673] Step 2: Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 146 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH4)+.
EXAMPLES 156-160[0674] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate alcohol. 175 3916 Example R Alcohol MS (ES) m/z 157 4-trifluoro- 4-trifluoro- 527 (M + NH4)+ methoxyphenyl methoxyphenol 158 4-isopropylphenyl 4-isopropylphenol 485 (M + NH4)+ 159 3-pyridyl 3-hydroxypyridine 427 (M + H)+ 160 4-pyridyl 4-hydroxypyridine 427 (M + H)+
EXAMPLE 161[0675] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate amine. 176 3917 Example R Amine MS (ES) m/z 161 4-(4-fluorobenzoyl) 4-(4-fluoro- 539 (M + H)+ piperidyl benzoyl)- piperidine
Example 162 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide[0676] 3918
[0677] Step 1: Aryl fluoride displacement of Resin MT-III. To a suspension of resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL) was added ethyl isonipecotate (5.25 mL), and the mixture was heated to 100° C. for 16 hours. The cooled reaction mixture was filtered and the resin was washed with methanol (3×25 mL), dichloromethane (1×10 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-V (4.21 g).
[0678] Step 2: Hydrolysis of resin MT-V. To a suspension of resin MT-V (4.13 g) in tetrahydrofuran (20 mL) was added 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days. The resin was filtered and washed with methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-VI.
[0679] Step 3: Conversion to amide. To a suspension of resin MT-VI (268 mg) in 1-methyl-2-pyrrolidinone (2 mL) were added 3,5-dimethyl-piperidine (299 &mgr;L), pyBOP (587 mg) and diisopropylethyl amine (393 &mgr;L), and mixture was stirred 40 hours. The resin was filtered and washed with dimethylformamide (3×2 mL), methanol (3×2 mL), 10% aqueous acetic acid (3×2 mL), methanol (3×2 mL), dichloromethane (3×2 mL) and glacial acetic acid (1×2 mL). The resin was treated with 95% aqueous trifluoroacetic acid (2 mL) and agitated 1 hour. The resin was washed with dichloromethane (2 mL) and methanol (2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]piperidyl] phenyl]sulfonyl]-4-thianecarboxamide (7.5 mg) MS (ES) m/z 524 (M+H)+.
EXAMPLE 163 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide[0680] N-hydroxy-4-[[4-[4-[(3,5-dimethyl-piperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide was prepared by the method of using cis-2,6-dimethylmorpholine as the amine. MS (ES) m/z 526 (M+H)+.
EXAMPLE 164 N-hydroxy-4[[[4-[4-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide[0681] 3919
[0682] Step 1: Preparation of amine 4-(4-fluorophenyl)methoxy piperidine. Ninety-five percent dry sodium hydride is weighted in a 25 mL vial. Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10. The Boc-protected amine is dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 hours and the solvent is evaporated to give 1.8 g of 4-(4-fluorophenyl)-methoxy piperidine. MS: M+H=210.1319.
[0683] Step 2: Preparation of N-hydroxy-4 [[[4-[4-(4-fluorophenyl)methoxy] piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. To a solution of N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide (100 mg, 0.26 mmol) in 1.5 mL of DMA are added the amine from step 1 (0.52 mmol, 2 eq.) and cesium carbonate (420 mg, 1.29 mmol). The reaction mixture is stirred at 100° C. for 48 hours. The reaction is treated with water and filtered through Celite eluting with dichloromethane. The solvent was evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature, the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[4-(4-fluorophenyl)methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+H=493.1792.
EXAMPLES 165-181[0684] The following hydroxamic acids were synthesized by the procedure of Example 164: 177 3920 HI Ex- Halide starting RES MS ample material R M + H 165 benzyl bromide 3921 475.1913 166 ethyl iodide 3922 413.1764 167 4-fluoro benzyl bromide 3923 493.1792 168 iodopropane 3924 427.1918 169 3,5-dimethyl benzyl bromide 3925 144.1391 170 4-chloro benzyl bromide 3926 509.1515 171 3-methyl benzyl bromide 3927 489.2059 172 4-methyl benzyl bromide 3928 489.2074 173 3-trifluoro- methoxy benzyl bromide 3929 559.1738 174 2-trifluoro- methyl benzyl bromide 3930 543.1780 175 4-trifluoro- methoxy benzyl bromide 3931 559.1730 176 3,4-dichloro- benzyl bromide 3932 543.1155 177 3-trifluoro- methyl benzyl bromide 3933 543.1779 178 3,5-dimethoxy- benzyl bromide 3934 535.2120 179 3,4-difluoro- benzyl bromide 3935 511.1705 180 4-cyano- benzyl bromide 3936 500.1835 181 2-phenyl benzyl bromide 3937 551.2196
Example 182 N-hydroxy-4-[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide[0685] 3938
[0686] N-hydroxy-4[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydro-pyrancarboxamide is prepared by the method of Example 164 starting from Boc-(3-hydroxy)-piperidine in step 1.
Examples 183-184[0687] The following hydroxamic acids were synthesized using a procedure similar to that of Example 182: 178 3939 Halide starting Example material R HI RES MS 183 4-fluroro benzyl bromide 3940 M + H =475.1913 184 benzyl bromide 3941 M + H =551.2196
Example 185 N-hydroxy-4[[[4-(4-phenoxy)-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide[0688] 3942
[0689] N-hydroxy-4 [[[4-(4-phenoxy)piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide is prepared by the method of Example 164 starting from 4-phenoxypiperidine in step 2.
Examples 186-187[0690] The following hydroxamic acids were synthesized using a procedure similar to that of Example 185: 179 3943 Ex- ample Amine starting material R HI RES MS 186 187 3944 H 3,5-di- methyl M + H = 461.1749 M + H = 489.2065
Example 188 Preparation of N-hydroxy-4[[[4-[(3-trifluoromethyl)phenylcarbamoxy]-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide[0691] 3945
[0692] Step 1: A solution of N-tetrahydro-pyranoxy-4-fluorophenylsulfonyl-1-tetrahydro-pyrancarboxamide (1 g, 2.58 mmol), 4-hydroxy-piperidine (392 mg, 3.87 mmol) and cesium carbonate (2.52 g, 7.74 mmol) in 20 mL of NMP is stirred at 100° C. for 48 hours. The reaction mixture is treated with water and neutralized to pH 4 with 5% aqueous HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic layer is dried using magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give N-tetrahydropyranoxy-4-[[(4-hydroxypiperidyl) phenyl] sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=491.2.
[0693] Step 2: To a solution of alcohol N-tetrahydro-pyranoxy-4[[(4-hydroxypiperidyl)-phenyl]sulfonyl]-1-tetrahydropyrancarboxamide (50 mg, 0.107 mmol) in 2 mL of dichloromethane is added alpha, alpha, alpha-trifluoro-M-tolyl isocyanate (21 mg, 0.112 mmol). The reaction mixture is stirred for 16 hours at room temperature and 21 mg of alpha,alpha,alpha-trifluoro-m-tolyl isocyanate is added. The mixture is stirred 48 hours at room temperature and treated with water. The solvent is evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[(3-trifluoromethyl)phenyl-carbamoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=594.1.
EXAMPLES 189-191[0694] The following hydroxamic acids were synthesized using a procedure similar to that of Example 188: 180 3946 Example Isocyanate starting material R MS 189 alpha,alpha,alpha-tri- fluoro-M-tolyl isocyanate 3947 M + Na = 594.1 190 4-ethoxyphenyl isocyanate 3948 M + Na = 570.2 191 4-fluorophenyl isocyanate 3949 M + H = 522.1742
Example 192 Preparation of N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]-sulfonyl]-1-[[(2-trifluoromethoxy)-phenyl]-sulfonyl-4-piperidinecarboxamide[0695] 3950
[0696] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-[[(2-trifluoromethoxy)phenyl]-sulfonyl-4-piperidinecarboxamide can be prepared using the method of Example 93 starting from 2-trifluoromethoxybenzene sulfonyl chloride.
EXAMPLES 193-197[0697] The following hydroxamic acids were synthesized using a procedure similar to that of Example 192: 181 3951 Sulfonyl chloride Example starting material R MS 193 2-trifluoro- methoxybenzene sulfonyl chloride 3952 M + NH4 =702.1003 194 benzene sulfonyl chloride 3953 M + NH4 =618.1216 195 alpha- toluenesulfonyl chloride 3954 M + NH4 =632.1337 196 3-trifluoro- methylbenzene sulfonyl chloride 3955 M + NH4 =686.1027 197 3-trifluoro- methane sulfonyl chloride 3956 M − H =591.1
EXAMPLE: 198[0698] 3957
[0699] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-(N-methylthiourea)-4-piperidinecarboxamide was prepared by the method of Example 192 starting with methyl isothiocyanate. M+H=77.
EXAMPLES 199-202[0700] The following hydroxamic acids were synthesized using the procedure of Example 198: 182 3958 Sulfonyl chloride MS Example starting material R M + H 199 2-morpholinoethyl isothiocyanate 3959 633.1643 200 2-piperidinoethyl isothiocyanate 3960 653.1694 201 pyridine-3- isothiocyanate 3961 597.1094 202 4-dimethylaminophenyl isothiocyanate 3962 639.1526
EXAMPLE 203 Preparation of 1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-[(2H)-pyridinecarboxylate[0701] 3963
[0702] Part A: An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than −70 degrees, a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than −65 degrees. After complete addition, the flask was stirred with cooling for 20 minutes. Then a solution of N-trifluoromethanesulfonimide (38.2 g, 0.107 mole) was added drop-wise maintaining the temperature less than −65 degrees. After complete addition, the dry ice/acetone bath was swapped with an ice/water bath. The reaction was stirred overnight (about eighteen hours), slowly warming to room temperature. After 16 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography on neutral alumina, yielding 26.53 g of product as a yellow oil. Electrospray mass spectroscopy showed m/z 332 (M+H).
[0703] Part B: A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 minutes, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hours, then cooled to room temperature. The solvent was removed in vacuo, then the residue was partitioned between 100 mL of methylene chloride and 100 mL of 2 M sodium carbonate with 3 mL concentrated ammonium hydroxide. The aqueous layer was extracted with an additional 100 mL methylene chloride, then the combined organic layers were dried over magnesium sulfate and concentrated to give 8.42 g of crude product as a dark brown oil. Purification via flash column chromatography (10% ethyl acetate3/hexanes) yielded 2.76 g of pure product as a yellow oil. Electrospray mass spectroscopy showed m/z 328 (M+H).
EXAMPLE 204 Preparation of 1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine[0704] 3964
[0705] The title compound of Example 203 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H).
EXAMPLE 205 Preparation of 4-[2-(trifluoromethyl) phenyl]piperidine[0706] 3965
[0707] Part A: A solution of the title compound of Example 203 (2.3 g, 7 mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 g of 4% palladium on carbon (0.38 mmol). The mixture was placed under 100 PSI hydrogen and heated to 50 degrees Celsius for 5 hours. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give 2.27 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 330 (M+H).
[0708] Part B: The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H).
EXAMPLE 206 General Description for Preparation of Hydroxamic Acids via Aryl Fluoride Displacement with Amines.[0709] Part A: A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-therm™ at 115 degrees Celsius. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products.
[0710] Part B: The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hours. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC.
EXAMPLES 207-214[0711] The following hydroxamic acids were prepared using the method described above in Example 106 with the indicated amine as the starting material. 183 3966 m/z from electrospray mass Example amine R spectroscopy 207 Product of Example 205 3967 513.3 (M + H) 208 Product of Example 204 3968 511.2 (M + H) 209 piperidine 3969 369.2 (M + H) 210 tetrahydro- piperidine 3970 367.2 (M + H) 211 4-(2-keto- benzimid- azolinyl)- piperidine 3971 501 (M + H) 212 hexamethyl- eneimine 3972 383.2 (M + H) 213 1-methylhomo- piperazine 3973 398.2 (M + H) 214 1,3,3-trimethyl- 6-azabicyclo- [3.2.1]octane 3974 437.3 (M + H)
EXAMPLES 215-223[0712] Using the procedures outlined in Examples 203, 204, 206 and other methods outlined above, the following analogs are made from the indicated boronic acid: 184 3975 Example Boronic acid R 215 3976 3977 216 3978 3979 217 3980 3981 218 3982 3983 219 3984 3985 220 3986 3987 221 3988 3989 222 3990 3991 223 3992 3993
EXAMPLE 224 Preparation of Tetrahydro-N-hydroxy-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide[0713] 3994
[0714] Part A: To a solution of the product of Preparative Example IV (2.5 g, 6 mmol) in dimethylformamide (50 mL) was added 4-pentafluroethyloxy phenol (2.0 g, 6 mmol) followed by cesium carbonate (5 g, 12 mmol). The reaction was heated at eighty degrees Celsius for twelve hours. Stripping the dimethylformamide in vacuo afforded a brown solid (5.5 g). The product was dissolvent in ethylacetate (150 ml) and extracted with water, brine and dried over sodium sulfate. The 1H NMR, MS, and HPLC was consistent with desired compound.
[0715] Part B: To the product of part A, crude THP-protected hydroxamate was disolved in acetonitrile/water (40 ml) was slowly added 10% aq HCl (10 ml). After stirring two hours, the acetonitrile was stripped. The resultant precipitate was collected, giving the title compound as a white solid (2.1 g). The 1H NMR, MS, and HPLC was consistent with desired compound. This solid was recrystallized from ethylacetate and hexanes (1.8 g). The 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 511, found 511.
EXAMPLE 225 Preparation of Tetrahydro-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide[0716] 3995
[0717] Part A. The product of Preparative Example V (2.5 g) was dissolved in methanol (60 mL). To this solution ammonium formate (3 g) was added, followed by Pd on charcoal 20% catalyst. The mixture was heated to reflux for 24 hour. After complete reaction the mixture was cooled filtered through a plug of Celite and the solvent removed under reduced pressure to give pure amide (1.7 g). The 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 445, found 445.
EXAMPLE 226 Preparation of 4-(4-pyridyloxy) thiophenol hydrochloride[0718] 3996
[0719] Part A: Phenol (1500 g, 15.9 mol) and 4-chloropyridine hydrochloride (800 g, 7.1 mol) were combined in a melt at 150° C. under a nitrogen atmosphere. After fifteen hours, the reaction was dissolve in 3N sodium hydroxide solution (5400 mL) and extracted with methylene chloride (4×). The organic extracts were combined, washed with 1N sodium hydroxide solution, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The isolated oil was dissolved in hexanes (1000 mL) and cooled to −60° C. The precipitate was collected and dried in vacuo to yield 452 g (38%) of the 4-phenoxypyridine as a white solid.
[0720] Part B: A solution of the 4-phenylpyridine from part A (400 g, 2.3 mol) in 1,2-dichloroethane (1250 mL) was cooled in an ice bath under a nitrogen atmosphere and treated with chlorosulfonic acid (400 mL, 6.0 mol). The reaction temperature was held below 12° C. during the addition. The reaction was then heated to 45° C. for 15 hours. The standard work-up procedure afforded 270 grams (40%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonic acid.
[0721] Part C: A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride.
[0722] Part D: A solution of triphenylphosphine (65.6 g, 250.28 mmol) in dry methylene chloride (240 mL) was cooled to zero degrees C. in an ice-water bath, then treated with dimethylformamide (3.4 mL, 3.2 g, 43.40 mmol). The reaction mixture was then treated with the sulfonyl chloride from part C (25.5 g, 83.43 mmol), added as a solid over one-half hour. After two hours in the ice bath, the reaction was treated with 1 N aqueous hydrochloric acid solution (150 mL) and stirred vigorously for one hour. The layers were separated and the aqueous layer was extracted with methylene chloride (1×). The aqueous layer was concentrated in vacuo to yield 17.9 grams (90%) of the 4-(4-pyridyloxy)thiophenol hydrochloride as a tan solid, m/z=204 (M+H).
EXAMPLE 227 Preparation of[0723] 3997
[0724] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (2.0 g, 8.34 mmol) and tert-butylbromoacetate (1.2 mL, 1.6 g, 8.34 mmol) in dry methanol (30 mL) was cooled to zero degrees C. and treated with triethylamine (2.4 mL, 1.8 g, 17.52 mmol). The addition was done at a rate which held the reaction temperature below 10° C. The ice bath was removed and after two hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 2.3 grams of the tert-butyl ester of the sulfide acid suitable for the next step.
[0725] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (2.3 g, 7.25 mmol) in dry anisole (85 mL, 8.1 g, 74.67 mmol) was added trifluoroacetic acid (25.5 mL, 37.7 g, 330.6 mmol). After one-half hour at ambient temperature, the reaction was concentrated in vacuo to 3.7 g of the TFA salt of the sulfide acid suitable for the next step.
[0726] Part C: To a solution of the TFA salt of the acid obtained from part B (2.7 g, 7.19 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole hydrate (1.5 g, 10.79 mmol), N-methylmorpholine (4.7 mL, 4.4 g, 43.16 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.5 g, 21.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.35 mmol). After sixteen hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 2.1 g (81%) of the THP sulfide hydroxamate as a dry, white foam, m/z=361 (M+H).
[0727] Part D: To a solution of the THP sulfide hydroxamate from part C (2.1 g, 5.83 mmol) in methanol/water (13 mL/2 mL) was added tetrabutylammonium Oxone (5.8 g, 61.29 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (6×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 0.9 g (40%) of the THP sulfone hydroxamate as a dry, white foam, m/z=393 (M+H).
[0728] Part E: To a slurry of the THP sulfone hydroxamate from part D (0.9 g, 2.29 mmol) in methanol (0.6 mL) was added 4N HCl dioxane solution (6 mL). After one hour at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL). Filtration afforded 0.6 grams (78%) of the title compound as a white solid, m/z=309 (M+H).
EXAMPLE 228 Preparation of[0729] 3998
[0730] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (18.0 g, 75.08 mmol) and tert-butylbromoacetate (10.5 mL, 13.9 g, 71.33 mmol) in dry methanol (250 mL) was cooled to 0° C. and treated with triethylamine (22.0 mL, 16.0 g, 157.68 mmol). The addition was done at a rate which held the reaction temperature below 1° C. The ice bath was removed and after one-half hour at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 21.7 grams of the tert-butyl ester of the sulfide acid suitable for the next step.
[0731] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (221.7 g, 68.37 mmol) in dry anisole (76.5 mL, 76.1 g, 704.12 mmol) was added trifluoroacetic acid (240 mL, 355 g, 3,117 mmol). After one hour at ambient temperature, the reaction was concentrated in vacuo to yield 34.7 g of the TFA salt of the sulfide acid suitable for the next step.
[0732] Part C: To a solution of the TFA salt of the sulfide acid from part B (34.7 g, 68.37 mmol) in dry methanol (100 mL) was added thionyl chloride (7.5 mL, 12.2 g, 102.5 mmol). After twelve hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 18.7 grams of the methyl ester of the sulfide acid suitable for the next step.
[0733] Part D: To a solution of the methyl ester of the sulfide acid obtained from part C (18.7 g, 67.92 mmol) in methylene chloride (325 mL) was added tetrabutylammonium Oxone (193 g, 543.4 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (9×). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 7.3 g (35%) of the methyl ester of the sulfone acid as a dry, white foam, m/z=308 (M+H).
[0734] Part E: To a solution of the methyl ester of the sulfone acid obtained from part D (2.7 g, 8.79 mmol) in dry dimethylformamide (20 mL) was added 18-crown-6 ether (0.5 g, 1.90 mmol) and potassium carbonate (4.9 g, 35.14 mmol). The reaction slurry was treated with bis-(2-bromoethyl)ether (1.1 mL, 2.0 g, 8.79 mmol) and then heated to 60° C. After fifteen hours at 60° C., the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, NH3-methanol-ethyl acetate/hexanes) afforded 1.6 g (48%) of the THP sulfone methyl ester as a tan solid, m/z=378 (M+H).
[0735] Part F: To a solution of the THP sulfone methyl ester from part E (1.6 g, 4.24 mmol) in dry tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (1.6 g, 12.72 mmol). After five hours at ambient temperature, the reaction was concentrated in vacuo to yield the potassium salt of the THP sulfone acid as a tan solid suitable for use in the next step.
[0736] Part G: To a slurry of the potassium salt of the THP sulfone acid obtained from part F (1.7 g, 4.24 mmol) in dimethylformamide (20 mL) was added N-hydroxybenzotriazole hydrate (1.1 g, 8.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.48 mmol). After heating the reaction mixture at 40° C. for one-half hour, N-methylmorpholine (1.4 mL, 1.3 g, 12.72 mmol) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.0 g, 8.48 mmol) were added. After heating at 45° C. for 15 hours, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% potassium carbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (13×). The organic extracts were combined, washed with water and brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, (2M ammonia in methanol-ethyl acetate)/hexanes) afforded 0.7 g (35%) of the THP-protected THP sulfone hydroxamate as a dry, white foam, m/z=463 (M+H).
[0737] Part H: To a slurry of the THP-protected THP sulfone hydroxamate from part G (0.7 g, 1.43 mmol) in methanol (0.4 mL) was added 4N HCl dioxane solution (4 mL). After thirty minutes at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL) and stirred for fifteen minutes. Filtration afforded 0.5 grams (83%) of the title compound as the HCl salt, m/z=379 (M+H).
EXAMPLE 229 Preparation of N-hydroxy-1-(4-methyl-phenyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride[0738] 3999
[0739] Part A: To a suspension of ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride Preparative Example II (2.56 g, 7.28 mmol) in H2O (50 mL) was added 1.25N NaOH (pH=9.0). The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the free amine as an off-white solid (1.72 g). To a solution of the free amine (1.70 g, 5.39 mmol) in toluene (25 mL) was added Cs2CO3 (2.34 g, 7.19 mmol) and a solution of 4-bromotoluene (0.877 g, 5.13 mmol) in toluene (5 mL). This was followed by the addition of tris(dibenzyldeneacetone)dipallidium (O) (0.047 g, 0.0513 mmol) and BINAP (0.096 g, 0.154 mmol). The resulting mixture was then heated to one hundred degress Celsius for 17 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the aniline as a yellow oil (1.59 g, 76%).
[0740] Part B: To a solution of the aniline of part A (1.56 g, 3.85 mmol) in N,N-dimethylformamide (8.0 mL) was added K2CO3 (1.06 g, 7.70 mmol) and 4-(trifluoromethoxy)phenol (0.823 g, 4.62 mmol). The resulting mixture was heated to ninety degrees Celsius for 19 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O and diethyl ether. The organic layer was washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the biaryl ether as a brown oil (2.42 g, >100%).
[0741] Part C: To a solution of the biaryl ether of part B (2.42 g, 3.85 mmol) in tetrahydrofuran (10 mL) and H2O (10 mL) was added NaOH (1.54 g, 38.50 mmol) in H2O (5.0 mL). The mixture was heated to sixty degrees Celsius for 6 hours then cooled to ambient temperature. The mixture was then acidified (pH=7) with 1N HCl. The solids were collected by vacuum filtration, then suspended in acetonitrile and concentrated in vacuo to give the acid as a tan solid (1.95 g, 95%).
[0742] Part D: To a suspension of the acid of part C (1.95 g, 3.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (0.596 g, 4.37 mmol), N-methylmorpholine (1.19 mL, 10.92 mmol), 0-(tetrahydropuranyl) hydroxylamine (1.28 g, 10.92 mmol) and 1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.977 g, 5.10 mmol). The resulting mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between H2O and ethyl acetate. The combined organic layers were washed with H2O, saturated NaHCO3, saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/ethyl acetate) provided the protected hydroxamate as a pale-yellow foam (1.90 g, 83%).
[0743] Part E: To the protected hydroxamate of part D (1.89 g, 3.00 mmol) was added 4N HCl in dioxane (7.50 mL, 30.0 mmol) and methanol (1.22 mL, 30.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then diethyl ether (5 mL) was added and the precipitate was collected by filtration to provide the title compound as a fine white solid (1.56 g, 89%). MS MH+ calculated for C26H25O6N2S1F3: 551, found 551.
EXAMPLE 230 Preparation of N-hydroxy-1-(2-hydroxyethyl)-4-[4-(4-trifluoro-methoxyphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, hydrochloride[0744] 4000
[0745] Part A: Ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride (3.95 g, 11.3 mmol) Preparative Example II, powdered potassium carbonate (3.45 g, 25 mmol), and N,N-dimethylformamide (11.3 mL) were combined. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.85 mL, 12 mmol) was added and the mixture was stirred for 48 hours at ambient temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired tetrahydropyranyl ether as an oil (4.44 g, 88%)
[0746] Part B: The tetrahydropyranyl ether from Part A was stirred at 110 degrees Celsius for 20 hours in the presence of powdered potassium carbonate (2.07 g, 15 mmol), 4-(trifluoromethoxy)phenol (2.67 mL, 15 mmol), and N,N-dimethyformamide (5 mL). The mixture was diluted with saturated sodium bicarbonate (50 mL) and was extracted with ethyl acetate (150, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired aryl ether as an oil (5.72 g, quantitative).
[0747] Part C: The aryl ether from Part C (1.28 g, 2.1 mmol) was refluxed in the presence of potassium hydroxide (954 mg, 16.8 mmol), ethanol (9 mL), and water (3 mL). After 2 hours, the reaction vessel was cooled to zero degrees Celsius. Concentrated hydrochloric acid was added drop-wise to adjust the pH to 4.0. The acidified reaction was concentrated, azeotroped with acetonitrile, and dried in vacuo, affording the crude carboxylic acid, which was used directly in Part D.
[0748] Part D: The carboxylic acid from Part C was converted to O-tetrahydropyranyl hydroxamate using O-tetrahydropyranyl hydroxylamine (351 mg, 3 mmol), N-methylmorpholine (0.5 mL), N-hydroxybenzotriazole (405 mg, 3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 3 mmol) in N,N-dimethylformamide (9 mL). The tetrahydropyranyl hydroxamate (855 mg, 60%) was obtained as an oil.
[0749] Part E: The tetrahydropyranyl hydroxamate (855 mg, 1.26 mmol) was dissolved in absolute methanol (10 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2-3 minutes. After 4 hours both tetrahydropyranyl groups had been cleaved. The reaction was concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo affording the title compound as a white foam (676 mg, 98%). MS (EI) MH+ calculated for C21H23F3N2O7S: 505, found 505.
EXAMPLE 231 Preparation of N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0750] 4001
[0751] Part A: To a solution of the compound of example N-tert-butoxycarbonyl-ethyl 4-(4-fluorophenylsulfonyl)-4-piperidinecarboxylate, hydrochloride of Preparative Example II (1.50 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and (4-trifluoromethylthio) phenol (1.05 g, 5.41 mmol) and the solution was heated to 100 degrees Celsius for 24 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and dried over sodium sulfate. Filtration through silica gel (ethyl acetate) provided the phenoxyphenol compound as an oil (2.35 g, quantitative yield). MS(CI) MH+ calculated for C26H30NO7S2F3: 590, found 590.
[0752] Part B: To a solution of phenoxyphenol compound of part A (2.35 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in water (5 mL). The solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated under a stream of nitrogen to remove the solvents and the residue was dissolved in water and acidified to pH=1 with 10% hydrochloric acid. The solution was extracted with ethyl acetate and washed with saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the carboxylic acid as an oil (2.0 g, quantitative yield).
[0753] Part C: To a solution of the carboxylic acid of part B (2.0 g, <3.61 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10.8 mmol) and O-tetrahydropyranyl hydroxylamine (634 mg, 5.41 mmol) and the solution was stirred for 30 minutes. The 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for seven days. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a clear, colorless oil (1.07 g, 45% yield). MS(CI) MNa+ calculated for C29H35N2O8S2F3: 683, found 683.
[0754] Part D: To a solution of the protected hydroxamate of part C (1.05 g, 1.60 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting white precipitate was collected by vacuum filtration to provide the title compound as a white solid (330 mg, 40% yield). MS(CI) MH+calculated for C19H19N2O5S2F3: 477, found 477. HRMS calculated for C19H19N2O5S2F3: 477.0766, found 477.0766. Analytical calculation for C19H19N2O5S2 HCl: C, 44.49; H, 3.93; N, 5.46; Cl, 6.91. Found: C, 44.51; H, 3.90; N, 5.38; Cl, 6.95.
EXAMPLE 232 Preparation of 1-[4-[[1-cyclopropyl-4-[(hydroxyamino)carbonyl]-4-piperidinyl] sulfonyl]phenyl]-N-methyl-N-(phenylmethyl)-4-piperidinecarboxamide, monohydrochloride[0755] 4002
[0756] Part A: To a solution of ethyl N-cyclopropyl-4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate (Preparative Example VI, Part A) (2.0 g, 5.11 mmol) in dimethylacetamide (10 mL) was added methyl isonipectotate (1.03 mL, 7.66 mmol) and cesium carbonate (4.16 g, 12.78 mmol) and was heated to one hundred ten degrees Celsius for 18 hours. The solution was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.81 g, 74%). MS(CI) MH+ calculated for C24H34N2O6S: 479, found 479.
[0757] Part B: To a solution of the phenylamine of part A (1.79 g, 3.74 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (960 mg, 7.49 mmol) and the resulting solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into water. The solution was acidified with 3N hydrochloric acid to pH=3. The resulting precipitate was collected and washed with ethyl ether to provide the acid as a light yellow solid (1.09 g, 63%). MS(CI) MH+ calculated for C23H32N2O6S: 465, found 465.
[0758] Part C: To a solution of the acid of part B (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole hydrate (160 mg, 1.19 mmol), triethylamine (0.15 mL, 1.19 mmol) and N-benzylmethylamine (0.33 mL, 2.38 mmol). After thirty minutes the 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the solution was stirred for 20 hours at ambient temperature. The solution was diluted with ethyl acetate and washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the amide as a white solid (480 mg, 78%). MS(CI) MH+ calculated for C31H41N3O5S: 568, found 568.
[0759] Part D: To a solution of the amide of part C (400 mg, 0.71 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (282 mg, 7.1 mmol) in water (3 mL). The solution was heated to sixty degrees Celsius for 24 hours. The solution was concentrated under a stream of nitrogen and the residue was diluted with water and acidified with 3N hydrochloric acid to pH=2. The solution was concentrated to provide the acid as a crude white solid which is used in the next step without further purification. MS(CI) MH+ calculated for C29H37N5O5S: 540, found 540.
[0760] Part E: To a solution of the crude acid of part D (<0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), 4-methylmorpholine (0.39 mL) and O-tetrahydropyranyl hydroxylamine (124 mg, 1.06 mmol). After thirty minutes 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) was added and the solution was stirred for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as an oil (184 mg, 41%). MS(CI) MH+ calculated for C34H46N4O6S: 0.639, found 639.
[0761] Part F: To a solution of the protected hydroxamate of part E (180 mg, 0.28 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. Trituration (ethyl ether) and vacuum filtration provided the title compound as a white solid (96.5 mg, 58%). MS(CI) MH+ calculated for C29H38N4O5S: 555, found 555. HRMS calc. 555.2641, found 555.2644.
EXAMPLE 233 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride[0762] 4003
[0763] Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After four hours the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90%).
[0764] Part B: To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.21 g, 89%).
[0765] Part C: To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII,
[0766] Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH+ calculated for C30H47N3O6S: 578, found 578.
[0767] Part D: To a solution of the phenylamine of part C (1.5 g, 2.6 mmol) in ethanol (9 mL) and tetrahydrofuran (9 mL) was added sodium hydroxide (1.02 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (500 mg, 33%). MS(CI) MH+calculated for C28H43N3O6S: 550, found 550.
[0768] Part E: To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the protected hydroxamate as an oil (524 mg, 96%). MS(CI) MH+ calculated for C33H51N4O7S: 649, found 649.
[0769] Part F: To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH+calculated for C28H44N4O6S: 565, found 565. HRMS calculated for C28H44N4O6S: 565.3060, found 565.3070. Analytical calculation for C28H44N4O6S 2 HCl:2H2O: C, 49.92; H, 7.48; N, 8.32; S, 4.76; Cl, 10.52. Found: C, 49.41; H, 7.55; N, 7.85; S, 4.53; Cl, 10.78.
EXAMPLE 234 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide[0770] 4004
[0771] Part A: A solution of the hydroxamate of Example 233, part F (50 mg, 0.08 mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. Concentration in vacuo provided the hydroxamate free base as an orange solid (35 mg, 75%).
EXAMPLE 235 Preparation of 1-[4-[[4[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]sulfonyl]phenyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-4-piperidine-carboxamide, dihydrochloride[0772] 4005
[0773] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxy-benzotriazole hydrate (620 mg, 4.59 mmol), 2-(2-methylaminoethyl)pyridine (0.69 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.03 g, 68%). MS(CI) MH+ calculated for C19H29N3O3: 348, found 348.
[0774] Part B: To a solution of the amide of part A (1.0 g, 2.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (716 mg, 1.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.20 g, 6.72 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.20 g, quantitative yield). MS(CI) MH+ calculated for C31H44N4O6S: 601, found 601.
[0775] Part C: To a solution of the phenylamine of part B (1.20 g, 2.00 mmol) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the crude acid as an oil. MS(CI) MH+ calculated for C29H40N4O6S: 573, found 573.
[0776] Part D: To a solution of the acid of part C (<2.0 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (324 mg, 2.04 mmol), 4-methylmorpholine (1.1 mL, 10.0 mmol), and O-tetrahydropyranyl hydroxylamine (351 mg, 3.00 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (536 mg, 2.80 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Reverse phase chromatography (on silica, acetonitrile/water) provided the protected hydroxamate as an oil (170 mg, 13% yield over two steps). MS(CI) MH+ calculated for C34H49N5O7S: 672, found 672.
[0777] Part E: To a solution of the protected hydroxamate of part D (160 mg, 0.24 mmol) in dioxane (7 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 30 minutes. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (90 mg, 57%). MS(CI) MH+calculated for C29H37N5O6S: 588, found 588. HRMS calculated for C29H37N5O6S: 558.2856, found 588.2857.
EXAMPLE 236 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(phenylamino)-carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride)[0778] 4006
[0779] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (4 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (752 mg, 4.28 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.47 mL, 4.28 mmol) was added. After two hours aniline (0.39 mL, 4.28 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.48 g, quantitative yield).
[0780] Part B: To a solution of the amide of part A (1.48 g, 4.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (1.06 mg, 2.85 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.25 g, 9.97 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.74 g, quantitative yield). MS(CI) MH+ calculated for C29H39N3O6S: 558, found 558.
[0781] Part C: To a solution of the phenylamine of part B (1.74 g, 2.85 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.14 g, 28.5 mmol) in water (7 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (1.62 g, quantitative yield). MS(CI) MH+ calculated for C27H35N3O6S: 530, found 530.
[0782] Part D: To a solution of the acid of part C (1.60 g, 2.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (458 mg, 3.40 mmol), 4-methylmorpholine (1.56 mL, 14.2 mmol), and O-tetrahydropyranyl hydroxylamine (497 mg, 4.24 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (759 mg, 3.96 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (790 mg, 44%). MS(CI) MH+ calculated for C32H44N4O7S: 629, found 629.
[0783] Part E: To a solution of the protected hydroxamate of part D (780 mg, 1.24 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (580 mg, 80%). MS(CI) MH+calculated for C27H36N4O6S: 545, found 545. HRMS calculated for C27H36N4O6S: 545.2434, found 545.2429.
EXAMPLE 237 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(3-phenyl-propyl)amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride[0784] 4007
[0785] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol), 3-phenyl-1-propylamine (0.72 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 18 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a yellow oil (1.4 g, 93%).
[0786] Part B: To a solution of the amide of part A (1.4 g, 4.05 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether. The solid was added to a solution of the compound of Preparative Example VII, Part A (1.01 mg, 2.70 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.07 g, 9.45 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.71 g, quantitative yield). MS(CI) MH+ calculated for C32H45N3O6S: 600, found 600.
[0787] Part C: To a solution of the phenylamine of part B (1.70 g, 2.70 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.08 g, 27.0 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a white solid (1.15 g, 75%). MS(CI) MH+ calculated for C30H41N3O6S: 572, found 572.
[0788] Part D: To a solution of the acid of part C (1.02 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (272 mg, 2.02 mmol), 4-methylmorpholine (0.92 mL, 8.4 mmol), and O-tetrahydropyranyl hydroxylamine (295 mg, 2.52 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as an oil (490 mg, 41%). MS(CI) MH+ calculated for C35H50N4O7S: 671, found 671.
[0789] Part E: To a solution of the protected hydroxamate of part D (480 mg, 0.72 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (400 mg, 90%). MS(CI) MH+ calculated for C30H42N4O6S: 587, found 587. Analytical calculation for C30H42N4O6S 2HCl :2H2O: C, 51.79; H, 6.95; N, 8.05; S, 4.61; Cl, 10.19. Found: C,51.34; H, 6.72; N, 7.82; S, 4.59; Cl, 10.92.
EXAMPLE 238 Preparation of rel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride[0790] 4008
[0791] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.4 g, quantitative yield).
[0792] Part B: To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to one hundred degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow solid (1.90 g, quantitative yield). MS(CI) MH+ calculated for C32H49N3O7S: 620, found 620.
[0793] Part C: To a solution of the phenylamine of part B (1.9 g, 3.0 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.2 g, 30 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with 1M hydrochloric acid and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a yellow oil (1.9 g, quantitative yield). MS(CI) MH+ calculated for C30H45N3O7S: 592, found 592.
[0794] Part D: To a solution of the acid of part C (1.87 g, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), and O-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as an oil (1.63 g, 79%).
[0795] Part E: To a solution of the protected hydroxamate of part D (1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 45 minutes. The solution was concentrated in vacuo and trituration (ethyl ether) a white solid. Reverse phase chromatography (on silica, acetonitrile/water(hydrochloric acid)) produced fractions A, B, C and D. Concentration in vacuo of fraction A provided the title compound as a white solid (59 mg). MS(CI) MH+ calculated for C25H38N4O5S: 507, found 507.
EXAMPLE 239 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate[0796] 4009
[0797] Part A: From the reverse phase chromatography of Example 238, Part E, fraction C was concentrated in vacuo to provide the title compound as a white solid (49 mg). MS(CI) MH+ calculated for C30H46N4O7S: 607, found 607.
EXAMPLE 240 Preparation of rel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride[0798] 4010
[0799] Part A: From the reverse phase chromatography of Example 238, Part E, fraction B was concentrated in vacuo to provide the title compound as a white solid (198 mg). MS(CI) MH+ calculated for C25H38N4O5S: 507, found 507.
EXAMPLE 241 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate[0800] 4011
[0801] Part A: From the reverse phase chromatography of Example 238, Part E, fraction D was concentrated in vacuo to provide the title compound as a white solid (242 mg). MS(CI) MH+calculated for C30H46N4O7S: 607, found 607.
EXAMPLE 242 Preparation of 4-[[4-[4-[[(2,3-dihydro-1H-inden-2-yl)amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidine-carboxamide, monohydrochloride[0802] 4012
[0803] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 2-aminoindane hydrochloride (853 mg, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a white solid (1.35 g, 90%).
[0804] Part B: To a solution of the amide of part A (1.35 g, 3.92 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid which was added directly to a solution of the title compound of Preparative Example VII, Part A, (976 mg, 2.61 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.97 g, 9.14 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.65 g, quantitative yield). MS(CI) MH+ calculated for C32H43N3O6S: 598, found 598.
[0805] Part C: To a solution of the phenylamine of part B (1.60 g, 2.61 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.04 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (1.06 g, 71%). MS(CI) MH+ calculated for C30H39N3O6S: 570, found 570.
[0806] Part D: To a solution of the acid of part E (1.0 g, 1.65 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (267 mg, 1.98 mmol), 4-methylmorpholine (0.91 mL, 8.25 mmol), and O-tetrahydropyranyl hydroxylamine (289 mg, 2.48 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate, methanol) provided the protected hydroxamate as an oil (575 mg, 52%). MS(CI) MH+ calculated for C35H48N4O7S: 669, found 669.
[0807] Part E: To a solution of the protected hydroxamate of part D (565 mg, 0.85 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (450 mg, 86%). MS(CI) MH+ calculated for C30H40N4O6S: 585, found 585. HRMS calculated for C30H40N4O6S: 585.2747, found 585.2776. Analytical calculation for C30H40N4O6S 2HCl :2H2O: C, 51.94; H, 6.68; N, 8.08; S, 4.62; Cl, 10.22. Found: C, 51.66; H, 6.25; N, 7.80; S, 4.73; Cl, 10.33.
EXAMPLE 243 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0808] 4013
[0809] Part A: To a solution of the product of Example 232, Part B (562 mg, 1.12 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (164 mg, 0.93 mmol) and 4-methylmorpholine (0.21 mL, 1.87 mmol). The solution was stirred for 45 minutes and aniline (0.085 mL, 0.93 mmol) was added. The solution was stirred for 72 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (434 mg, 86%). MS(CI) MH+calculated for C29H37N3O5S: 540, found 540.
[0810] Part B: To a solution of the amide of part A (425 mg, 0.79 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (315 mg, 7.89 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (261 mg, 60%). MS(CI) MH+ calculated for C27H33N3O5S: 512, found 512.
[0811] Part C: To a solution of the acid of part B (245 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (73 mg, 0.54 mmol), 4-methylmorpholine (0.25 mL, 2.25 mmol), and O-tetrahydropyranyl hydroxylamine (79 mg, 0.68 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as a yellow oil (242 mg, 88%). MS(CI) MH+ calculated for C32H42N4O6S: 611, found 611.
[0812] Part D: To a solution of the protected hydroxamate of part C (235 mg, 0.38 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (114 mg, 53%). MS(CI) MH+ calculated for C27H34N4O5S: 527, found 527. HRMS calculated for C27H34N4O5S: 527.2328, found 527.2339.
EXAMPLE 244 Preparation of 1-[4-[[4-[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]-sulfonyl]phenyl]-N-methyl-N-phenyl-4-piperidinecarboxamide, monohydrate[0813] 4014
[0814] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (500 mg, 2.18 mmol) in dichloromethane (2 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (319 mg, 1.82 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.20 mL, 1.82 mmol) was added. After two hours, N-methylaniline (0.20 mL, 1.82 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (445 mg, 77%).
[0815] Part B: To a solution of the amide of part A (440 g, 1.38 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (344 mg, 0.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (1.05 g, 3.22 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (440 mg, 84%).
[0816] Part C: To a solution of the phenylamine of part B (440 mg, 0.77 mmol) in ethanol (7 mL) and tetrahydrofuran (7 mL) was added sodium hydroxide (308 mg, 7.7 mmol) in water (3 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a yellow solid and carried on to the next step without additional purification.
[0817] Part D: To a solution of the acid of part C (<0.77 mmol) in N,N-dimethylformamide (10 mL) was added-1-hydroxybenzotriazole hydrate (125 mg, 0.92 mmol), 4-methylmorpholine (0.43 mL, 3.85 mmol), and O-tetrahydropyranyl hydroxylamine (135 mg, 1.16 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (150 mg, 30%). MS(CI) MH+ calculated for C33H46N4O7S: 643, found 643.
[0818] Part E: To a solution of the protected hydroxamate of part D (150 mg, 0.23 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (75 mg, 55%). MS(CI) MH+ calculated for C28H38N4O6S: 559, found 559. HRMS calculated for C28H38N4O6S: 559.2590, found 559.2613.
EXAMPLE 245 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide[0819] 4015
[0820] Part A: To a solution of the N-Boc-amide of Preparative Example III, Part B, (6.9 g, 11.4 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D (3.15 g, 7.6 mmol) in dimethylacetamide (30 mL). Cesium carbonate (8.65 g, 26.6 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a tan solid (3.92 g, 86%).
[0821] Part B: To a solution of the phenylamine of part A (3.90 g, 6.51 mmol) in methanol (20 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 3 hours. Concentration in vacuo followed by trituration (ethyl ether) provided the amine hydrochloride salt as a yellow solid (3.25 g, 93%).
[0822] Part C: To a solution of the amine hydrochloride salt of part B (500 mg, 0.93 mmol) in dichloromethane (5 mL) was added triethylamine (0.40 mL, 2.79 mmol) followed by acetyl chloride (0.07 mL, 1.02 mmol). The solution was stirred for 3 hours. The solution was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the acylated compound as an oil (390 mg, 77%). MS(CI) MH+ calculated for C28H35N3O6S: 542, found 542.
[0823] Part D: To a solution of the acylated compound of part C (390 mg, 0.72 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (58 mg, 1.44 mmol) in water (1 mL) and the solution was heated to sixty degrees Celsius for 3 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with water and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white solid (137 mg, 37%). MS(CI) MH+ calculated for C26H31N3O6S: 514, found 514.
[0824] Part E: To a solution of the acid of part D (137 mg, 0.27 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added 1-hydroxybenzotriazole hydrate (44 mg, 0.32 mmol), 4-methylmorpholine (0.10 mL, 1.08 mmol), and O-tetrahydropyranyl hydroxylamine (47 mg, 0.41 mmol). After one hour 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a white solid (140 mg, 85%). MS(CI) MH+ calculated for C31H40N4O7S: 613, found 613.
[0825] Part F: To a solution of the protected hydroxamate of part E (130 mg, 0.21 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (51 mg, 48%). MS(CI) MH+ calculated for C26H32N4O6S: 528, found 528.
EXAMPLE 246 Preparation of 4-[[4-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrate[0826] 4016
[0827] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (940 mg, 89%).
[0828] Part B: To a solution of the amide of part A (935 g, 2.83 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A, (705 mg, 1.89 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (893 mg, 81%). MS(CI) MH+ calculated for C31H41N3O6S: 584, found 584.
[0829] Part C: To a solution of the phenylamine of part B (885 g, 1.52 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (607 mg, 15.2 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (475 g, 53%). MS(CI) MH+ calculated for C29H37N3O6S: 556, found 556.
[0830] Part D: To a solution of the acid of part C (465 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), and O-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (305 mg, 60%). MS(CI) MH+ calculated for C34H46N4O7S: 655, found 655.
[0831] Part E: To a solution of the protected hydroxamate of part D (300 mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CI) MH+calculated for C29H34N4O6S: 571, found 571.
EXAMPLE 247 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(phenylmethyl) amino]carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0832] 4017
[0833] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole hydrate (463 mg, 3.43 mmol) and diisopropylethylamine (1.25 mL, 7.19 mmol). After thirty minutes, benzylamine (0.41 mL, 3.76 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (320 mg, 31%).
[0834] Part B: To a solution of the amide of part A (320 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D, (288 mg, 0.77 mmol) in dimethylacetamide (10 mL). Cesium carbonate (878 g, 2.7 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (367 mg, 83%). MS(CI) MH+ calculated for C30H41N3O6S: 572, found 572.
[0835] Part C: To a solution of the phenylamine of part B (367 g, 0.64 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (257 mg, 6.4 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (415 g, quantitative yield). MS(CI) MH+calculated for C28H37N3O6S: 544, found 544.
[0836] Part D: To a solution of the acid of part C (415 g, <0.64 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol), 4-methylmorpholine (0.35 mL, 3.20 mmol), and O-tetrahydropyranyl hydroxylamine (112 mg, 0.96 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (9 mg, 2%). MS(CI) MH+ calculated for C33H46N4O7S: 643, found 643.
[0837] Part E: To a solution of the protected hydroxamate of part D (9 mg, 0.014 mmol) in dioxane (1 mL) was added 4M hydrochloric acid in dioxane (1 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (2.5 mg, 30%). MS(CI) MH+ calculated for C28H34N4O6S: 559, found 559.
EXAMPLE 248 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride[0838] 4018
[0839] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, 4-(trifluoromethoxy)aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.16 g, 93%).
[0840] Part B: To a solution of the amide of part A (1.16 g, 2.99 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII,
[0841] Part A (743 mg, 1.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.26 g, 6.90 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.38 g, quantitative yield). MS(CI) MH+ calculated for C30H38N3O7SF3: 642, found 642.
[0842] Part C: To a solution of the phenylamine of part B (1.38 g, 2.00 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL), and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (536 g, 41%). MS(CI) MH+ calculated for C28H34N3O7SF3: 614, found 614.
[0843] Part D: To a solution of the acid of part C (536 g, 0.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (134 mg, 0.99 mmol), 4-methylmorpholine (0.46 mL, 4.15 mmol), and O-tetrahydropyranyl hydroxylamine (145 mg, 1.24 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (287 mg, 48%). MS(CI) MH+ calculated for C33H43N4O8SF3: 713, found 713.
[0844] Part E: To a solution of the protected hydroxamate of part D (280 mg, 0.39 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (228 mg, 88%). MS(CI) MH+ calculated for C28H35N4O7SF3: 629, found 629.
EXAMPLE 249 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[[3-(trifluoro-methoxy)phenyl]amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride[0845] 4019
[0846] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was ,added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours 3-(trifluoromethoxy)-aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.20 g, 97%).
[0847] Part B: To a solution of the amide of part A (1.20 g, 3.10 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII, Part A, (770 mg, 2.06 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.34 g, 7.21 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.72 g, quantitative yield). MS(CI) MH+ calculated for C30H38N3O7SF3: 642, found 642.
[0848] Part C: To a solution of the phenylamine of part B (1.72 g, <2.06 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (824 mg, 20.6 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the acid as a crude brown oil which was used in the next step without additional purification.
[0849] Part D: To a solution of the acid of part C (<2.06 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (334 mg, 2.47 mmol), 4-methylmorpholine (1.13 mL, 10.3 mmol), and O-tetrahydropyranyl hydroxylamine (361 mg, 3.09 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (64 mg, 4% for 2 steps). MS(CI) MH+ calculated for C33H43N4O8SF3: 713, found 713.
[0850] Part E: To a solution of the protected hydroxamate of part-D (63 mg, 0.089 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (48 mg, 81%). MS(CI) MH+ calculated for C28H35N4O7SF3: 629, found 629.
EXAMPLE 250 Preparation of 1-(2-ethoxyethyl)-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride[0851] 4020
[0852] Part A: To a solution of the product of Preparative Example II, Part D, (1.0 g, 2.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl ethyl ether (0.33 mL, 2.87 mmol) and the solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the ethoxyl ethyl amine as a light yellow gel (0.68 g, 65.4%).
[0853] Part B: To a solution of ethoxyl ethyl amine (0.68 g, 1.56 mmol) of part A and powdered potassium carbonate (0.43 g, 3.1 mmol) in N,N-dimethylformamide (5 mL) was added 4-(trifluoromethoxy)phenol (0.4 mL, 3.08 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the desired trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (1.0 g, quantitative).
[0854] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (1.0 g, 1.72 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydroxide (0.688 g, 17.2 mmol) in water (4 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitate provided the acid as a white solid (0.94 g, quantitative yield).
[0855] Part D: To a solution of the acid of part C (0.94 g, 1.86 mmol), N-methyl morpholine (0.61 mL, 5.55 mmol), 1-hydroxybenzotriazole (0.76 g, 5.59 mmol) and O-tetrahydropyranyl hydroxylamine (0.33 g, 2.7 mmol) in N,N-dimethylformamide (40 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.06 g, 5.59 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.74 g, 66.1%).
[0856] Part E: To a solution of 4N hydrochloric acid (3 mL, 12 mmol)) in dioxane was added a solution of the tetrahydropyranyl amide of part D (0.74 g, 1.2 mmol) in methanol (0.4 ml) and dioxane (1.2 mL) and was stirred at ambient temperature for 3 hours. Filtration of precipitation gave the title compound as white solid (0.217 g, 32.9%). Analytical calculation for C22H25N2O7SF3.HCl.0.5H2O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
EXAMPLE 251 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide monomethane-sulfonate (salt)[0857] 4021
[0858] Part A: To the ethanol solution of the product of Preparative Example VII, Part D, (0.3 g, 0.5 mmol) was added methane sulfonic acid (0.042 mL, 0.65 mmol). After two hours stirring at room temperature the solution was cooled to zero degree Celsius. Filtration of the precipitate gave the title compound as a white crystalline solid (0.105 g, 35%). Analytical calculation for C22H25N2O7SF3. CH4O3S. H2O: C, 43.67; H, 4.94; N, 4.43. Found: C, 43.96; H, 4.62; N, 4.47.
EXAMPLE 252 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide[0859] 4022
[0860] Part A: The title compound of Preparative Example VII (15 g, 27 mmol) was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, water, brine and dried over magnesium sulfate. Concentration in vacuo and recrystallization from hot toluene gave the title compound as white crystals (13.14 g, 93.9%). Analytical calculation for C22H25N2O7SF3: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Found: C, 51.33; H, 5.11; N, 5.29; S, 6.50.
EXAMPLE 253 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methyl-benzenesulfonate) (salt)[0861] 4023
[0862] Part A: To the ethanol solution of Preparative Example VII (8 g, 13.32 mmol) was added p-toluenesulfonic acid (2.9 g, 15.24 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as white crystals (6.58 g, 71.8%). Analytical calculation for C22H25N2O7SF3.C7H8SO3: C, 50.43; H, 4.82; N, 4.06; S, 9.28. Found: C, 50.36; H, 4.95; N, 4.00; S, 9.47.
EXAMPLE 254 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide sulfate (2:1) (salt)[0863] 4024
[0864] Part A: To a solution of Preparative Example VII (0.35 g, 0.58 mmol) in ethanol (1.5 mL) was added sulfuric acid (17 ?L, 0.32 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of solvent and recrystallization from hot acetonitrile gave the title compound as a white powder (180 mg, 54.6%). Analytical calculation for C22H25N2O7SF3.0.7H2SO4: C, 45.00; H, 4.53; N, 4.77; S, 9.28. Found: C, 44.77; H, 4.97; N, 4.41; S, 9.19.
EXAMPLE 255 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (1:1) (salt)[0865] 4025
[0866] Part A: To the ethyl acetate solution (4 mL) of Example 252 (0.5 g, 0.9 mmol) was added concentrated phosphoric acid (85%, 0.1248 g, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white powder (0.4917 g, 82.7%). Analytical calculation for C22H25N2O7SF3.H3PO4.H2O: C, 41.64; H, 4.77; N, 4.42. Found: C, 41.14; H, 4.64; N, 4.25.
EXAMPLE 256 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monoacetate (salt)[0867] 4026
[0868] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added concentrated acetic acid (63.7 mg, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethyl acetate gave the title compound as a white crystalline solid (0.4635 g, 83.0%). Analytical calculation for C22H25N2O7SF3.0.7C2H4O2: C, 50.14; H, 5.00; N, 5.00; S, 5.72. Found: C, 50.47; H, 5.09; N, 5.00; S, 6.13.
EXAMPLE 257 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide 2-hydroxy-1,2,3-propanetri-carboxylate (3:1) (salt)[0869] 4027
[0870] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added citric acid (41 mg, 0.21 mmol) and the solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white crystalline solid (0.181 g, 53.7%). Analytical calculation for C22H25N2O7SF3.(⅓)C6H9O7. 0.9H2O: C, 48.34; H, 4.99; N, 4.70; S, 5.38. Found: C, 48.42; H, 4.99; N, 4.70; S, 5.38.
EXAMPLE 258 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monobenzenesulfonate (salt)[0871] 4028
[0872] Part A: To a solution of Preparative Example VII, Part D (0.4 g, 0.66 mmol) in ethanol (2.5 mL) was added benzene sulfonic acid (0.11 g, 0.69 mmol) and the solution was stirred at ambient temperature for 3 hours. Evaporation of the solvent and recrystallization from hot ethanol at minus 20 degrees Celsius gave the title compound as white crystals (0.28 g, 64.3%). Analytical calculation for C22H25N207SF3.C6H6SO3.0.2H2O: C, 49.44; H, 4.65; N, 4.12; S, 9.43. Found: C, 49.18; H, 4.67; N, 4.08; S, 9.75.
EXAMPLE 259 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide (2R,3R)-2,3-dihydroxy-butanedioate (2:1) (salt)[0873] 4029
[0874] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added tartaric acid (48 mg, 0.3 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.2 g, 58.3%). Analytical calculation for C22H25N2O7SF3.0.5C4H6O6. 1.25H2O: C, 46.79; H, 4.99; N, 4.55; S, 5.20. Found: C, 47.17; H, 5.20; N, 4.07; S, 5.03
Example 260 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (3:1) (salt)[0875] 4030
[0876] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added phosphoric acid (37 mg, 0.32 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.312 g, 59%). Analytical calculation for C22H25N207SF3.0.33H3PO4. 0.5H2O: C, 47.18; H, 4.86; N, 5.00. Found: C, 47.15; H, 4.73; N, 4.90.
EXAMPLE 261 Preparation of N-hydroxy-1-[2-(1H-imidazol-1-yl)ethyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride[0877] 4031
[0878] Part A: The aryl ether from Example 230, Part B (3.12 g, 5.2 mmol) was dissolved in absolute methanol (50 mL). Acetyl chloride (2.1 mL, 30 mmol) was added over 1 minute. The reaction was stirred for 4 hours, concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo, affording the desired hydroxyethyl compound as a white solid (2.75 g, 96%). The desired hydroxyethyl product was characterized by NMR spectroscopy.
[0879] Part B: To the dichloromethane solution of the hydroxyethyl compound of Part A (1 g, 1.9 mmol) was added thionyl chloride (3.8 mmol) and reaction solution was stirred at ambient temperature for 12 hours. Concentration in vacuo provided the chloride as a light yellow gel. To the solution of the chloride and potassium carbonate (0.54 g, 3.8 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (0.4 g, 5.7 mmol) and solution was stirred at ambient temperature for 12 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the imidazole ethyl ester as a light yellow gel (0.82 g, 75.2%).
[0880] Part C: To a solution of imidazole ethyl ester of part A (0.82 g, 1.44 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.57 g, 14.4 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic-acid, N-methyl morpholine (0.62 mL, 5.7 mmol), 1-hydroxybenzotriazole (0.59 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.83 g, 5.7 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.27 g, 29.7%).
[0881] Part D: To a solution of 4N hydrochloric acid in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part B (0.27 g, 0.45 mmol) in methanol (1 ml) and 1,4-dioxane (3 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and trituration with ethyl ether gave the title compound as a white solid (0.179 g, 67%). Analytical calculation for C24H25N4O6SF3.2HCl.1.25H2O: C, 44.35; H, 4.57; N, 8.62. Found: C, 44.57; H, 4.36; N, 7.95.
EXAMPLE 262 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide trihydrochloride[0882] 4032
[0883] Part A: To a solution of the product of Preparative Example II, Part D, (1.5 g, 3.6 mmol) and powdered potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (10 mL) was added 4-(1,2,4-triazole-1-yl)phenol (0.87 g, 5.4 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 32 hours. Solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the N-Boc diaryl ether as a light yellow gel (0.907 g, 44.5%).
[0884] Part B: To a solution of N-Boc diaryl ether of part A (0.907 g, 1.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.44 g, 3.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl methyl ether (0.36 mL, 3.8 mmol) and solution was stirred at ambient temperature for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the methoxyl ethyl amine as a light yellow gel (0.82 g, 91%).
[0885] Part C: To a solution of the methoxyl ethyl amine of part B (0.80 g, 1.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.56 g, 14 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue until the pH=1 and concentration in vacuo gave the carboxylic acid as product. To a solution of the carboxylic acid, N-methyl morpholine (0.92 mL, 8.4 mmol), 1-hydroxybenzotriazole (0.57 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.80 g, 4.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.39 g, 47.6%).
[0886] Part D: To a solution of 4N hydrochloric acid in dioxane (1.6 mL, 6.4 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.39 g, 0.66 mmol) in methanol (2 ml) and dioxane (6 mL) and was stirred at ambient temperature for 3 hours. Evaporation of the solvent and trituration with ethyl ether gave the title compound as a white solid (0.34 g, 83%). ESI MS calculated for C23H27N5O6S: 501, found 501.
EXAMPLE 263 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride[0887] 4033
[0888] Part A: To a methanol solution of the product of Example 253 (1.0 g, 1.4 mmol) and 20% palladium on carbon (1.5 g) was added ammonium formate (2.4 g, 38 mmol) and reaction solution was heated to reflux for 72 hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on a C-18 reverse phase column eluting with acetonitrile/water with hydrochloric acid provided the title compound as a white powder (181 mg, 23.2%). Analytical calculation for C22H25N2O6SF3.HCl: C, 49.03; H, 4.86; N, 5.20. Found: C, 48.80; H, 4.93; N, 5.29.
EXAMPLE 264 Preparation of N-hydroxy-1-[3-(4-morpholinyl)propyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide dihydrochloride[0889] 4034
[0890] Part A: To a solution of the product of Preparative Example II, Part D, (15 g, 36 mmol) and powdered potassium carbonate (10 g, 72 mmol) in N,N-dimethylformamide (200 mL) was added 4-(trifluoromethoxy)phenol (19.3 mL, 72 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (20 g, quantitative).
[0891] Part B: To a solution of trifluoromethoxyl phenoxyphenyl sulfone (1.0 g, 1.75 mmol) of part A in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.48 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added morpholino propyl chloride (0.68 g, 3.5 mmol) and solution was stirred at 40 degree Celsius for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the morpholino propyl amine as a light yellow gel (1 g, quantitative yield).
[0892] Part C: To a solution of morpholino propyl amine of part B (1 g, 1.6 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.67 g, 16 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic acid, N-methyl morpholine (0.18 mL, 4.8 mmol), 1-hydroxybenzotriazole (0.45 g, 3.2 mmol) and O-tetrahydropyranyl hydroxylamine (0.3 g, 2.5 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.64 g, 3.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.56 g, 50%).
[0893] Part D: To a solution of 4N hydrogen chloride in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.56 g, 0.83 mmol) in methanol (3 ml) and dioxane (8 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and tritration with ethyl ether gave the title compound as a white solid (0.476 g, 86.5%). Analytical calculation for C26H32N3O7SF3.2HCl: C, 47.28; H, 5.19; N, 6.36; S, 4.85. Found: C, 46.86; H, 5.35; N, 6.29; S, 5.09.
EXAMPLE 265 Preparation of N-hydroxy-1-(1H-imidazol-2-ylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy] phenyl]-sulfonyl]-4-piperidinecarboxamide dihydrochloride[0894] 4035
[0895] Part A: To a suspension of the hydrochloride salt from Preparative Example VIII, Part F, (0.988 g, 21.6 mmol) and 2-imidazolecarboxaldehyde (315 mg, 3.28 mmol) in methanol (5 mL) at room temperature was added borane-pyridine complex (0.41 mL, 3.28 mmol). After 18 hours the reaction was concentrated under a stream of nitrogen. Saturated aqueous sodium bicarbonate was then added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a residue which was purified on silica gel eluting with ammonia-saturated methanol/methylene chloride (3/97) to afford the desired 4(5)-imidazole derivative (1.04 g, 89.7%) as a yellow solid. MS MH+ calculated for C25H26N3O5SF3: 538, found 538.
[0896] Part B: A solution of sodium hydroxide (766 mg, 19.2 mmol) in water (5 mL) was added to a solution of the 4(5)-imidazole derivative of Part A (1.03 g, 1.92 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) and the resulting solution was stirred at ambient temperature for 66 hours. The solution was concentrated in vacuo to afford a residue which was treated with 2 N aqueous hydrochloric acid (14.4 mL, 28.8 mmol). Concentration afforded the desired carboxylic acid as a yellow foam which was used directly without purification.
[0897] Part C: To a solution of the carboxylic acid of
[0898] Part B in dimethylformamide (15 mL) was added sequentially N-methylmorpholine (1.16 g, 11.5 mmol), N-hydroxybenzotriazole (311 mg, 2.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (478 mg, 2.50 mmol), and O-tetrahydropyranyl hydroxylamine (303 mg, 2.6 mmol). After 16 hours at ambient temperature the reaction was warmed to 51 degrees Celsius for 2 hours and then concentrated in vacuo. Water was added and the mixture was extracted sequentially with ethyl acetate and with methylene chloride. The combined organic extracts were washed with brine and dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel eluting with ammonia-saturated methanol/methylene chloride (7/93) to afford the desired tetrahydropyranyl-protected hydroxamate (0.50 g, 43%) as an off-white foam. MS MH+calculated for C28H31F3N4O6S: 609, found 609.
[0899] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of part C (500 mg, 0.82 mmol) in methanol (1 mL) and 1,4-dioxane (5 mL) was added 4 N hydrogen chloride/dioxane (2.5 mL). After stirring at ambient temperature for 1 hours, the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (490 mg, quantitative yield). HRMS MH+ calculated for C23H23N4SO5F3: 525. Found: 525. MS MH+ calculated for C23H23F3N4O5S: 525, found 525.
EXAMPLE 266 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide[0900] 4036
[0901] To a solution of the product of Preparative Example IX (2.08 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8 and the solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40° C. for 48 hours to afford the title compound as a white solid (1.82 g, 94%). Analytical calculation for C22H23N2SF3O5:H2O, 52.50; H, 5.01; N, 5.57; S, 6.38. Found: C, 52.24; H, 4.65; N, 5.46; S, 6.75.
EXAMPLE 267 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate) (salt)[0902] 4037
[0903] To a solution of the product of Example 266 (550 mg, 1.10 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (240 mg, 1.26 mmol) and the reaction was then stirred for 3.5 hour. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (633 mg, 86%). Recrystallized from methanol/water afforded the title compound as analytically pure material. Analytical Calculation for C29H31N2S2F3O9: 51.78; H, 4.64; N, 4.16. Found: C, 51.44; H, 4.32; N, 4.18.
EXAMPLE 268 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)[0904] 4038
[0905] To a solution of the product of Example 266 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (82 &mgr;L) and the reaction was then stirred for 3.5 hours. Concentration in vacuo afforded the title compound as a solid (640 mg, 97%). Recrystallization from methanol afforded analytically pure title compound. Analytical Calculation for C23H27N2S2F3O9: 46.30; H, 4.56; N, 4.70, S, 10.75. Found: C, 46.10; H, 4.71; N, 4.65; S, 10.99.
EXAMPLE 269 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide[0906] 4039
[0907] To a solution of the product of Preparative Example X (2.15 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8. The solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40 degrees Celsius for 48 hours to afford the titled compound as a white solid (1.96 g, 98%). Analytical Calculation for C22H23N2SF3O5:2H2O: C, 51.26; H, 5.24; N, 5.44; S, 6.21. Found: C, 50.58; H, 4.72; N, 5.33; S, 6.04.
EXAMPLE 270 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate)(salt)[0908] 4040
[0909] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (248 mg, 1.26 mmol) and the solution was stirred for 3.5 hours. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (705 mg, 95%). Recrystallized from methanol afforded analytically pure material. Analytical Calculation for C29H31N2S2F308: C, 53.04; H, 4.76; N, 4.27; S, 9.77 Found: C, 52.94; H, 4.46; N, 4.30; S, 9.99.
EXAMPLE 271 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)[0910] 4041
[0911] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (79 &mgr;L) and the reaction was stirred for 3.5 hours. Concentration in vacuo gave the title compound as a solid (569 mg, 87%). Analytical Calculation for C23H27N2S2F308: C, 47.58; H, 4.69; N, 4.82. Found: C, 47.15; H, 4.18; N, 4.74.
EXAMPLE 272 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide[0912] 4042
[0913] Part A: To a solution of the product of Preparative Example II, Part D (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2-g, 200 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 g, quantitative yield).
[0914] Part B: To a solution of the diaryl sulfide from part A (24 g, 42.8 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (100 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5.0 and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (23.0 g, quantitative yield)
[0915] Part C: To a solution of carboxylic acid of part B (22.8 g, 43.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous Hydrogen chloride for 20 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (21.0 g, quantitative yield).
[0916] Part D: To a solution of the hydrochloride salt of part C (17.0 g, 35.0 mmol) in acetone (125 mL) and water (125 mL) was added triethyl amine (24 mL, 175 mmol). The reaction was cooled to zero degrees Celsius and acetyl chloride (3.73 mL, 53.0 mmol) was added. The solution was then stirred at ambient temperature for 18 hours. Concentration in vacuo gave a residue which was acidified with aqueous hydrochloric acid to pH 1.0 and then extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired methanesulfonamide as a white solid (17.0 g, quantitative yield).
[0917] Part E: To a solution of the methanesulfonamide of part D (14.4 g, 29.6 mmol) in dimethylformamide (250 mL) was added 1-hydroxybenzotriazole (4.8 g, 35.5 mmol), N-methyl morpholine (12.3 mL, 88.8 mmol) and O-tetrahydropyranyl hydroxylamine (5.2 g, 44.4 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (7.99 g, 41.4 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C18 reverse phase column eluting with acetonitrile/water provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (12.0 g, 71%).
[0918] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (12.0 g, 20.5 mmol) in dioxane (250 mL) and methanol (50 mL) was added 4 N hydrogen chloride/dioxane (51 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether and filtration provided the title compound as a white solid (8.84 g, 85%). HRMS MH+ calculated for C21H21N2SO7F3: 503502.1021. Found 502.0979.
EXAMPLE 273 Preparation of N-hydroxy-1-(methyl sulfonyl)-4-[[4-[4-sulfonyl]-(trifluoromethoxy) phenoxy] phenyl]-4-piperidinecarboxamide[0919] 4043
[0920] Part A: To a solution of the product of Preparative Example II, Part D, (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2 gm, 200.0 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 gm, quantitative yield).
[0921] Part B: To a solution of the diaryl sulfide from part A (21 g, 37.0 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (75 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=5.0, and then extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (19.3 g, 97%)
[0922] Part C: To a solution of carboxylic acid of part B (19.3 g, 37.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous hydrogen chloride for 30 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (15.8 g, 93%).
[0923] Part D: To a solution of the hydrochloride salt of part C (15.8 g, 33.0 mmol) in acetone (100 mL) and water (100 mL) was added triethyl amine (23 mL, 164 mmol). The reaction was cooled to zero degrees Celsius and methanesulfonyl chloride (5.1 mL, 66.0 mmol) was added. The solution was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo and acidified with aqueous hydrochloric acid to pH 1.0. The aqueous residue was extracted ethyl acetate. The organic extract was washed with water, saturated sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid methanesulfonamide as a white solid (17.6 gm, quantitative yield).
[0924] Part E: To a solution of the methanesulfonamide of part D (18 g, 35.0 mmol) in dimethylformamide (150 mL) was added 1-hydroxybenzotriazole (5.66 gm, 42.0 mmol), N-methyl morpholine (14.0 mL, 105.0 mmol) and O-tetrahydropyranyl hydroxylamine (6.1 g, 52 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (9.4 gm, 49.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C18 reverse phase column eluting with acetonitrile/water provided desired tetrahydropyranyl-protected hydroxamate as a white solid (8.17 g, 41%).
[0925] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (8.17 g, 13.0 mmol) in dioxane (100 mL) and methanol (100 mL) was added 4 N hydrogen chloride/dioxane (50 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (6.83 g, 92%). MS MH+ calculated for C20H21NS2O8F: 539. Found 539.
[0926] The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) procedures utilizing reactions such as acylation and nucleophilic displacement:
EXAMPLE 274[0927] 4044
EXAMPLE 275[0928] 4045
EXAMPLE 276[0929] 4046
EXAMPLES: 277-315[0930] 185 4047 MS (ES) Example R1R2NH Amine m/z 277 4048 Ethyl amine 592 (M + H) 278 4049 3-(Aminomethyl) pyridine 655 (M + H) 279 4050 Imidazole 615 (M + H) 280 4051 3-Amino-1-propanol 622 (M + H) 281 4052 Histamine 658 (M + H) 282 4053 2-Thiophene methyl amine 660 (M + H) 283 4054 Morpholine 634 (M + H) 284 4055 2-(Aminomethyl) pyridine 655 (M + H) 285 4056 4-(Aminomethyl) pyridine 655 (M + H) 286 4057 Ethanolamine 608 (M + H) 287 4058 N,N,N-Trimethyl ethylenediamine 649 (M + H) 288 4059 1-Methylpiperazine 647 (M + H) 289 4060 N,N-Dimethyl ethylenediamine 635 (M + H) 290 4061 Piperazine 633 (M + H) 291 4062 Thiomorpholine 650 (M + H) 292 4063 N-Propylcyclopropne methylamine 660 (M + H) 293 4064 (Aminomethyl) cyclopropane 618 (M + H) 294 4065 Dimethylamine 592 (M + H) 295 4066 Diethylamine 620 (M + H) 296 4067 Piperidine 632 (M + H) 297 4068 (R)-(−)-2- Pyrrolidine methanol 648 (M + H) 298 4069 Pyrrolidine 618 (M + H) 299 4070 1-(2-(2- Hydroxyethoxy) ethyl)piperazine 721 (M + H) 300 4071 Isonipecotamide 675 (M + H) 301 4072 2-(2-Aminoethoxy) ethanol 652 (M + H) 302 4073 3,3′-Iminobis(N,N- dimethylpropylamine) 734 (M + H) 303 4074 Bis(2-Methoxy ethyl)amine 680 (M + H) 304 4075 4-Hydroxy piperidine 648 (M + H) 305 4076 N-(Carboethoxy methylpiperazine 719 (M + H) 306 4077 1-(2-Morpholinoethyl) piperazine 746 (M + H) 307 4078 1-(2-Methoxyethyl) piperazine 691 (M + H) 308 4079 1-(2- Dimethylaminoethyl) piperazine 704 (M + H) 309 4080 2-Methoxyethylamine 622 (M + H) 310 4081 2,2,2-Trifluoroethyl amine 646 (M + H) 311 4082 1,2,4-Triazole 616 (M + H) 312 4083 Methoxyamine 594 (M + H) 313 4084 Ethyl isonipecotate 704 (M + H) 314 4085 2-Pyrrolidinone 632 (M + H) 315 4086 Isonipecotic acid 676 (M + H)
EXAMPLES: 316-332[0931] 186 Example R1R2NH Amine MS (ES) m/z 316 4087 3-(Aminomethyl) pyridine 593 (M + H) 317 4088 Imidazole 553 (M + H) 318 4089 Piperidine 570 (M + H) 319 4090 Morpholine 572 (M + H) 320 4091 2-(Aminomethyl) pyridine 593 (M + H) 321 4092 Ethanolamine 546 (M + H) 322 4093 2,2,2-Trifluoro ethylamine 584 (M + H) 323 4094 N,N,N-Trimethyl ethylenediamine 587 (M + H) 324 4095 1-Methylpiperazine 585 (M + H) 325 4096 4-(Aminomethyl) pyridine 593 (M + H) 326 4097 Pyrrolidine 556 (M + H) 327 4098 Bis(2-Methoxy ethyl)amine 618 (M + H) 328 4099 Piperazine 571 (M + H) 329 4100 4-(Ethylamino methyl)pyridine 621 (M + H) 330 4101 1-(2-Methoxy ethyl)pyridine 629 (M + H) 331 4102 N- Propylcyclopropane methylamine 598 (M + H) 332 4103 2-Methoxyethylamine 560 (M + H)
EXAMPLES: 333-347[0932] 187 Example R1R2NH Amine MS (ES) m/z 333 4104 3-(Aminomethyl) pyridine 635 (M + H) 334 4105 Piperidine 612 (M + H) 335 4106 Morpholine 614 (M + H) 336 4107 2-(Aminomethyl) pyridine 635 (M + H) 337 4108 Ethanolamine 588 (M + H) 338 4109 N,N,N-Trimethyl ethylenediamine 629 (M + H) 339 4110 1-Methylpiperazine 627 (M + H) 340 4111 4-(Aminomethyl) pyridine 636 (M + H) 341 4112 Pyrrolidine 598 (M + H) 342 4113 Bis(2-Methoxy ethyl)amine 660 (M + H) 343 4114 Piperazine 613 (M + H) 344 4115 4-(Ethylamino methyl)pyridine 663 (M + H) 345 4116 1-(2-Methoxy ethyl)pyridine 671 (M + H) 346 4117 N-Propylcyclopropane methylamine 640 (M + H) 347 4118 2-Methoxyethylamine 602 (M + H)
EXAMPLES 348-942[0933] The following compounds were prepared in a manner similar to that used in the preceding examples. In the tables that follow, a generic structure is shown above the table with substituent groups being illustrated in the table along with available mass spectral data. 188 4119 Example R K MS (ES) m/z 348 4120 4121 349 4122 4123 499.1131 350 4124 4125 583 351 4126 4127 580.1366 352 4128 4129 538.1282 353 4130 4131 610 354 4132 4133 355 4134 4135 648 356 4136 4137 357 4138 4139 610 358 4140 4141 359 4142 4143 648 360 4144 4145 361 4146 4147 616 362 4148 4149 614 363 4150 4151 616 364 4152 4153 648 365 4154 4155 614 366 4156 4157 648 367 4158 4159 368 4160 4161 369 4162 4163 370 4164 4165 371 4166 4167 372 4168 4169 539.1201 373 4170 4171 374 4172 4173 567.1120 375 4174 4175 590.1174 376 4176 4177 378 4178 4179 474.1567 379 4180 4181 555 380 4182 4183 537.1412 381 4184 4185 523 382 4186 4187 383 4188 4189 384 4190 4191 547.1279 385 4192 4193 386 4194 4195 555.1516 387 4196 4197 607.1061 388 4198 4199 389 4200 4201 516 390 4202 4203 539 391 4204 4205 538.1272 392 4206 4207 538.1252 393 4208 4209 394 4210 4211 395 4212 4213 522.1351 396 4214 4215 582.2245 397 4216 4217 532.2280 398 4218 4219 399 4220 4221 528 400 4222 4223 401 4224 4225 515.3344 402 4226 4227 582.2266 403 4228 4229 404 4230 4231 550 405 4232 4233 550 406 4234 4235 555 407 4236 4237 408 4238 4239 600.2162 409 4240 4241 548 410 4242 4243 411 4244 4245 412 4246 4247 502 413 4248 4249 529 414 4250 4251 600.2141 415 4252 4253 600 416 4254 4255 489 417 4256 4257 530 418 4258 4259 598.2200 419 4260 4261 548.2013 420 4262 4263 569.2259 421 4264 4265 570.2186 422 4266 4267 635.2185 423 4268 4269 636.2104 424 4270 4271 586.2059 425 4272 4273 562.1957 426 4274 4275 585.1968 427 4276 4277 586.1936 428 4278 4279 637.2137 429 4280 4281 638.2072 430 4282 4283 637.2146 431 4284 4285 638.2075 432 4286 4287 602.1731 433 4288 4289 654.1921 434 4290 4291 654.1932 435 4292 4293 636 436 4294 4295 596 437 4296 —H 502 438 4297 4298 579 439 4299 4300 411.1211 440 4301 4302 480 441 4303 4304 542 442 4305 4306 540 443 4307 —H 440 444 4308 4309 518 445 4310 4311 566 446 4312 4313 618 447 4314 4315 616 448 4316 4317 550.2387 449 4318 4319 616 450 4320 4321 451 4322 4323 580.1370 452 4324 4325 453 4326 4327 454 4328 4329 614 455 4330 4331 456 456 4332 4333 585 457 4334 4335 463 458 4336 4337 549 459 4338 4339 532 460 4340 —H 574 461 4341 4342 564 462 4343 4344 616 463 4345 4346 598 464 4347 4348 514
[0934] 189 4349 Example R MS (ES) m/z 465 4350 505.1746 466 4351 551 (+Na) 467 4352 468 4353 463.1704 469 4354 486 470 4355 503 471 4356 537 472 4357 533.2348 473 4358 499.2304 474 4359 504 475 4360 476 4361 532.2522 477 4362 478 4363 479 4364 539.0842 480 4365 545.1595 481 4366 574.1483 482 4367 503.2238 483 4368 515.2234 484 4369 417 485 4370 475.1910 486 4371 383 487 4372 460 488 4373 438 489 4374 452 490 4375 474 491 4376 476 492 4377 383 493 4378 472 494 4379 472 495 4380 383 496 4381 383 497 4382 517 498 4383 499 4384 503 500 4385 521 501 4386 571 502 4387 571 503 4388 571 504 4389 489.2059 505 4390 507.1987 506 4391 557 507 4392 557 508 4393 557 509 4394 503.2226 510 4395 521.2122 511 4396 571.2056 512 4397 571.2054 513 4398 571.1464 514 4399 379.0964 515 4400 504.1831 516 4401 532.2105 517 4402 470.1935 518 4403 576.2355 519 4404 596.2033 520 4405 518.1945 521 4406 538.1372 522 4407 519 523 4408 560 524 4409 399 525 4410 413 526 4411 493 527 4412 581 528 4413 343.1742 529 4414 399.1597 530 4415 483 531 4416 501 532 4417 551 533 4418 407 534 4419 515 535 4420 460 536 4421 460 537 4422 464 538 4423 460 539 4424 412 540 4425 495.4984 541 4426 479.1416 542 4427 572.2800 543 4428 539.2017 544 4429 489.2049 545 4430 497 546 4431 506 547 4432 479 548 4433 524 549 4434 542 550 4435 520 551 4436 520 552 4437 506 553 4438 476 554 4439 547.2525 555 4440 561.2692 556 4441 561.2679 557 4442 576.2184 558 4443 511.1755 559 4444 500.1830 560 4445 500.1888 561 4446 577.1650 562 4447 413.1750 563 4448 427.1903 564 4449 385.1457 565 4450 637.2067 566 4451 532.2448 567 4452 529.1631 568 4453 529.1603 569 4454 574.1478 570 4455 597.0849 571 4456 574.1473 572 4457 513.1228 573 4458 509.1536 574 4459 509.1529 575 4460 493.1803 576 4461 493.1838 577 4462 476.1847 578 4463 476.1865 579 4464 553.1057 580 4465 476.1879 581 4466 489.2076 582 4467 507.2016 583 4468 584 4469 585 4470 415.1559 586 4471 401.1399 587 4472 443 588 4473 477 589 4474 515 590 4475 538 591 4476 452 592 4477 466 593 4478 472 594 4479 502 595 4480 556 596 4481 457 597 4482 598 4483 415.1911 599 4484 471 600 4485 575.2777 601 4486 575 602 4487 589.2947 603 4488 589.2914 604 4489 601.2936 605 4490 587.2808 606 4491 551.2225 607 4492 587.2048 608 4493 619.2098 609 4494 687.1978 610 4495 857.2070 611 4496 719.2024 612 4497 401.1746 613 4498 581.2323 614 4499 511.1900 615 4500 495.1368 616 4501 521.1980 617 4502 529.0962 618 4503 505.2031 619 4504 475.1898 620 4505 529.1604 621 4506 456.1761 622 4507 398.1751 623 4508 414.1690 624 4509 434.1651 629 4510 510 634 4511 483.1992 635 4512 425 636 4513 507.1910 637 4514 489.2064 638 4515 511.1910 639 4516 521.1962 640 4517 505.2006 641 4518 513.1277 642 4519 517.2410 643 4520 519.2190 644 4521 505 645 4522 428.1821 646 4523 428 647 4524 503 648 4525 506.1830 649 4526 524 650 4527 524.1531 651 4528 490.1912 652 4529 487 653 4530 487 654 4531 491 655 4532 503 656 4533 473 658 4534 659 4535 665 4536 510.1353 666 4537 541.1815 667 4538 475 668 4539 510.1366 669 4540 510.1358 670 4541 671 4542 524 672 4543 535 673 4544 594 674 4545 524 675 4546 578 676 4547 578 677 4548 578 678 4549 540 679 4550 594 680 4551 555 681 4552 528 682 4553 528 683 4554 570 684 4555 514 685 4556 516 686 4557 384.1593 688 4558 527.1658 (M + NH4) 690 4559 535 691 4560 568 692 4561 423.1946 693 4562 441.2080 694 4563 506.1857 695 4564 530.1565 696 4565 540 697 4566 592.1401 698 4567 554.1659 699 4568 608.1355 706 4569 490.1929 707 4570 491 708 4571 714 4572 560.1568 720 4573 459.1987 721 4574 508.2019 722 4575 480.1700 723 4576 441.2053 724 4577 509 725 4578 557 726 4579 557 727 4580 541 728 4581 491 729 4582 541 730 4583 501 731 4584 509 732 4585 501 733 4586 501 734 4587 517 735 4588 521 736 4589 505 737 4590 501 738 4591 559 740 4592 741 4593 752 4594 572 755 4595 467 756 4596 453 757 4597 453 758 4598 451 759 4599 451 760 4600 488 761 4601 451 781 4602 444 782 4603 444 784 4604 786 4605 499 787 4606 499 788 4607 515 789 4608 529 790 4609 516 791 4610 517 793 4611 794 4612 796 4613 517 797 4614 798 4615 799 4616 802 4617 807 4618 811 4619 815 4620 816 4621 822 4622 823 4623 825 4624 826 4625 827 4626 828 4627 829 4628 830 4629 831 4630 832 4631 833 4632 834 4633 835 4634 836 4635 838 4636 841 4637 842 4638 844 4639 845 4640 846 4641 847 4642 848 4643 850 4644 851 4645 852 4646 853 4647 854 4648 856 4649 857 4650 858 4651 859 4652 860 4653 861 4654 862 4655 863 4656 864 4657 867 4658 868 4659 869 4660 872 4661 873 4662 877 4663 878 4664 881 4665 882 4666 883 4667 884 4668 885 4669 886 4670 887 4671 888 4672 889 4673 890 4674 891 4675 892 4676 893 4677 894 4678 895 4679 899 4680 901 4681 902 4682 905 4683 906 4684 909 4685 910 4686 911 4687 912 4688 913 4689 914 4690 915 4691 916 4692 920 4693 921 4694 922 4695 924 4696 926 4697 931 4698 932 4699 939 4700
[0935] 190 4701 Example R K MS 940 4702 4703 941 4704 4705 942 4706 4707
Example 943 In Vitro Metalloprotease Inhibition[0936] The compounds prepared in the manner described in the Examples above were assayed for activity by an in vitro assay. Following the procedures of Knight et al., FEBS Lett. 296(3):263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of the inhibitor compound at room temperature for 5 minutes.
[0937] More specifically, recombinant human
[0938] MMP-13, MMP-1, MMP-2 and MMP-9 enzymes were prepared in laboratories of the assignee following usual laboratory procedures. MMP-13 from a full length cDNA clone was expressed as a proenzyme using a baculovirus as discussed in V. A. Luckow, Insect Cell Expression Technology, pages 183-218, in Protein Engineering: Principles and Practice, J. L. Cleland et al eds., Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol., 67:4566-4579 (1993); .O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, W. H. Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman & Hall, London (1992) for further details on use of baculovirus expression systems. The expressed enzyme was purified first over a heparin agarose column and then over a chelating zinc chloride column. The proenzyme was activated by APMA for use in the assay.
[0939] MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of Washington University, St. Louis, Mo. The enzyme was also activated using APMA and was then purified over a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells that expressed MMP-9. Transfected cells that expressed MMP-2 were provided by Dr. Gregory Goldberg, also of Washington University. Studies carried out using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below with an asterisk. Studies with MMP-7 were carried out at pH 7.5 in the presence of 0.02% 2-mercaptoethanol using conditions otherwise similar to those used for the other enzymes. The enzyme was obtaind from a hMMP-7-expressing E. coli clone that was a gift of Dr. Steven Shapiro of Washington University, St. Louis, Mo. Further specifics for preparation and use of these enzymes can be found in the scientific literature describing these enzymes. See, for example, Enzyme Nomenclature, Academic Press, San Diego, Calif. (1992) and the citations therein, and Frije et al., J. Biol. Chem., 26(24): 16766-16773 (1994). The enzyme substrate is a methoxycoumarin-containing polypeptide having the following sequence:
[0940] MCA-ProLeuGlyLeuDpaAlaArgNH2, wherein MCA is methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.
[0941] The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl2 and 0.05 percent polyethyleneglycol (23) lauryl ether at a pH value of 7.5. Assays were carried out at room temperature, and dimethyl sulfoxide (DMSO) at a final concentration of 1 percent was used to dissolve inhibitor compound.
[0942] The assayed inhibitor compound in
[0943] DMSO/buffer solution was compared to an equal amount of DMSO/buffer with no inhibitor as control using Microfluor White Plates (Dynatech). The inhibitor or control solution was maintained in the plate for 10 minutes and the substrate was added to provide a final concentration of 4 &mgr;M.
[0944] In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescence intensity (excitation at 328 nm/emission at 415 nm). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration, using a Perkin Elmer L550 plate reader. The IC50 values were calculated from those values. The results are set forth in the Inhibition Table A, below, reported in terms of IC50 to three significant figures, where appropriate. 191 Inhibition Table A (nM) Example MMP-13 MMP-2 MMP-1 Number IC50(nM) IC50(nM) IC50(nM) 1 22.7 8.5 >10,000 2 5,500 6,000 >10,000 8 15.6 2,900 >10,000 9 15.6 2,900 >10,000 10 18.1 >10,000 >10,000 11 18.0 4,500 >10,000 12 50.0 2,500 >10,000 13 12.2 5,600 >10,000 14 40.0 6,000 >10,000 15 37.0 2,700 >10,000 16 6.70 1,400 >10,000 17 31.6 3,500 >10,000 18 45.0 >10,000 >10,000 19 28.0 5,500 >10,000 20 42.5 4,800 >10,000 21 70.0 7,000 >10,000 22 >10,000 >10,000 >10,000 23 90.0 10,000 >10,000 24 23.5 4,500 >10,000 25 6.00 1,600 >10,000 26 10.7 3,600 >10,000 27 6.40 1,600 >10,000 28 6.70 700 >10,000 29 4.00 445 >10,000 32 10.0 800 >10,000 33 20.0 4,500 >10,000 34 18.1 >10,000 >10,000 35 30.0 9,000 >10,000 36 15.8 2,100 >10,000 37 30.0 1,750 >10,000 38 67.4 6,000 67.4 39 19.3 3,700 >10,000 40 26.8 900 >10,000 41 70.0 5,400 >10,000 42 82.5 >10,000 >10,000 43 17.9 5,000 >10,000 44 19.0 1,050 >10,000 45 360 5,000 >10,000 46 80.0 5,700 >10,000 47 11.4 6,000 >10,000 48 27.0 3,200 >10,000 49 20.0 6,500 >10,000 51 370 7,000 >10,000 52 90.0 1,900 >10,000 53 28.9 1,400 >10,000 54 40.0 5,700 >10,000 55 10.0 >10,000 >10,000 56 55.0 3,500 >10,000 57 80.0 2,700 >10,000 58 22.0 4,000 >10,000 59 4.00 530 >10,000 60 13.9 3,700 >10,000 61 7.00 1,500 >10,000 62 14.0 690 >10,000 63 20.0 2,900 >10,000 64 19.3 770 >10,000 65 5.00 195 >10,000 66 8.00 240 >10,000 68 13.0 1,800 >10,000 69 18.1 3,500 >10,000 70 10.6 700 >10,000 71 7.70 270 >10,000 72 13.0 800 >10,000 73 15.4 2,000 >10,000 74 9.00 80.0 >10,000 75 11.5 500 >10,000 76 9.00 250 >10,000 77 75.0 3,400 >10,000 78 11.7 730 >10,000 79 20.0 2,000 >10,000 80 4.10 562 >10,000 81 60.0 158 >10,000 82 6.70 490 >10,000 83 2.70 21.1 3,100 84 28.6 1,400 >10,000 85 130 370 >10,000 86 0.6 12.1 >10,000 87 4.00 15.5 >10,000 88 9.00 40.0 >10,000 91 0.3 <0.1 >10,000 92 0.8 0.1 >10,000 95 0.3 <0.1 3,600 96 0.4 0.1 7,300 97 0.6 <0.1 >10,000 98 1.70 0.2 >10,000 99 1.00 <0.1 >10,000 100 0.5 <0.1 6,000 101 1.10 0.8 >10,000 102 0.6 0.2 >10,000 103 1.80 0.3 >10,000 104 0.25 0.2 10,000 105 1.10 0.3 10,000 106 0.2 0.15 >10,000 106 0.1 <0.1 8,200 108 0.2 <0.1 5,000 109 0.3 <0.1 >10,000 110 0.6 0.2 >10,000 111 0.8 0.15 >10,000 112 0.5 <0.1 >10,000 113 0.3 <0.1 >10,000 114 0.4 <0.1 >10,000 115 0.1 <0.1 >10,000 116 0.3 <0.1 >10,000 117 0.2 0.1 >10,000 118 0.2 <0.1 >10,000 119 0.3 0.3 >10,000 120 0.4 0.1 >10,000 121 0.2 0.1 5,000 122 0.2 <0.1 3,000 123 0.7 <0.1 >10,000 124 <0.1 <0.1 >10,000 125 0.4 <0.1 >10,000 126 0.7 <0.1 >10,000 127 2.90 0.2 >10,000 128 0.1 <0.1 3,400 129 37.2 3.00 >10,000 130 0.5 0.3 1,600 131 0.2 <0.1 8,000 132 0.5 <0.1 >10,000 133 1.40 0.3 >10,000 134 1.80 0.3 >10,000 135 0.6 0.3 10,000 136 0.9 <0.1 >10,000 137 0.8 0.1 10,000 138 3.90 0.25 >10,000 140 11.4 0.8 >10,000 141 20.0 9.00 >10,000 142 12.6 10.0 >10,000 143 22.0 14.5 >10,000 144 0.4 0.2 10,000 145 0.4 0.2 3,700 146 0.2 0.3 3,000 147 0.4 0.2 7,700 148 2.50 3.70 >10,000 149 15.8 13.8 480 150 175 175 >10,000 151 270 290 >10,000 152 2.00 59.0 >10,000 153 50.0 5,000 >10,000 154 18.0 3,700 >10,000 155 130 240 >10,000 156 2.20 0.45 >10,000 157 0.5 0.2 >10,000 160 300 90.0 >10,000 161 32.6 900 >10,000 162 27.8 7,000 >10,000 163 44.5 2,500 >10,000 164 3.50 440 >10,000 165 3.00 48.5 >10,000 166 32.7 240 >10,000 168 50.0 285 >10,000 169 20.0 175 >10,000 170 2.40 200 >10,000 171 5.40 186 >10,000 172 3.80 160 >10,000 173 6.70 330 3,400 174 23.5 800 >10,000 175 2.50 290 >10,000 176 4.00 250 >10,000 177 8.80 520 10,000 178 18.1 325 >10,000 179 20.6 170 >10,000 180 1.10 41.8 >10,000 181 190 2,300 >10,000 183 300 1,500 >10,000 184 480 1,500 >10,000 185 2.20 32.6 >10,000 187 10.0 600 >10,000 188 7.0 235 >10,000 189 7.00 235 >10,000 190 4.70 136 >10,000 191 3.50 25.1 >10,000 193 3.50 0.15 >10,000 194 0.3 <0.1 >7,300 195 1.00 0.2 >10,000 196 1.60 <0.1 >10,000 197 2.70 <0.1 >10,000 198 0.375 0.25 7,300 199 0.2 <0.1 3,000 200 0.2 <0.1 3,000 201 0.3 0.2 >10,000 202 0.4 0.2 >10,000 207 28.8 900 >10,000 208 110 1,000 >10,000 209 50.0 130 >10,000 210 5.40 4.50 4,000 211 11.4 1,200 >10,000 212 160 240 >10,000 213 1,400 2,700 >10,000 214 4,900 3,500 >10,000 224 <0.1 <0.1 4,500 225 180 41.8 >10,000 227 28.8 21.7 >10,000 228 2,448 2,000 >10,000 229 0.18 0.1 >10,000 231 0.2 0.1 >10,000 233 43.5 2,050 >10,000 235 235 5,300 >10,000 236 9.00 400 >10,000 237 13.0 1,900 >10,000 238 80.0 10,000 >10,000 239 9.00 8,300 >10,000 240 76.9 10,000 >10,000 241 4.80 >10,000 >10,000 242 42.5 1,500 >10,000 243 11.3 420 >10,000 244 67.4 4,400 >10,000 245 20.0 800 >10,000 246 32.7 2,700 >10,000 247 34.5 1,600 >10,000 248 2.29 270 >10,000 249 13.0 235 >10,000 251 <0.1 <0.1 5,840 252 <0.1 <0.1 3,933.33 253 <0.1, 3,400 <0.1 0.15 256 0.2 0.1 3,200 257 0.2 0.1 4,100 258 0.2 0.1 >10,000 260 0.1 <0.1 5,300 261 <0.1 <0.1 3,700 262 1.50 0.9 >10,000 264 0.2 <0.1 4,500 265 0.2 1.30, >10,000 <0.1 266 0.1 <0.1 5,500 267 0.2 0.15 10,000 268 <0.1, 4,000 <0.1 0.2 269 0.2 <0.1 >10,000 270 1.00 1.00 >10,000 271 0.3 0.17 >10,000 272 0.2 0.1 3,600 273 0.3 0.1 >10,000 274 160 >10,000 >10,000 275 70.0 >10,000 >10,000 276 37.3 >10,000 >10,000 277 70.0 >10,000 >10,000 278 19.3 >10,000 >10,000 279 20.0 7,300 >10,000 280 90.0 >10,000 >10,000 281 105 >10,000 >10,000 282 14.8 9,000 >10,000 283 13.8 >10,000 >10,000 284 130 >10,000 >10,000 285 19.3 9,000 >10,000 286 60.0 >10,000 >10,000 287 150 >10,000 >10,000 288 35.0 >10,000 >10,000 289 50.0 >10,000 >10,000 290 50.0 >10,000 >10,000 292 100 >10,000 >10,000 293 63.1 >10,000 >10,000 294 59.1 >10,000 >1,000 295 50.0 >10,000 >10,000 296 50.0 >10,000 >10,000 297 34.9 >10,000 >10,000 298 40.0 >10,000 >10,000 299 30.6 9,000 >10,000 300 37.3 >10,000 >10,000 301 90.0 >10,000 >10,000 302 175 >10,000 >10,000 303 115 >10,000 >10,000 304 30.6 7,000 >10,000 305 28.6 >10,000 >10,000 306 60.0 >10,000 >10,000 307 40.0 >10,000 >10,000 308 40.0 10,000 >10,000 309 48.5 >10,000 >10,000 310 60.0 10,000 >10,000 311 120 >10,000 >10,000 312 200 >10,000 >10,000 313 77.0 >10,000 >10,000 314 65.0 >10,000 >10,000 315 420 >10,000 >10,000 316 0.4 0.2 >10,000 317 1.40 0.4 >10,000 318 0.3 0.1 >10,000 319 0.5 0.2 >10,000 320 12.1 4.00 >10,000 321 0.5 0.3 >10,000 322 0.3 0.3 >10,000 323 1.30 0.4 >10,000 324 0.7 0.4 >10,000 325 0.9 0.2 >10,000 326 0.6 0.45 >10,000 327 0.9 0.3 >10,000 328 0.35 0.4 >10,000 329 0.9 0.4 >10,000 330 0.5 0.7 >10,000 331 0.7 0.2 >10,000 332 2.10 0.4 >10,000 333 0.8 0.2 >10,000 334 0.7 0.3 >10,000 335 0.9 0.15 >10,000 336 1.00 <0.1 >10,000 337 2.70 0.2 >10,000 338 1.90 0.2 >10,000 339 1.00 0.3 >10,000 340 0.3 <0.1 >10,000 341 0.6 0.2 >10,000 342 4.00 0.3 >10,000 343 1.70 0.8 >10,000 344 2.90 0.65 >10,000 346 1.20 0.2 >10,000 347 3.00 0.7 >10,000 348 16.5 0.8 >10,000 349 0.2 <0.1 2600 350 0.1 <0.1 6000 351 — — — 352 1.4 0.3 >10,000 353 0.3 <0.1 >10,000 354 1.6 15.4 355 0.4 <0.1 7000 356 2.4 32.6 357 0.3 0.1 >10,000 358 — — — 359 34.9 12.2 >10,000 360 10.0 5.6 361 0.5 <0.1 5000 362 2.7 <0.1 >10,000 363 0.4 0.2 8800 364 1.0 0.2 >10,000 365 0.3 0.1 >10,000 366 13.0 2.5 >10,000 367 — — — 368 0.5 7.0 369 3.3 5.4 370 371 11.1 400 372 — — — 373 3.0 80.0 374 3.3 4.0 >10,000 375 16.9 15.6 >10,000 376 5.5 230 378 1.7 0.3 200 379 0.3 0.1 >10,000 380 — — — 381 — — — 382 11.4 260 383 3.0 700 >10,000 384 — — — 385 — — — 386 0.4 0.2 2100 387 — — — 388 50.0 430 389 1.7 16.1 >10,000 390 — — — 391 0.1 <0.1 5400 392 0.2 0.1 >10,000 393 4.5 427 >10,000 394 0.5 8.0 395 0.9 0.5 >10,000 396 4.8 330 >10,000 397 4.4 70.0 >10,000 398 7.0 70.0 >10,000 399 1.2 0.3 >10,000 400 23.5 520 401 16.9 195 >10,000 402 15.8 340 >10,000 403 55.3 4.0 >10,000 404 0.5 0.25 >10,000 405 406 407 1.2 0.1 >10,000 408 25.1 800 >10,000 409 22.4 275 >10,000 410 0.6 0.25 >10,000 411 0.2 <0.1 >10,000 412 0.4 0.2 6400 413 1.1 0.3 8000 414 50.5 1500 >10,000 415 50.4 246 >10,000 416 0.4 0.2 3000 417 0.7 4.5 >10,000 418 7.0 1400 >10,000 419 4.2 400 >10,000 420 — — — 421 — — — 422 — — — 423 — — — 424 5.5 80.0 >10,000 425 20.0 1000 >10,000 426 — — — 427 — — — 428 — — — 429 — — — 430 — — — 431 — — — 432 13.9 100 >10,000 433 450 3500 >10,000 434 190 3700 >10,000 435 5.9 1500 >10,000 436 1.8 330 >10,000 437 18.1 800 >10,000 438 1.4 160 >10,000 439 1070 1600 >10,000 440 26.8 240 >10,000 441 6.0 420 >10,000 442 10.0 211 >10,000 443 90.0 2200 >10,000 444 — — — 445 90.0 1200 >10,000 446 270 7000 >10,000 447 23.9 155 >10,000 448 2.4 540 >10,000 449 — — — 450 — — — 451 0.3 0.1 3700 452 <0.1 <0.1 453 0.4 35.0 >10,000 454 2.1 100 >10,000 455 6.3 26.8 >10,000 456 — — — 457 1800 2700 >10,000 458 210 2100 >10,000 459 136 3100 >10,000 460 4.0 200 >10,000 461 20.0 145 >10,000 462 2.9 80.0 >10,000 463 16.9 210 >10,000 464 120 400 >10,000 465 80 370 >10,000 466 9.4 60 >10,000 467 27.0 140 >10,000 468 — — — 469 0.8 12.0 >10,000 470 140 2000 >10,000 471 2400 >10,000 >10,000 472 4.0 200 >10,000 473 160 3300 >10,000 474 12.1 300 >10,000 475 27.1 500 >10,000 476 25.4 140 >10,000 477 11.3 160 >10,000 478 16.4 306 >10,000 479 5.0 60.0 >10,000 480 18.6 155 >10,000 481 50.0 1400 >10,000 482 6.0 4.0 >10,000 483 32.6 10.6 >10,000 484 240 100 >10,000 485 8.0 4.2 >10,000 486 5400 4000 >10,000 487 140 800 >10,000 488 140 370 >10,000 489 770 1900 >10,000 490 61.0 3000 >10,000 491 >10,000 >10,000 >10,000 492 6100 >10,000 >10,000 493 >10,000 >10,000 >10,000 494 650 3300 >10,000 495 14.5 21.1 >10,000 496 30.7 200 >10,000 497 50.0 8000 >10,000 499 0.9 19.3 >10,000 500 3.0 22.0 >10,000 501 2.5 180 >10,000 502 14.0 63 >10,000 503 10.0 50.0 >10,000 504 6.3 220 >10,000 505 14.0 72.0 >10,000 506 5.0 400 >10,000 507 15.8 210 >10,000 508 19.3 210 >10,000 509 520 >10,000 >10,000 510 7700 >10,000 >10,000 511 9000 6000 >10,000 512 7700 >10,000 >10,000 513 7700 >10,000 >10,000 514 1.0 0.6 5,000 515 8.0 27.0 >10,000 516 14.8 300 >10,000 517 14.0 1100 >10,000 518 11.4 350 >10,000 519 45.4 1300 >10,000 520 22.5 250 >10,000 521 3.5 50.0 >10,000 522 2.4 94.0 >10,000 523 2.4 190 >10,000 524 2700 6400 >10,000 525 290 700 >10,000 526 >10,000 >10,000 >10,000 527 6700 9000 >10,000 528 7700 >10,000 >10,000 529 8800 >10,000 >10,000 530 20.0 60.7 >10,000 531 13.0 10.0 >10,000 532 10.0 150 >10,000 533 60.0 150 >10,000 534 30.0 480 >10,000 535 1.9 35.0 >10,000 536 7.7 88.0 >10,000 537 70.0 55.0 5200 538 80.0 370 >10,000 539 270 350 >10,000 540 11.4 500 >10,000 541 0.7 2.0 >10,000 542 — — — 543 33.7 5400 >10,000 544 35.0 3100 >10,000 545 7.7 120 >10,000 546 2.7 18.6 >10,000 547 5.0 64.7 >10,000 548 40.0 800 >10,000 549 55.3 2900 >10,000 550 20.0 2000 >10,000 551 9.0 140 >10,000 552 12.8 140 >10,000 553 12.8 50.0 >10,000 554 3.7 140 >10,000 555 3.7 220 >10,000 556 4.5 170 >10,000 557 16.9 200 >10,000 558 4.5 66.4 >10,000 559 7.2 80.0 >10,000 560 4.5 306 >10,000 561 6.0 500 >10,000 562 1200 6300 >10,000 563 70.0 235 >10,000 564 150 550 >10,000 565 5.5 700 >10,000 566 15.8 57.1 >10,000 567 5.0 87.7 >10,000 568 120 4600 >10,000 569 16.9 87.7 >10,000 570 290 >10,000 >10,000 571 28.6 140 >10,000 572 37.2 3000 >10,000 573 11.4 235 >10,000 574 10.6 220 >10,000 575 10.7 110 >10,000 576 8.8 78.0 >10,000 577 107 2200 >10,000 578 160 2000 >10,000 579 2.7 100 >10,000 580 37.2 700 >10,000 581 27.0 480 >10,000 582 30.0 1800 >10,000 583 70.0 4700 >10,000 584 2700 3500 >10,000 585 1400 3500 >10,000 586 >10,000 >10,000 >10,000 587 1.8 1.0 >10,000 588 — — — 589 70.0 >10,000 >10,000 590 121 80.0 >10,000 591 70.0 730 >10,000 592 57.0 690 >10,000 593 420 650 >10,000 594 570 650 >10,000 595 270 425 >10,000 596 1.1 10.6 >10,000 597 670 700 >10,000 598 25.4 145 >10,000 600 9.0 600 >10,000 601 9.0 1300 >10,000 602 70.0 3000 >10,000 603 15.8 2300 >10,000 604 20.0 2500 >10,000 605 10.6 2000 >10,000 606 3.0 77.0 >10,000 607 2.9 220 >10,000 608 3.0 250 >10,000 609 30.6 2800 >10,000 610 425 1300 >10,000 611 139 1800 >10,000 612 290 2200 >10,000 613 8.0 30.7 >10,000 614 22.0 25.4 >10,000 615 3.1 11.0 >10,000 616 4.0 3.7 >10,000 617 7.0 5.7 >10,000 618 — — — 619 4.3 5.7 >10,000 620 27.8 225 >10,000 621 120 1500 >10,000 622 500 1600 >10,000 623 350 1400 >10,000 624 120 940 >10,000 634 4.4 60.7 >10,000 635 13.9 260 >10,000 636 3.0 8.0 >10,000 637 3.8 22 >10,000 638 — — — 639 1.5 1.5 9400 640 4.2 15.8 >10,000 641 4.0 13.7 >10,000 642 2.2 1.1 >10,000 643 1.8 1.2 6000 644 1.6 3.3 8800 645 370 1200 >10,000 646 — 7800 >10,000 647 6.0 160 >10,000 648 25.8 110 >10,000 649 130 1400 >10,000 650 14.7 1200 >10,000 651 13.7 60 >10,000 652 0.4 82.0 >10,000 653 0.8 160 >10,000 654 3.2 35.0 >10,000 655 37.3 1400 >10,000 656 3.1 120 >10,000 658 12.2 1000 >10,000 659 1.0 3.7 >10,000 665 2.3 29.2 >10,000 666 48.4 330 >10,000 667 30 135 >10,000 668 2.0 25.8 >10,000 669 4.3 22.7 >10,000 670 671 6.0 130 >10,000 672 6.7 60 >10,000 673 14.8 455 >10,000 674 8.0 110 >10,000 675 13.0 88 6000 676 7.7 90 >10,000 677 7.0 34.7 >10,000 678 5.0 50 >10,000 679 680 681 682 683 11.3 290 >10,000 684 60 1450 >10,000 685 3/0 34.7 >10,000 686 4200 3700 >10,000 688 17.6 110 >10,000 690 7.3 41.8 >10,000 691 10.0 130 >10,000 692 10.0 22.7 >10,000 693 210 1900 >10,000 694 3.1 23.2 >10,000 695 2.0 22.7 >10,000 696 10.0 140 >10,000 697 18.1 1500 >10,000 698 16.9 700 >10,000 699 50.0 455 >10,000 705 44.5 1100 >10,000 706 4.3 40 >10,000 707 2.3 9.0 >10,000 708 114 3000 >10,000 714 28.8 420 >10,000 720 4.5 36.9 >10,000 724 28.6 300 >10,000 725 25.1 210 >10,000 726 15.8 250 >10,000 727 34.9 240 >10,000 728 9.4 106 >10,000 729 14.8 240 >10,000 730 37 3000 >10,000 731 1.9 35 >10,000 732 3.1 590 >10,000 733 1.6 270 >10,000 734 6.0 3300 >10,000 735 9.0 800 >10,000 736 0.9 145 >10,000 737 3.0 1280 >10,000 738 22.0 270 >10,000 740 61 175 >10,000 741 50 125 >10,000 752 14.8 271 >10,000 755 2.2 20 >10,000 756 7.0 28.8 >10,000 757 3.3 28.8 >10,000 758 5.0 34.7 >10,000 759 3.0 60.8 >10,000 760 6.0 25.4 >10,000 761 5.0 41.8 >10,000 769 5.0 0.7 >10,000 770 270 485 >10,000 771 500 10,000 >10,000 772 350 4200 >10,000 773 6.0 2.7 >10,000 774 — — — 775 120 270 >10,000 776 3.0 10.0 >10,000 777 2.5 6.5 >10,000 778 3.3 12 >10,000 779 40 210 >10,000 780 17.5 80 >10,000 781 800 5100 >10,000 782 21.1 100 >10,000 784 6.0 4500 >10,000 786 3.7 700 >10,000 787 1.2 175 >10,000 788 3.0 445 >10,000 789 12.2 3700 >10,000 790 4.5 700 >10,000 791 2.0 700 >10,000 793 4.0 23.5 >10,000 794 1500 2900 >10,000 796 5.7 130 >10,000 797 4.0 175 >10,000 798 20.0 210 >10,000 799 10.6 43.5 >10,000 802 2.3 10,000 >10,000 807 200 1400 >10,000 811 14.8 110 >10,000 815 140 1400 >10,000 816 1200 >10,000 >10,000 820 29.0 1400 >10,000 821 4.0 10.0 >10,000 822 10.0 210 >10,000 823 7.0 505 >10,000 825 11.3 70.0 >10,000 826 40.0 650 ND 827 10.0 540 >10,000 828 1.5 12.8 ND 829 6.0 22.0 ND 830 17.9 2100 >10,000 831 2.3 170 >10,000 832 18.1 2000 >10,000 833 11.0 1750 >10,000 834 150 780 ND 835 6.0 20.0 >10,000 836 135 4200 ND 838 3.0 70.0 >10,000 841 285 1900 ND 842 5.5 45.4 >10,000 844 5.0 4700 >10,000 845 28.6 2000 ND 846 4.5 186 >10,000 847 20.0 1800 ND 848 — — ND 850 4.5 150 >10,000 851 3.7 42.5 ND 852 25.0 3000 ND 853 15.8 120 ND 854 40.0 3300 ND 856 1.2 250 ND 857 1.3 120 ND 858 3.7 600 >10,000 859 5.5 440 ND 860 2.7 1500 >10,000 861 2.0 34.9 ND 862 1.7 40.0 ND 863 — — ND 864 — — ND 867 16.5 10,000 >10,000 868 — — ND 869 2.0 76.9 ND 870 305 6000 ND
Example 944 In Vivo Angiogenesis Assay[0945] The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.
[0946] In this assay, uniformLy sized Hydron pellets containing bFGF and sucralfate were prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets were formed by making a suspension of 20 &mgr;L sterile saline containing 10 &mgr;g recombinant bFGF, 10 mg of sucralfate and 10 &mgr;L of 12 percent Hydron in ethanol. The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the mesh were separated to release the pellets.
[0947] The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a jeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet was placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet was then advanced to the temporal end of the pocket. Antibiotic ointment was then applied to the eye.
[0948] Mice were dosed on a daily basis for the duration of the assay. Dosing of the animals was based on bioavailability and overall potency of the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po. Neovascularization of the corneal stroma begins at about day three and was permitted to continue under the influence of the assayed compound until day five. At day five, the degree of angiogenic inhibition was scored by viewing the neovascular progression with a slit lamp microscope.
[0949] The mice were anesthetized and the studied eye was once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet was measured. In addition, the contiguous circumferential zone of neovascularization was measured as clock hours, where 30 degrees of arc equals one clock hour. The area of angiogenesis was calculated as follows. 1 area = ( 0.4 × clock hours × 3.14 × vessel length ( in mm ) ) 2
[0950] Five to six mice were utilized for each compound in each study. The studied mice were thereafter compared to control mice and the difference in the area of neovascularization was recorded as an averaged value. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition.
EXAMPLE 350 In Vivo PC-3 Tumor Reduction[0951] PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to 90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested using a rubber scraper, and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cell-containing medium was maintained on ice until used.
[0952] Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/l mL) diluted 1:60 into phosphate-buffered sline] and 3-5×106 of the above cells in 0.2 mL of medium were injected into the left flank of each mouse. Cells were injected in the morning, whereas dosing with an inhibitor began at 6 PM. The animals were gavaged BID from day zero (cell injection day) to day 25-30, at which time the animals were euthanized and tumors weighed.
[0953] Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1% polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, or diluted to provide a 10 mg/kg (mpk) dose twice each day. Tumor measurements began on day 7 and continued every third or fourth day until completion of the study. Groups of ten mice were used in each study and nine to ten survived. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table.
EXAMPLE 945 Tumor Necrosis Factor Assays[0954] Cell Culture.
[0955] The cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow. The assay is carried out as follows:
[0956] 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R-10 supplement to a concentration of 1.540×106 cells/mL.
[0957] 2. Add test compound in 65 &mgr;L R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (0.100 mM compound) provides a 400 &mgr;M solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 &mgr;l (in triplicate) yields final compound test concentrations of 100 &mgr;M, 33.3 &mgr;M, 11.1 &mgr;M, 3.7 &mgr;M, 1.2 &mgr;M and 0.4 &mgr;M.
[0958] 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 &mgr;L are added to the wells.
[0959] 4. Incubation is for 45 minutes to one hour at 37° C. in 5% CO2 in a water saturated container.
[0960] 5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well.
[0961] 6. The test system is incubated at 37° C. in 5% CO2 overnight (18-20 hours) under 100% humidity.
[0962] 7. Supernatant, 150 &mgr;L, is carefully removed from each well for use in the ELISA assay.
[0963] 8. For toxicity, a 50 &mgr;L aliquot of working solution containg 5 mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37° C. in 5% CO2 until the color develops. The system is excited at 570 nm and read at 630 nm.
[0964] TNF Receptor II ELISA Assay
[0965] 1. Plate 100 &mgr;L/well 2 &mgr;g/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate. Incubate the plate at 4° C. overnight (about 18-20 hours).
[0966] 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).
[0967] 3. Add 200 &mgr;L 5% BSA in PBS and block at 37° C. in a water saturated atmosphere for 2 hours.
[0968] 4. Wash the plate with PBS-Tween.
[0969] 5. Add sample and controls (100 &mgr;l of each) to each well. The standards are 0, 50, 100, 200, 300 and 500 &mgr;g recombinant human TNFrII (R&D Systems #226-B2) in 100 &mgr;L 0.5% BSA in PBS. The assay is linear to between 400-500 pg of standard.
[0970] 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hours.
[0971] 7. Wash the plate with PBS-Tween.
[0972] 8. Add 100 &mgr;L goat anti-human TNFrII polyclonal (1.5 &mgr;g/mL R&D Systems #AB226-PB in 0.5% BSA in PBS).
[0973] 9. Incubate at 37° C. in a saturated atmosphere for 1 hour.
[0974] 10. Wash the plate with PBS-Tween.
[0975] 11. Add 100 &mgr;L anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS, Sigma #A5420).
Claims
1-66. (canceled).
67. A compound or a pharmaceutically acceptable salt thereof, wherein:
- the compound corresponds in structure to the following formula:
- 4708
- R14 is selected from the group consisting of hydrogen and C(W)R25;
- W is selected from the group consisting of O and S;
- R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein:
- the amino C1-C6-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or
- the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
- g is zero, 1, or 2;
- m is zero, 1, or 2;
- n is zero, 1, or 2;
- p is zero, 1, or 2;
- the sum of m+n+p=1,2,3, or 4; as to X, Y, and Z:
- (a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7, and the remaining two of X, Y, and Z are CR8R9, and CR10R11, or
- (b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR60, SS, NR6NR6, and OC(O), with the remaining one of X and Y being CR8R9, or
- (c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
- 4709
- wherein wavy lines are bonds to the atoms of the depicted ring;
- R6 and R6′ are independently selected from the group consisting of hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, 5- to 6-membered heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, 5- to 6-membered heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, and R8R9-amino-C1-C6-alkyl;
- R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
- as to R8:
- R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or
- R8 and R9 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R9:
- R9 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R10:
- R10 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl,
- R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or
- R10 and R11 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R11:
- R11 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- only one of R8 and R9 or R10 and R11 is hydroxy;
- R12 and R12′ are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroarylalkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl;
- R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, and C1-C6-hydroxyalkyl;
- Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms;
- A is selected from the group consisting of:
- (1)—O—,
- (2) —S—,
- (3) —NR17—,
- (4) —CO—N(R17),
- (5) —N(R17)—CO—,
- (6) —CO—O—,
- (7) —O—CO—,
- (8) —O—CO—O—,
- (9) —HC═CH—,
- (10) —NH—CO—NH—,
- (11) —C≡C—,
- (12)—NH—CO—O—,
- (13) —O—CO—NH—,
- (14) —N═N—,
- (15) —NH—NH—,
- (16) —CS—N(R17)—,
- (17) —N(R17)—CS—, and
- (18) a bond;
- R17 is selected from the group consisting of hydrogen, C1-C4-alkyl, and phenyl;
- R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocyclothioalkyl, wherein:
- the aryl, heteroaryl, cycloalkyl, or heterocyclo is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
- R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
- E is selected from the group consisting of:
- (1) —CO(R19)—,
- (2) —(R19)CO—,
- (3) —CONH—,
- (4) —HNCO—,
- (5) —CO—,
- (6) —SO2—R19—,
- (7) —R19—SO2—,
- (8) —SO2—,
- (9)—NH—SO2—,
- (10) —SO2—NH—,
- (11) —S—,
- (12) —NH—CO—O—,
- (13) —O—CO—NH—, and
- (14) a bond;
- R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and
- Y2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
- the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
- the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
68. A compound or salt according to claim 67, wherein g is 2.
69. A compound or salt according to claim 68, wherein A-R-E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
70. A compound or salt according to claim 69, wherein R14 is hydrogen.
71. A compound or salt according to claim 69, wherein:
- R14 is C(W)R25;
- W is O; and
- R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, and aryloxy.
72. A compound or salt according to claim 69, wherein A is selected from the group consisting of —O— and —S—.
73. A compound or salt according to claim 69, wherein R is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo.
74. A compound or salt according to claim 69, wherein the compound corresponds in structure to formula B-1A:
- 4710
75. A compound or salt according to claim 69, wherein Q is a 5-membered ring.
76. A compound or salt according to claim 69, wherein Q is a 7-membered ring.
77. A compound or salt according to claim 69, wherein Q is a 6-membered ring.
78. A compound or salt according to claim 77, wherein the compound corresponds in structure to the following formula:
- 4711
79. A compound or salt according to claim 78, wherein:
- the compound corresponds in structure to the following formula:
- 4712
- Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
80. A compound or salt according to claim 79, wherein R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, and cycloalkylthioalkyl, wherein:
- the aryl, heteroaryl, or cycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl.
81. A compound or salt according to claim 80, wherein R is selected from the group consisting of aryl, heteroaryl, and cycloalkyl.
82. A compound or salt according to claim 79, wherein Z is S.
83. A compound or salt according to claim 68, wherein the compound corresponds in structure to the formula:
- 4713
84. A compound or salt according to claim 83, wherein R-E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
85. A compound or salt according to claim 84, wherein:
- the compound corresponds in structure to formula XI-1:
- 4714
- Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
86. A compound or a pharmaceutically acceptable salt thereof, wherein:
- the compound corresponds in structure to the following formula:
- 4715
- R14 is selected from the group consisting of hydrogen and C(W)R25;
- W is selected from the group consisting of O and S;
- R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein:
- the amino C1-C6-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or
- the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
- g is zero, 1, or 2;
- m is zero, 1, or 2;
- n is zero, 1, or 2;
- p is zero, 1, or 2;
- the sum of m+n+p=1, 2, 3, or 4;
- as to X, Y, and Z:
- (a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7, and the remaining two of X, Y, and Z are CR8R9, and CR10R11, or
- (b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR60, SS, NR6NR6, and OC(O), with the remaining one of X and Y being CR8R9, or
- (c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
- 4716
- wherein wavy lines are bonds to the atoms of the depicted ring;
- R6 and R6 are independently selected from the group consisting of hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, 5- to 6-membered heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, 5- to 6-membered heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, and R8R9-amino-C1-C6-alkyl;
- R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
- as to R8:
- R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or
- R8 and R9 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R9:
- R9 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol -C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R10:
- R10 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl,
- R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or
- R10 and R11 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- as to R11:
- R11 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
- R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
- only one of R8 and R9 or R10 and R11 is hydroxy;
- R12 and R12 are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroarylalkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
- the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl;
- R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, and C1-C6-hydroxyalkyl;
- Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms;
- E is selected from the group consisting of:
- (1) —CO(R19)—,
- (2) —(R19)CO—,
- (3) —CONH—,
- (4) —HNCO—,
- (5) —CO—,
- (6) —SO2—R19—,
- (7) —R19—SO2—,
- (8) —SO2—,
- (9) —NH—SO2—,
- (10) —SO2—NH—,
- (11) —S—,
- (12) —NH—CO—O—,
- (13) —O—CO—NH—, and
- (14) a bond;
- R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and
- Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
- the aryl, heteroaryl, aralkyl, heterocyclo, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
- the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
87. A compound or salt according to claim 86, wherein g is 2.
88. A compound or salt according to claim 87, wherein the compound corresponds in structure to the following formula:
- 4717
89. A compound or salt according to claim 87, wherein:
- the compound corresponds in structure to formula IX-2:
- 4718
- Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
90. A compound or salt according to claim 87, wherein E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
91. A compound or salt according to claim 90, wherein Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
- the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
- the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
92. A compound or salt according to claim 90, wherein R14 is hydrogen.
93. A compound or salt according to claim 90, wherein:
- R14 is C(W)R25;
- W is O; and
- R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-Cs-cycloalkyl-C1-C6-alkyl, and aryloxy.
94. A compound or salt according to claim 90, wherein the compound corresponds in structure to formula B-3A:
- 4719
95. A compound or salt according to claim 90, wherein Q is a 5-membered ring.
96. A compound or salt according to claim 90, wherein Q is a 7-membered ring.
97. A compound or salt according to claim 90, wherein Q is a 6-membered ring.
98. A compound or salt according to claim 97, wherein the compound corresponds in structure to the following formula:
- 4720
99. A compound or salt according to claim 98, wherein:
- the compound corresponds in structure to formula IX-1:
- 4721
- Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
100. A compound or salt according to claim 99, wherein Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
- the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
- the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
101. A compound or salt according to claim 99, wherein Z is S.
102. A compound or salt according to claim 101, wherein the compound corresponds in structure to the formula:
- 4722
103. A method for treating a pathological condition in a mammal, wherein:
- the condition is treatable by inhibiting matrix metalloprotease activity;
- the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition;
- the compound corresponds in structure to a compound recited in claim 68; and
- the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
104. A method according to claim 103, wherein A is a bond.
105. A method according to claim 103, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
106. A method according to claim 105, wherein the pathological condition is osteoarthritis.
107. A method according to claim 103, wherein the compound or salt is administered a plurality of times.
108. A method for treating a pathological condition in a mammal, wherein:
- the condition is treatable by inhibiting matrix metalloprotease activity;
- the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition;
- the compound corresponds in structure to a compound recited in claim 87; and
- the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
109. A method according to claim 108, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
110. A method according to claim 109, wherein the pathological condition is osteoarthritis.
111. A method according to claim 108, wherein the compound or salt is administered a plurality of times.
112. A pharmaceutical composition that comprises a compound or salt according to claim 68 dissolved or dispersed in a pharmaceutically acceptable carrier.
113. A pharmaceutical composition according to claim 112, wherein A is a bond.
114. A pharmaceutical composition that comprises a compound or salt according to claim 87 dissolved or dispersed in a pharmaceutically acceptable carrier.
Type: Application
Filed: Dec 29, 2003
Publication Date: Nov 25, 2004
Inventors: Thomas E. Barta (Wilmette, IL), Daniel P. Becker (Glenview, IL), Louis J. Bedell (Prospect Heights, IL), Terri L. Boehm (Ballwin, MO), Jeffery N. Carroll (St. Louis, MO), Gary A. DeCrescenzo (St. Charles, MO), Yvette M. Fobian (Wildwood, MO), John N. Freskos (Clayton, MO), Daniel P. Getman (Chesterfield, MO), Susan L. Hockerman (Kirkwood, MO), Carol P. Howard (Fenton, MO), Stephen A. Kolodziej (Ballwin, MO), Madeleine H. Li (Plainsboro, NJ), Joseph J. McDonald (Wildwood, MO), Deborah A. Mischke (Defiance, MO), Joseph G. Rico (O'Fallon, MO), Nathan W. Stehle (Grafton, WI), Michael B. Tollefson (Dardenne Prairie, MO), William F. Vernier (St. Louis, MO), Clara I. Villamil (Glenview, IL)
Application Number: 10747796
International Classification: A61K031/553; A61K031/335;
