Selective NPY (Y5) antagonists (triazines)
This invention is directed to triazine derivatives which are selective antagonists for a NPY (Y5) receptor. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
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[0001] Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references may be found at the end of this application, preceding the claims.
[0002] The peptide neurotransmitter neuropeptide Y (NPY) is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system (Dumont et al., 1992). The family includes the pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, 1991; Dumont et al., 1992; Wahlestedt and Reis, 1993). All pancreatic polypeptide family members share a compact structure involving a “PP-fold” and a conserved C-terminal hexapeptide ending in Tyr36 (or Y36 in the single letter code). The striking conservation of Y36 has prompted the reference to the pancreatic polypeptides' receptors as “Y-type” receptors (Wahlestedt et al., 1987), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992). NPY and its relatives elicit a broad range of physiological effects through activation of at least five G protein-coupled receptor subtypes known as Y1, Y2, Y3, Y4 (or PP), and the “atypical Y1”. While the Y1, Y2, Y3, and Y4 (or PP) receptors were each described previously in both radioligand binding and functional assays, the “atypical Y1” receptor is unique in that its classification is based solely on feeding behavior induced by various peptides including NPY.
[0003] The role of NPY in normal and abnormal eating behavior, and the ability to interfere with NPY-dependent pathways as a means to appetite and weight control, are areas of great interest in pharmacological and pharmaceutical research (Sahu and Kalra, 1993; Dryden et al., 1994). NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark et al., 1984; Levine and Morley, 1984; Stanley and Leibowitz, 1984). The stimulation of feeding behavior by NPY is thought to occur primarily through activation of the hypothalamic “atypical Y1” receptor. For example, direct injection of NPY into the hypothalamus of satiated rats can increase food intake up to 10-fold over a 4-hour period (Stanley et al., 1992). Similar studies using other peptides has resulted in a pharmacologic profile for the “atypical Y1” receptor according to the rank order of potencies of peptides in stimulating feeding behavior as follows: NPY2-36≧NPY˜PYY˜[Leu31,Pro34]NPY>NPY13-36 (Kalra et al., 1991; Stanley et al., 1992). The profile is similar to that of a Y1-like receptor except for the anomalous ability of NPY2-36 to stimulate food intake with potency equivalent or better than that of NPY. A subsequent report in J. Med. Chem. by Balasubramaniam and co-workers (1994) showed that feeding can be regulated by [D-Trp32]NPY. While this peptide was presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp32]NPY on feeding. In contrast to other NPY receptor subtypes, the “feeding” receptor has never been characterized for peptide binding affinity in radioligand binding assays.
[0004] This problem has been addressed by cloning rat and human cDNAs which encode a single receptor protein, referred to herein as Y5, whose pharmacologic profile links it to the “atypical Y1” receptor. The identification and characterization of a single molecular entity which explains the “atypical Y1” receptor allows the design of selective drugs which modulate feeding behavior (WO 96/16542). It is important to note, though, that any credible means of studying or modifying NPY-dependent feeding behavior must necessarily be highly selective, as NPY interacts with multiple receptor subtypes, as noted above (Dumont et al., 1992).
[0005] As used in this inventor., the term “antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific but by no means limiting examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase, and inositol phospholipid hydrolysis. Conversely, the term “agonist” refers to a compound which binds to, and increases the activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
[0006] In order to test compounds for selective binding to the human Y5 receptor the cloned cDNAs encoding both the human and rat Y2 and Y4 (or PP) receptors have been used. The human and rat Y5 receptors are described in coassigned U.S. Pat. No. 5,602,024 and in PCT International Application US95/15646, published Jun. 6, 1996, as WO 96/16542, the contents of which are hereby incorporated by reference into this application. The human and rat Y2 receptors are described in coassigned U.S. Pat. No. 5,545,549 and in PCT International Application US95/01469, published Aug. 10, 199, as WO 95/21245, the contents of which are hereby incorporated by reference into this application. The human and rat Y4 receptors are described in coassigned U.S. Pat. No. 5,516,653 and in PCT International Application PCT/US94/14436, published Jul. 6, 1995, as WO 95/17906, the contents of which are hereby incorporated by reference into this application. The Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar et al., 1992; Herzog et al., 1992; Eva et al., 1990; Eva et al., 1992).
[0007] Using the NPY-Y5-selective antagonist CGP 71683A, it was demonstrated recently that food intake in free-feeding and energy-derived lean rats is mediated by the Y5 receptor (Criscione et al., 1998). CGP 71683A has high affinity for the cloned rat NPY-Y5 receptor subtype, but 1,000-fold lower affinity for the cloned rat NPY-Y1, Y2, and Y4 receptors. Examples of additional NPY-Y5-selective compounds are disclosed in WO 97/20823, WO 98/35957, and WO 98/35944.
[0008] In one embodiment of this invention the synthesis of novel triazine compounds which bind selectively to the cloned human Y5 receptor, compared to the other cloned human NPY receptors, and inhibit the activation of the cloned human Y5 receptor as measured in in vitro assays is disclosed. The in vitro receptor binding and activation assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single Y-type receptor.
[0009] In addition, the compounds of the present invention may be used to treat abnormal conditions such as feeding disorders (obesity and bulimia nervosa), sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of a Y5 receptor may be beneficial.
SUMMARY OF THE INVENTION[0010] This invention provides a compound having the structure 1
[0011] wherein R1 is F; Cl; Br; I; NR3R4; or phenyl or heteroaryl; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0012] wherein R2 is NR3R4;
[0013] wherein R3 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)NR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0014] wherein R4 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0015] or R3 and R4 taken together with the nitrogen atom to which they are attached are 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl, wherein the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl is substituted with one or more of F, —CN, —(CH2)nNR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5. —(CH2)nC(Y)N R5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, a C3-C7 cycloalkyl or cycloalkenyl, or phenyl or heteroaryl; wherein if —(CH2)nNR5R6, —(CH2)nYR5, or —(CH2)nNR5C(Y)R5 are in the 2-position, then n is not 0; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2P5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0016] or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl, wherein the morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl or [1,4]diazepanyl ring is substituted with —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0017] wherein each of R5, R6 and R7 is independently H; or straight chained or branched C1-C7 alkyl;
[0018] wherein each n is independently an integer from 0 to 6 inclusive;
[0019] wherein each t is independently an integer from 1 to 4 inclusive;
[0020] wherein each u is independently, an integer from 2 to 4 inclusive;
[0021] wherein Y is O or S;
[0022] wherein R8 is 2
[0023] provided that if R8 contains a piperidinyl group and m is O, then the compound is not an &agr;-aminal-containing compound;
[0024] wherein each of R9 and R10 is independently H; straight chained or branched C1-C4 alkyl;
[0025] wherein R11 is H or 3
[0026] wherein R12 is H:
[0027] wherein R13 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; C1-C7 alkyl substituted with one or more F or Cl; C3-C7 cycloalkyl-C1-C7 alkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0028] or R12 and R13 together with the amide linkage to which they are attached are pyrrolidinonyl or piperidonyl;
[0029] wherein R14 is H; straight chained or branched C1-C7 alkyl; F; or —(CH2)nOR5;
[0030] wherein R15 is H, straight chained or branched C1-C7 alkyl, or F;
[0031] wherein R16is NR3R4, unsubstituted straight chained or branched C2-C7 alkyl, substituted straight chained or branched C1-C7 alkyl, wherein the C1-C7 alkyl may be substituted with one or more of F, Cl, —CN, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)YR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nOCF3, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl, or C3-C7 cycloalkyl or cycloalkenyl, phenyl, heteroaryl, or C1-C7 phenylalkyl, wherein the phenyl, heteroaryl, or C1-C7 phenylalkyl may be substituted with one or more of F. Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; quinolinyl, 1-naphthyl, 2-naphthyl, or 2,1,3-benzothiadiazolyl; with the provisos that when R1 is F, Cl, Br, or I, then R16 is 1-naphthyl; and when R1 and R2 are morpholinyl, then R16 is not NR3R4;
[0032] wherein each m is independently an integer from 0 to 3 inclusive;
[0033] wherein each s is independently an integer from 1 to 6 inclusive;
[0034] wherein each p is independently an integer from 0 to 2 inclusive;
[0035] wherein each q is independently an integer from 1 to 2 inclusive;
[0036] wherein each r is independently an integer from 1 to 2 inclusive;
[0037] wherein X is N or C;
[0038] or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE FIGURES[0039] FIGS. 1A-1F
[0040] Structures of compounds described herein within the Experimental Details section in Examples 1-58.
DETAILED DESCRIPTION OF THE INVENTION[0041] This invention provides a compound having the structure 4
[0042] wherein R1 is F; Cl; Br; I; NR3R4; or phenyl or heteroaryl; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5; —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0043] wherein R2 is NR3R4;
[0044] wherein R3 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0045] wherein R4 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0046] or R3 and R4 taken together with the nitrogen atom to which they are attached are 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl, wherein the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl is substituted with one or more of F, —CN, —(CH2)nNR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, a C3-C7 cycloalkyl or cycloalkenyl, or phenyl or heteroaryl; wherein if —(CH2)nNR5R6, —(CH2)nYR5, or —(CH2)nNR5C(Y)R5 are in the 2-position, then n is not 0; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0047] or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl, wherein the morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl or [1,4]diazepanyl ring is substituted with —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0048] wherein each of R5, R6 and R7 is independently H; or straight chained or branched C1-C7 alkyl;
[0049] wherein each n is independently an integer from 0 to 6 inclusive;
[0050] wherein each t is independently an integer from 1 to 4 inclusive;
[0051] wherein each u is independently an integer from 2 to 4 inclusive;
[0052] wherein Y is O or S;
[0053] wherein R8 is 5
[0054] provided that if R8 contains a piperidinyl group and m is O, then The compound is not an &agr;-aminal-containing compound;
[0055] wherein each of R9 and R10 is independently H; straight chained or branched C1-C4 alkyl;
[0056] wherein R11 is H or 6
[0057] wherein R12 is H;
[0058] wherein R13 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; C1-C7 alkyl substituted with one or more F or Cl; C3-C7 cycloalkyl-C1-C7 alkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
[0059] or R12 and R13 together with the amide linkage to which they are attached are pyrrolidinonyl or piperidonyl;
[0060] wherein R14 is H; straight chained or branched C1-C7 alkyl; F; or —(CH2)nOR5;
[0061] wherein R15 is H, straight chained or branched C1-C7 alkyl, or F;
[0062] wherein R16 is NR3R4, unsubstituted straight chained or branched C2-C7 alkyl, substituted straight chained or branched C1-C7 alkyl, wherein the C1-C7 alkyl may be substituted with one or more of F, Cl, —CN, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, (CH2)nCO2R5, —(CH2)nOCF3, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl, or C3-C7 cycloalkyl or cycloalkenyl, phenyl, heteroaryl, or C1-C7 phenylalkyl, wherein the phenyl, heteroaryl, or C1-C7 phenylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; quinolinyl, 1-naphthyl, 2-naphthyl, or 2,1,3-benzothiadiazolyl; with the provisos that when R1 is F, Cl, Br, or I, then R16 is 1-naphthyl; and when R1 and R2 are morpholinyl, then R16 is not NR3R4;
[0063] wherein each m is independently an integer from 0 to 3 inclusive;
[0064] wherein each s is independently an integer from 1 to 6 inclusive;
[0065] wherein each p is independently an integer from 0 to 2 inclusive;
[0066] wherein each q is independently an integer from 1 to 2 inclusive;
[0067] wherein each r is independently an integer from 1 to 2 inclusive;
[0068] wherein X is N or C;
[0069] or a pharmaceutically acceptable salt thereof.
[0070] An &agr;-aminal-containing compound is a compound in which a nitrogen is directly attached to the &agr;-carbon of the piperidinyl group.
[0071] In one embodiment, the compound of this invention comprises the (+) enantiomer. In another embodiment, the compound comprises the (−) enantiomer.
[0072] In one embodiment, R8 is 7
[0073] In another embodiment, R1 is F, Cl, Br, I, or NR3R4.
[0074] In another embodiment, R1 and R2 are both NR3R4 where R3 and R4 are independently H; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, piperazinyl, or 1-pyrrolidinyl, wherein the morpholinyl, piperazinyl, or 1-pyrrolidinyl is substituted with one or more straight chained or branched C1C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl ring is substituted with H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl.
[0075] In another embodiment, R16 is phenyl, 1-naphthyl, quinolinyl, or 2,1,3-benzothiadiazolyl; wherein the phenyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)YR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl.
[0076] In another embodiment, R9 is H, R10 is H, p is 1, and m is 1.
[0077] In a presently preferred embodiment, the compound is selected from the group consisting of: 8
[0078] In another presently preferred embodiment, the compound is selected from the group consisting of: 9
[0079] In a further presently preferred embodiment, the compound is selected from the group consisting of: 10
[0080] In the present invention, the term “heteroaryl” is used to mean and include five and six membered aromatic rings that may contain one or more heteroatoms such as oxygen, sulfur, nitrogen. Heteroaryl groups include, but are not limited to, pyrazolyl (preferably 1-pyrazolyl), pyrrolyl, furanyl, pyridyl (preferably 2-pyridyl or 3-pyridyl), imidazolyl (preferably 1-imidazolyl), oxazolyl, pyrimidinyl, isoxazolyl, and thienyl.
[0081] Included within the scope of this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the acids and bases listed herein. The salts include, but are not limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The salts include, but are not limited to the inorganic base, ammonia. The salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
[0082] The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
[0083] The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
[0084] This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is an amount from about 0.01 mg to about 800 mg. In another embodiment, the amount of he compound is an amount from about 0.01 mg to about 500 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. In another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg. In another embodiment, the amount of the compound is an amount from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet. In a further embodiment, the carrier is a gel and the composition is a suppository.
[0085] This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
[0086] This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
[0087] In the subject invention a “therapeutically effective amount” is any amount of a compound which, when administered to a subject s,suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
[0088] In the practice of this invention the “pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
[0089] In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
[0090] A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
[0091] Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
[0092] Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
[0093] The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
[0094] The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
[0095] Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
[0096] One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating the above noted disorders.
[0097] This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
EXPERIMENTAL DETAILS AND RESULTS I. SYNTHETIC METHODS FOR EXAMPLES[0098] General Procedures Relating to Examples:
[0099] For the stepwise addition of amines to cyanuric chloride (2,4,6,-trichloro-1,3,5-triazine), see, for example, Campbell, J. R. and Hatton, R. E., 1961; and Nestler, H. and Furst, H., 1963.
[0100] For more recent references concerning the formation of amino-1,3,5-triazines, see, for example, Kreutzberger, A, et al., 1991; U.S. Pat. No. 4,383,113; and U.S. Pat. No. 3,947,374.
[0101] For the formation of cyanoguanidines from amines and sodium dicyanamide (NaN(CN)1) and/or formation of the biguinides, see, for example, Shaw, J. T. and Gross, F. J., 1959; Curd, F. H. S., et al., 1948; Curd, F. H. S. and Rose F. L., 1946; May, E. L., 1947; and Neelakantan, L., 1957.
[0102] The cyclization of biguinides to 2,4-diamino-1,3,5-triazines can be accomplished using a number of carboxylic acid derivatives such as acid chlorides, esters, anhydrides, carboxylates, etc. See, for example, Furukawa, M., et al., 1961; Koshelev, V. N., et al., 1995; Tsitsa, P., et al., 1993; Shaw, J. T., et al., 1959; Vanderhoek, R., et al., 1973; Nagasaka, H., et al., 1967; U.S. Pat. No. 3,891,705; U.S. Pat. No. 5,348,956; and U.S. Pat. No. 5,258,513.
[0103] All reactions were performed under an inert atmosphere (Argon) and the reagents, neat or in appropriate, solvents, were transferred to the reaction vessel via syringe and cannula techniques. The parallel synthesis reaction arrays were performed in vials (without an inert atmosphere) using J-KEM heating shakers (Saint Louis, Mo.). Unless stated otherwise all solvents were AR grade and used as supplied. Anhydrous solvents were purchased from Aldrich Chemical Company and used as received. The examples described in the patent (1-58) were named using ACD/Name program (version 2.51, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).
[0104] Flash chromatography (silica gel, mesh size 230-400) and preparative thin layer chromatography (Analtech, 2000 micron) were used for chromatographic separations. Thin layer chromatography was used for analytical analysis of the mixtures. 1H NMR spectra were recorded on a GE (QE Plus, 300 MHz) instrument and the spectra were either calibrated by the lock signal of the deuterated solvent or tetramethylsilane (TMS) as the internal standard. Signals in the 1H NMR spectra are described as: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; sextet; septet; m, multiplet; b, broad. Elemental analyses were performed by Robertson Microlit Laboratories, Inc., Madison, N.J.
[0105] General Procedure for the Synthesis of the Amino Side Chains (H2N—(CH2)n-Pyrazole and Imidazole):
[0106] The synthesis of 5-(1H-1-pyrazolyl)-1-pentanamine is typical: Sodium hydride (1.2 mol-equivalents) was added to a mixture of pyrazole or imidazole (one mol-equivalent) and 1-N-bromoalkylphthalimide (one mol-equivalent) in DMF (1 M with respect to the reagents). Once the bubbling subsided, the mixture was heated at reflux temperature for two days. The reaction mixture was cooled, triturated with water, the precipitate was collected, washed with water and dried under reduced pressure to give the phthalimide protected product.
[0107] A mixture of the phthalimide such as 2-[5-(1H-1-pyrazolyl)pentyl]-1,3-isoindolinedione and hydrazine (one equivalent) in methanol were heated to reflux temperature for 12 hours and cooled. 1 N HCl (1-5 equivalents) was added and the mixture was filtered and washed with methanol and water and then concentrated to give 5-(1H-1-pyrazolyl)-1-pentanamine as a viscous oil. (Scheme 1G)
[0108] General Procedure for the Synthesis of the Amino Side Chains Such as:
[0109] N1-[4-(aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide
[0110] N1-[4-(aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide
[0111] N1-[4-(aminomethyl)cyclohexyl]methyl-4-(tert-butyl)-1-benzenesulfonamide
[0112] N′-[4-(aminomethyl)cyclohexyl]methyl-N,N-dimethylsulfamide
[0113] Dimethylsulfamoyl chloride (one mol-equivalent, ClSO2N(CH3)2) was added to a stirred solution of 1,4-bis-aminomethylcyclohexane (3 mol-equivalents) and diisopropylethylamine (1 mol-equivalent) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure and chromatographed silica) to give the desired product as viscous oils. (Scheme 1A)
[0114] N1-[4-(aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide: Synthesized According to Scheme 1A, 1H NMR (CDCl3) &dgr;7.86 (m, 2H), 7.19 (apparent t, J=8.1 Hz), 4.65 (broad, 1H), 2.86 and 2.78 (two d, 2H, ratio of 2:1 respectively, J=7.2 and 6.9 Hz respectively), 2.55 and 2.50 (two d, 2H, ratio of 2:1 respectively, J=6.3 Hz each), 1.82−0.90 (m, 10H).
[0115] General Procedure for the Synthesis of 2,4-dichloro-6-amino-1,3,5-Triazines:
[0116] One mole equivalent of the amine was added dropwise to a solution of one mole-equivalent of 1,3,5-trichlorotriazine and 2 mole-equivalents of diisopropylethylamine in dichloromethane or THF at −78° C. under argon. The resulting solution was stirred for 1 hour at −78° C., quenched with ether, precipitated salts removed by filtration, solvent removed under reduced pressure and the crude product was chromatographed (silica) to give the desired product.
[0117] 2,4-Dichloro-6-isopropylamino-1,3,5-triazine:
[0118] Isopropylamine (neat, 4.13 g, 69.8 mmmol) was added dropwise to a stirred solution of diisopropylethylamine (9.02 g, 69.8 mmmol) and 2,4,6-trichlorotriazine (12.9 g, 69.8 mmmol) in 100 ml of dry THF at −78° C. under argon. The resulting mixture was stirred at −78° C. for 0.5 hour, 200 ml of ether was added, filtered and the solids were washed with ether. The combined filtrates were concentrated and chromatographed (5% ethyl acetate-hexane, silica) to give 8.06 g of the desired product: Synthesized According to Scheme 2 and 3; 1H NMR (CDCl3) &dgr;5.80 (broad, 1H, 4.21 (septet, 1H, J=6.6 Hz), 1.25 (d, 6H, J=6.6 Hz)
[0119] 2,4-Dichloro-6-cyclopropylamino-1,3,5-triazine:
[0120] Synthesized According to Scheme 2 and 3; 1H NMR (CDCl3) &dgr;5.93 (broad, 1H), 2.88 (m, 1H), 0.94 (m, 2H) 0.63 (m, 1H).
[0121] General Procedure for the Synthesis of 2-Chloro-4,6-diamino-1,3,5-triazines:
[0122] One mole-equivalent of an amine, one mol-equivalent of 2,4-dichloro-6-amino-1,3,5-triazines and 2 mole-equivalents of diisopropylethylamine were stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the crude product was chromatographed on silica to give the desired product:
[0123] N1-{[4-({[4-Chloro-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: A suspension of 2,4-dichloro-6-isopropyltriazine (1.04 g, 5.02 mmol), diisopropylethylamine (1.50 g, 10.0 mmol) and cyclohexylmethylamine (1.66 g, 5.00 mmol) in 15 ml of dry THF were stirred at room temperature for 3 days under argon. The initial suspension turned clear. The solvent was removed under reduced pressure, the solids were partitioned between ethyl acetate-hexane (50 ml, 1:9) and water (50 ml), separated and solvent removed to give 2.75 g of a white solid in 60% yield: Synthesized According to Scheme 2; 503 and 505 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.62 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.95 (dd, J=8.0, 0.9 Hz), 7.72−7.50 (m, 3H), 5.20−3.95 (m, 4H), 4.04 (septet, 1H, J=6.6 Hz, 3.21 and 3.06 (two t, 2H, J=6.6 Hz), 2.72 (t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.19 (d, 6H, J=6.6 Hz)
[0124] General Procedure for the Synthesis of 2,4,6-Triamino-1,3,5-triazines from 2,4-diamino-6-chlorotriazines:
[0125] Parallel synthesis was used to prepare the triaminotriazines. The crude products were chromatographed (Preparative TLC) to give the final products.
[0126] A solution of 0.0200 mmol of N1-{[4-({[4-Chloro-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide, 10 mg of a primary or secondary amine and 30 &mgr;l of diisopropylethylamine in 200 &mgr;l &mgr;l of DMF or dioxane were heated to 100-140° C. for at least 8 hours. The resulting mixture was cooled, applied to a preparative thin layer chromatography plate (2000 microns, Analtech) and eluted with an appropriate solvent to give the desired product. In cases where DMF was used as the solvent, a side product corresponding to a dimethylamino substitution (Example 17) of the chloro group of N1-{[4-({[4-chloro-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide in about 20% yield was also obtained especially when primary amines were used to displace the chloro group. This product was separated from the desired product using Preparative Thin Layer Chromatography. (Scheme 2)
[0127] General Procedure for the Synthesis of 2,4,6-Triamino-1,3,5-triazines from 2,4-diamino-6-chlorotriazines:
[0128] A mixture of 2,4-diethylamino-6-chloro-1,3,5-triazine (1 mol-equivalents), diisopiropylethylamine (one mol-equivalent) and 1,4-bis-aminomethylcyclohexane (3 equivalents) in dioxane were heated at reflux temperature for 3 days, cooled, concentrated and chromatographed on silica to give N1-[4-(aminomethyl)cyclohexyl]methyl-N3,N5-diethyl-1,3,5-benzenetriamine in 65% yield: Anal. Calc. for C15H29N7: C, 58.60; H, 9.51; N, 31.89. Found: C, 58.84; N, 9.61; N, 31.64; 1H NMR (CDCl3) &dgr;4.78 (broad, 3H), 3.45−3.10 (m, 6H), 2.60 and 2.51 (two d, 2H, J=6.3 Hz), 1.90−0.70 (m, 11H), 1.17 (t, 6H, J=7.3 Hz). (Scheme 3)
[0129] General Procedure for the Synthesis of 2,4,6-Triamino-1,3,5-triazines Containing Sulfonyl Ureas from 2,4-diamino-6-chlorotriazines or 2,4,6-Triaminotriazines Containing Dimethylamino Sulfonyl Ureas:
[0130] A transamination reaction was used to synthesize the sulfonyl ureas from dimethylaminosulfonyl ureas. A solution of one mol-equivalent of dimethyl sulfonyl urea, two mol-equivalents of diisopropylethylamine and one mol-equivalent of an amine such as morpholine or cyclopropylamine were heated at 100° C. in dioxane for 16 hours. The reaction mixture was cooled, concentrated and chromatographed to give the desired product. (Schemes 4A, 4B, 4C, and 4D)
[0131] Compounds in Table 1 (DMF as solvent unless otherwise noted):
EXAMPLE 1[0132] Synthesized According to Scheme 2.
[0133] N1-{[4-({[4-(Isopropylamino)-6-(methylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 60% yield (90% yield in dioxane), Anal. Calc. For C25H35N7O2S1+0.2H2O: C, 59.90; H, 7.12; N, 19.56. Found: C, 59.91; H, 7.31; N, 19.23; 498 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.63 (d, 1H, J=8.5 Hz), 8.24 (dd, 1H, J=7.2, 0.9 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (dd, 1H, J=7.2, 0.9 Hz), 7.68−7.52 (m, 3H), 4.73 (broad, 4H) 4.11 (m, 1H), 3.13 (m, 2H), 2.88 (broad, 3H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.90−0.70 (m, 7H), 1.16 (d, 6H, J=6.3 Hz).
EXAMPLE 2[0134] Synthesized According to Scheme 2.
[0135] N1-[4-([4-(ethylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 41% yield, 512 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=8.7, 1.3 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.96 (dd, 1H, J=8.0, 1.3 Hz), 7.70−7.50 (m, 3H), 4.76 (broad, 1H), 4.10 (broad, 1H), 3.37 (broad, 1H), 3.14 (broad, 1H), 2.73 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 9H), 1.18 (d, 6H, J=6.6 Hz), 1.15 (t, 2 H, J=7.2 Hz).
EXAMPLE 3[0136] Synthesized According to Scheme 2.
[0137] N1-{[4-({[4-(Allylamino)6-(isopropylamino)-1,3,5,-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 20% yield (84% yield in dioxane); Anal. Calc. for C23H37N7O2S1+1.0H2O: C, 59.87; N, 7.26; N, 18.10. Found: C, 60.32; H, 7.08; N, 17.89; 524 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.62 (d, 1H, J=8.6 Hz), 8.24 (dd, 1H, J=8.6, 1.3 Hz), 8.07 (d, 1H, J=8.1 Hz), 7.95 (dd, 1H, J=8.1, 0.6 Hz), 7.68−7.52 (m, 3H), 5.90 (ddt, 1H, J=17.1, 10.3, 1.5 Hz), 5.20 (apparent dq, 1H, J=17.1, 1.5 Hz), 5.10 (apparent dq, 1H, J=10.3, 1.5 Hz), 4.85 (broad, 1H), 4.62 (m, 1H), 4.08 (broad, 1H), 3.97 (m, 2H), 3.14 (m, 2H), 2.72 (t, 2H, J=6.6 Hz), 1.80−0.70 (m, 11H), 1.16 (d, 6H, J=6.6 Hz).
EXAMPLE 4[0138] Synthesized According to Scheme 2.
[0139] N1-{[4-({[4,6-Di(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 29% yield; 526 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.4 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (dd, 1H, J=7.5 Hz), 7.68−7.52 (m, 3H), 5.10−4.40 (broad, 3H), 4.71 (apparent t, 1H, J=6.6 Hz), 4.15 (m, 2H), 3.18 (m, 2H), 2.72 (apparent t, 2H, J=6.6 Hz), 2.20−0.65 (m, 7H), 1.17 (d, 12H, J=6.6 Hz).
EXAMPLE 5[0140] Synthesized According to Scheme 2.
[0141] N1-[4-([4-(isopropylamino)-6-(propylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 55% yield; 526 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.65 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=8.0 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (d, 1H, J=8.0 Hz), 7.72−7.50 (m, 3H), 5.10 (broad, 1H), 4.88 (m, 1H), 4.09 (m, 1H), 3.40−3.00 (m, 4H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 9H), 1.18 (d, 6H, J=6.6 Hz), 0.94 (t, 3H, J=7.2 Hz).
EXAMPLE 6[0142] Synthesized According to Scheme 2.
[0143] N1-[4-([4-(butylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 56% yield; 540 (MH+, ESI) 1H NMR (CDCl3) &dgr;8.65 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=8.0 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (d, 1H, J=8.0 Hz), 7.70−7.50 (m, 3H), 5.20−4.60 (broad, 3H), 4.10 (broad, 1H), 3.33 (broad, 2H), 3.14 (broad, 2H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.70−0.60 (m, 11H), 2.72 (d, 6H, J=6.6 Hz), 0.92 (t, 3H, J=7.1 Hz).
EXAMPLE 7[0144] Synthesized According to Scheme 2.
[0145] N1-[4-([4-(cyclobutylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 58% yield; 538 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.65 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=8.7, 0.9 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (dd, 1H, J=8.0, 0.9 Hz), 7.72−7.52 (m, 3H), 5.50−4.50 (broad, 4H), 4.40 (m, 1H), 4.09 (M, 1H), 3.13 (m, 2H), 2.72 (apparent t, 2H, J=6.6 Hz), 2.34 (m, 2H), 2.00−0.65 (m, 13H), 1.17 (d, 6H, J=6.6 Hz).
EXAMPLE 8[0146] Synthesized According to Scheme 2.
[0147] N1-[4-([4-(cyclopropylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 57% yield; 524 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.67 (d, 1H, J=8.7 Hz), 8.26 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.70−7.52 (m, 3H), 5.20−4.60 (broad, 4H), 4.11 (broad, 1H), 3.14 (broad, 2H, 2.71 2.19 (broad, 2H), 1.80−0.40 (m, 11H), 1.16 (d, 6H, J=6.3 Hz)
EXAMPLE 9[0148] Synthesized According to Scheme 2.
[0149] N1-[4-([4-(isopropylamino)-6-(pentylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 49% yield; 554 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.24 (dd, 1H, J=8.7, 1.3 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 5.05 (broad, 1H), 4.78 (broad, 1H), 3.81 (broad, 2H), 3.14 (broad, 1H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 13H), 1.18 (d, 6H, J=6.6 Hz), 0.89 (t, 3H, J=7.1 Hz).
EXAMPLE 10[0150] Synthesized According to Scheme 2.
[0151] N1-[4-([4-[(2-cyanoethyl)amino]-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 43% yield; 537 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.24 (dd, 1H, J=8.7, 1.3 Hz), 8.08 (d, 1H, J 8.0 Hz), 7.95 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 6.08 (broad, 1H), 5.30 (broad, 1H), 4.81 (apparent t, 1H, J=6.6 Hz), 4.08 (broad, 1H), 3.70−2.50 (m, 6H), 1.80−0.65 (m, 7H), 1.17 (d, 6H, J=6.6 Hz).
EXAMPLE 11[0152] Synthesized According to Scheme 2.
[0153] N1-[4-([4-[(2-hydroxyethyl)amino]-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 36% yield; 528 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.24 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 5.58 (broad, 1H), 5.26 (broad, 1H), 5.10 (broad, 1H), 4.91 (broad, 1H), 4.08 (broad, 1H), 3.70 (t, 2H, J-6.6 Hz), 3.37 (p, 2H, J=6.6 Hz), 3.203.50−2.65 (m, 4H), 1.80−0.65 (m, 7H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 12[0154] Synthesized According to Scheme 2.
[0155] N1-(4-[(4-(isopropylamino)-6-[(2-methoxyethyl)amino]-1,3,5-triazin-2-ylamino)methyl]cyclohexylmethyl)-1-naphthalenesulfonamide: 63% yield; 542 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.24 (dd, 1H, J=8.7, 1.3 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 5.93 (broad, 1H), 5.23 (broad, 1H), 4.80 (apparent t, 1H, J=6.6 Hz), 4.10 (m, 1H), 3.60−3.05 (m, 6H), 3.75 (s, 3H), 2.72 (t, apparent t, 2H, J=6.6 Hz), 1.75−0.65 (m, 7H, 1.17 (d, 6H, J=6.6 Hz).
EXAMPLE 13[0156] Synthesized According to Scheme 2.
[0157] N1-(4-[(4-(isopropylamino)-6-[(3-methoxypropyl)amino]-1,3,5-triazin-2-ylamino)methyl]cyclohexylmethyl)-1-naphthalenesulfonamide: 83% yield; 556 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.24 (dm, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.95 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 6.30−5.80 (broad, 2H), 5.20−4.50 (broad, 2H), 4.10 (broad, 1H), 3.60−3.05 (m, 6H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 9H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 14[0158] Synthesized According to Scheme 2.
[0159] N1-{[4-({[4-{[2-(dimethylamino)ethyl]amino)-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 78% yield; 555 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.63 (d, 1H, J=8.5 Hz), 8.24 (dd, 1H, J=7.2, 0.9 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (dd, 1H, J=7.2, 0.9 Hz), 7.68−7.52 (m, 3H), 5.70−4.60 (broad, 3H), 4.15 (septet, 1H, J=6.6 Hz), 3.70 (broad, 1H), 3.45 (m, 2H), 3.14 (m, 2H), 2.71 (apparent t, 2H, J=6.3 Hz), 2.53 (t, 2H, J=6.0 Hz), 2.30 (s, 6H), 1.80−0.65 (m, 7H), 1.17 (d, 6H, J=6.6 Hz).
EXAMPLE 15[0160] Synthesized According to Scheme 2.
[0161] N1-[4-([4-[3-(1H-1-imidazolyl)propyl]amino-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 93% yield; 592 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.69 (d, 1H, J=8.7 Hz), 8.26 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.70−7.52 (m, 4H), 7.05 (m, 1H), 6.94 (m, 1H), 6.15 (broad, 1H), 5.70−5.00 (broad, 3H), 4.02 (t, 2H, J=6.9 Hz), the triplet at 4.02 partially covers a multiplet at 4.09 (1H), 3.40−3.00 (m, 4H), 2.71 (t, 2H, J-6.3 Hz), 2.00−0.65 (m, 13H), 1.16 (d, 6H, J=6.7 Hz).
EXAMPLE 16[0162] Synthesized According to Scheme 2.
[0163] N1-({4-[({4-(isopropylamino)-6-[(4-methoxyphenethyl)amino]-1,3,5-triazin-2-yl}amino)methyl]cyclohexyl}methyl)-1-naphthalenesulfonamide: 50% yield, 618 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz). 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 5.10−4.60 (m, 4H), 4.15 (m, 1H), 3.79 (s, 3H), 3.54 (m, 2H), 3.14 (m, 2H) 2.80 (m, 2H), 2.71 (t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.17 (d, 6H).
EXAMPLE 17[0164] Synthesized According to Scheme 2.
[0165] N1-{[4-({[4-(dimethylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 512 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.63 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=8.7, 1.3 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.95 (dd, 1H, J=8.0, 1.3 Hz), 7.72−7.50 (m, 3H), 5.90 (broad, 1H), 4.65 (apparent t, 1H, J=6.6 Hz), 4.12 (septet, 1H, J=6.6 Hz), 3.15 (m, 2H), 3.09 (broad s, 6H), 2.72 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 18[0166] Synthesized According to Scheme 2.
[0167] N1-[4-([4-[ethyl(methyl)amino]-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 58% yield; 556 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz) 8.24 (dd, 1H, J=7.5, 0.9 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H, 4.68 (t, 1H, J=6.3 Hz), 4.12 (septet, 1H, J=6.6 Hz), 3.57 (q, 2H, J=7.1 Hz), 3.13 (t, 2H, J=6.6 Hz), 3.03 (broad s, 3H), 2.72 (t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.18 (d, 6H, J=6.6 Hz), 1.12 (t, 3H, J=7.1 Hz).
EXAMPLE 19[0168] Synthesized According to Scheme 2.
[0169] N1-[4-([4-(diethylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 95% yield; 540 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.26 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.96 (d, J=8.0 Hz), 7.72−7.50 (m, 3H), 5.50−4.50 (broad, 2H), 4.10 (septet, 1H, J=6.6 Hz), 3.52 (q, 4H, J=7.1 Hz), 3.13 (apparent t, 2H, J=6.6 Hz), 2.71 (apparent t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.17 (d, 6H, J=6.6 Hz), 1.14 (t, 6H, J=7.1 Hz).
EXAMPLE 20[0170] Synthesized According to Scheme 2.
[0171] N1-[4-([4-(isopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 12% yield; 538 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=8.7, 1.3 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.95 (d, J=8.0, Hz), 7.72−7.50 (m, 3H), 5.15 (broad, 1H), 4.90 (broad, 1H), 4.70 (broad, 1H), 4.12 (septet, 1H, J=6.6 Hz), 3.50 (m, 4H), 3.15 (apparent t, 2H, J=6.6 Hz), 2.72 (apparent t, 2H, J=6.6 Hz), 1.70−0.60 (m, 11H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 21[0172] Synthesized According to Scheme 2.
[0173] N1-(4-[(4-(isopropylamino)-6-[(2S)-2-(methoxymethyl)tetrahydro-1H-1-pyrrolyl]-1,3,5-triazin-2-ylamino)methyl]cyclohexylmethyl)-1-naphthalenesulfonamide: 87% yield; 554 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 5.50−4.40 (m, 4H), 4.15 (m, 1H), 3.92 (m, 2H), 3.70−3.20 m, 6H), 3.75 (s, 3H), 2.72 (t, 2H, J=6.6 Hz), 2.20−0.60 (m, 11H), 1.17 (d, 6H).
EXAMPLE 22[0174] Synthesized According to Scheme 2.
[0175] N1-{[4-({[4-(isopropylamino)-6-piperidino-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: Anal. Calc. For C29H41N7O2S1+0.3EtOAc: C, 62.74; H, 7.57; N, 16.96. Found: C, 62.70; H, 7.57; N, 16.94; 552 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz) 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 4.67 (b, 2H), 4.55 (b, 1H), 4.11 (septet, 1H, J=6.3 Hz), 3.67 (m, 4H), 3.48 (apparent t, 2 H, J=5.7 Hz), 3.30 (apparent t, 2 H, J=5.7 Hz), 3.14 (m, 2H), 2.71 (t, 2H, J=6.3 Hz) 2.00−0.60 (m, 13H), 1.16 (d, 6H, J=6.3 Hz).
EXAMPLE 23[0176] Synthesized According to Scheme 2.
[0177] N1-[4-([4-(isopropylamino)-6-(2-methylpiperidino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 92% yield; 566 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 5.10−4.60 (broad, 4H) 4.15 (septet, 1H, J=6.6 Hz), 3.40−2.70 (m, 6H), 2.80 and 2.64 (two s, 3H), 2.74 (apparent t, 2H, J=6.3 Hz), 1.75−0.60 (m, 13H), 1.13 (d, 6H, J=6.6 Hz).
EXAMPLE 24[0178] Synthesized According to Scheme 2.
[0179] N1-[4-([4-(isopropylamino)-6-morpholino-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 93% yield; 554 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 5.2−4.6 (broad, 4H), 4.15 (septet, 1H, J=6.6 Hz), 4.00−3.00 (m, 8H), 2.72 (t, 2H, J-6.6 Hz), 1.80−0.60 (m, 7H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 25[0180] Synthesized According to Scheme 2.
[0181] N1-{[4-({[4-[(2R,6S)-2,6-dimethyl-1,4-oxazinan-4-yl]-6-(isopropylamino)-1,3,5-triazin-2-yl]amino)methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 94% yield, 582 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.63 (d, 1H, J=8.5 Hz), 8.24 (dd, 1H, J=7.2, 0.9 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (dd, 1H, J=7.2, 0.9 Hz), 7.68−7.52 (m, 3H), 4.76−4.30 (m, 4H), 4.09 (septet, 1H, J=6.6 Hz), 3.54 (m, 4H), 3.14 (apparent t, 2H, J=6.6 Hz), 2.74 (t, 2H, J=6.6 Hz) 2.60−0.65 (m, 7H), 1.18 (d, 6H, J-6.6 Hz), 1.16 (dm, 6H, J=6.6 Hz).
EXAMPLE 26[0182] Synthesized According to Scheme 2.
[0183] N1-[4-([4-[(2-hydroxyethyl)(methyl)amino]-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonamide: 93% yield; 542 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1 H, J=8.7 Hz), 8.24 (dd, 1H, J=7.5, 0.9 Hz), 8.09 (d, 1H, J=8.1 Hz), 7.95 (d, J=8.0 Hz), 7.70−7.52 (m, 3H), 5.10−4.60 (broad, 4H, 4.15 m, 1H), 3.75−2.80 (m, 6H), 3.05 (s, 3H), 2.72 (t, 2H, J-6.6 Hz), 1.80−0.65 (m, 7H), 1.18 (d, 6H, J=6.6 Hz).
EXAMPLE 27[0184] Synthesized According to Scheme 2.
[0185] N1-{[4-({[4-(4-acetylpiperazino)-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl)-1-naphthalenesulfonamide: 77% yield; 595 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.63 (d, 1H, J=8.5 Hz), 8.24 (d, 1H, J=7.2 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (d, 1H, J=7.2 Hz), 7.68−7.52 (m, 3H), 5.00−4.40 (broad, 3H), 4.70 (t, 1H, J=6.6 Hz), 4.15 (septet, 1H, J=6.6 Hz), 3.71 (m, 4H), 3.61 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H) 2.72 (t, 2H, J-6.3 Hz), 2.13 (s, 3H), 1.90−0.65 (m, 7H), 1.17 (d, 6H, J=6.6 Hz).
EXAMPLE 28[0186] Synthesized According to Scheme 2.
[0187] N1-{[4-({[4-(isopropylamino)-6-(4-isopropylpiperazino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 60% yield; 595 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.64 (d, 1H, J=8.5 Hz), 8.24 (dd, 1H, J=7.2, 0.9 Hz), 8.07 (d, 1H, J=8.4 Hz), 7.95 (dd, 1H, J=7.2, 0.9 Hz), 7.68−7.52 (m, 3H), 5.20−4.40 (broad, 2H), 4.71 (apparent t, 1H, J=6.6 Hz), 4.13 (septet, 1H, J=6.6 Hz), 3.76 (m, 4H), 3.16 (apparent t, 2H, J=6.6 Hz), 2.74 overlapping a multiplet (t, 3H, J=6.6 Hz), 2.53 (m, 4H), 1.64 (ABm, 4H), 1.50−0.60 (m, 3H), 1.16 (d, 6H, J=6.6 Hz), 1.06 (d, 6H, J=6.6 Hz).
[0188] Compounds in Table 2 (Dichloromethane as Solvent):
EXAMPLE 29[0189] Synthesized According to Scheme 3.
[0190] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-(tert-butyl)-1-benzenesulfonamide: 40% yield; Anal. Calc. For C25H41N7SO2+0.10 CH2Cl2: C, 59.60; H, 8.20; N, 19.40. Found: C, 58.42; H, 7.98; N, 18.16; 504 (MH+, ESI); 1H NMR (CDCl3) &dgr;7.80 (d, 2H, J=8.6 Hz), 7.50 (d, 2H, J=8.6 Hz), 5.40 (broad, 1H), 5.20−4.75 (broad, 3H), 3.40−3.15 (m, 6H), 2.75 (t, 2H, J=4.5 Hz), 1.80−1.10 (m, 14H), 1.25 (s, 9H), 0.80−0.70 (broad, 2H).
EXAMPLE 30[0191] Synthesized According to Scheme 3.
[0192] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide: 30% yield, Anal. Calc. For C21H30N7FSO2+0.10 CH2Cl2: C, 54.10; H, 6.90; N, 21.00. Found: C, 53.77 H, 6.75; N, 20.43; 1H NMR (CDCl3) &dgr;7.85 (d, 2H, J=8.6 Hz), 7.15 (d, 2H, J=8.6 Hz), 5.00−4.50 (broad. 4H), 3.40−3.15 (m, 6H), 2.80−2.70 (m, 2H), 1.80−1.20 (m, 14H), 0.90−0.80 (broad, 2H).
Example 31[0193] Synthesized According to Scheme 3.
[0194] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2-methoxy-5-methyl-1-benzenesulfonamide: 86% yield; 492 (MH+, ESI); Anal. Calc. for C23H37N7O3S1+1.5CH3OH: C, 54.52; H, 8.03; N, 18.17. Found: C, 54.09; H, 7.84; N, 18.18; 1H NMR (CDCl3) &dgr;7.81 (m, 1H), 7.33 (broad d, 1H, J=8.0 Hz), 6.93 (d, 1H, J=8.0 Hz), 5.20−4.60 (broad, 4H), 3.94 (s, 3H), 3.50−3.10 (m, 6H), 2.76 and 2.67 (two t, 2H, J=6.3 Hz), 2.50−2.30 (m, 4H), 1.90−0.70 (m, 11H), 1.17 (t, 6H, J=7.2 Hz).
EXAMPLE 32[0195] Synthesized According to Scheme 3.
[0196] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2-fluoro-1-benzenesulfonamide: 86% yield; 466 (MH+, ESI); Anal. Calc. for C21H32F1N7O2S1+1.5CH3OH: C, 52.61; H, 7.46; N, 19.09. Found: C, 52.14, H, 7.10; N, 19.17; 1H NMR (CDCl3) &dgr;7.90 (m, 1H), 7.58 (m, 1H), 7.40−7.18 (m, 2H), 5.50−4.60 (broad, 4H), 3.50−3.10 (m, 6H), 2.91 and 2.82 (two t, 2 H, J=6.2 Hz), 1.90−0.60 (m, 11H), 1.17 (t, 6H, J=7.2 Hz).
EXAMPLE 33[0197] Synthesized According to Scheme 3.
[0198] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2-methyl-1-benzenesulfonamide: 28% yield; 462 (MH+, ESI); Anal. Calc. for C22H35N7O2S1+0.7CH3OH.C, 56.33; H, 7.87, N, 20.26. Found: C, 56.34; H, 7.82; N, 20.01; 1H NMR (CDCl3) &dgr;7.40 (m, 4H), 5.10−4.60 (broad, 4H), 4.26 and 4.25 (two t, 2H, J=6.2 Hz), 2.10−0.70 (m, 11H), 1.18 (t, 6H, J=7.2 Hz).
EXAMPLE 34[0199] Synthesized According to Scheme 3.
[0200] N3-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-3-pyridinesulfonamide: 94% yield; 449 (MH+, ESI); Anal. Calc. for C20H32N8O2S1+1.5CH3OH: C, 52.00; H, 7.71; N, 22.56. Found: C, 51.84; H, 7.65; N, 22.27; 1H NMR (CDCl3) &dgr;9.08 (m, 1H), 8.81 (dm, 1H, J=5.3 Hz), 8.16 (dm, 1H, J=8.1 Hz), 7.46 (ddm, 1H, J=5.3, 8.1 Hz), 5.20−4.60 (broad, 4H), 3.50−3.10 (m, 6H), 2.92 and 2.83 (two d, 2H, J=6.3 Hz), 1.85−0.80 (m, 11H), 1.15 (t, 6H, J=7.3 Hz)
EXAMPLE 35[0201] Synthesized According to Scheme 3.
[0202] N1-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-methoxy-1-benzenesulfonamide: 86% yield; 478 (MH+, ESI); Anal. Calc. for C22H35N7O3S1+0.5CH3CH: C, 54.30; H, 7.46; N, 20.15. Found: C, 54.30; H, 7.42; N, 19.66; 1H NMR (CDCl3) &dgr;7.80 (dm, 2H, J=8.9 Hz), 6.98 (dm, 2H, J=8.9 Hz), 5.20−4.60 (broad, 4H), 3.86 (s, 3H), 1.90−0.70 (m, 11H), 1.16 (t, 6H, J=7.3 Hz).
EXAMPLE 36[0203] Synthesized According to Scheme 3.
[0204] N5-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2,4-dimethyl-1,3-oxazole-5-sulfonamide: 86% yield; 467 (MH+, ESI); Anal. Calc. for C20H34N8O3S1: C, 51.48; H, 7.34; N, 24.01. Found: C, 51.26; H, 7.34; N, 23.81; 1H NMR (CDCl3) &dgr;5.10−4.50 (broad, 4H), 3.50−2.70 (m, 6H), 2.64 (two s, 3H), 2.40 (two s, 3H), 2.10−0.80 m, 11H), 1.18 t, 6H, J=7.3 Hz).
EXAMPLE 37[0205] Synthesized According to Scheme 3.
[0206] N2-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2-thiophenesulfonamide: 93% yield; 454 (MH+, ESI); Anal. Calc. for C19H31N7O2S2+0.5H2O: C, 49.33; H, 6.97; N, 21.19. Found: C, 49.36; H, 6.91; N, 20.82; 1H NMR (CDCl3) &dgr;7.62 (m, 2H), 7.10 (m, 1H), 5.30−4.50 (broad, 3H), 3.50−2.80 (m, 8H), 2.60−1.90 (b, 1H), 1.90−0.70 (m, 11H), 1.17 (t, 6H, J=7.3 Hz).
EXAMPLE 38[0207] Synthesized According to Scheme 3.
[0208] N4-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-methyl-1H-4-imidazolesulfonamide: 90% yield; 452 (MH+, ESI); Anal. Calc. for C19H33N9O2S1+0.7CH3OH: C, 49.92; H, 7.61; N, 26.59. Found: C, 49.65; H, 7.18; N, 27.09; 1H NMR (CDCl3) &dgr;7.50 (m, 1H), 7.46 (m, 1H), 5.50−4.80 (broad, 4H), 3.75 (s, 3H), 3.50−2.70 (m, 6H), 2.70−2.00 (broad, 1H, 1.90−0.70 (m, 11H), 1.16 (t, 6H, J=6.3 Hz)
EXAMPLE 39[0209] Synthesized According to Scheme 3.
[0210] N1-[4-([4,6-di(ethylamino)-]1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-methyl-1-benzenesulfonamide: 95% yield; 462 (MH+, ESI); Anal. Calc. for C22H35N7O2S1+0.5CH3OH: C, 56.58; H, 7.81; N, 20.53. Found: C, 56.79; H, 7.74; N, 20.36; 1H NMR (CDCl3) &dgr;7.76 (dm, 2H, J=8.1 Hz), 7.32 (dm, 2H, J=8.1 Hz), 5.30−4.6 (broad, 4H), 3.50−3.00 (m, 6H), 2.42 (s, 3H), 1.90−0.70 (m, 11H), 1.14 (t, 6H, J=7.3 Hz).
Example 40[0211] Synthesized According to Scheme 3.
[0212] N5-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-2,1,3-benzothiadiazole-5-sulfonamide: 84% yield; 506 (MH+, ESI); 1H NMR (CDCl3) &dgr;8.27 (m, 2H), 7.73 (m, 1H), 5.60 (broad, 1H), 5.40 (broad, 3H), 3.45−3.00 (m, 6H), 2.82 and 2.72 (two d, 2H, J=6.8 Hz), 1.80−0.70 (m, 11H), 1.15 (t, 6H, 7.3 Hz).
EXAMPLE 41[0213] Synthesized According to Scheme 3.
[0214] N8-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-8-quinolinesulfonamide: 48% yield; 499 (MH+, ESI); Anal. Calc. for C24H34N8O2S1+0.5CH3OH: C, 57.18; H, 7.05; N, 21.77. Found: C, 57.22; H, 7.15; N, 21.67; 1H NMR (CDCl3) &dgr;9.03 (m, 1H), 8.45 (dm, 1H, J=8.0 Hz), 8.30 (d, 1H, J=8.0 Hz), 8.06 (dm, 1H, J=8.0 Hz), 7.67 (mt, 1H, J=8.0 Hz), 7.57 (dd, 1H, 4.8, 8.0 Hz)6.34 (m, 1H), 4.88 (broad, 3H), 3.50−3.00 (m, 6H), 2.76 and 2.67 (two t, 2H, J=6.4 Hz), 2.30 (broad, 2H, 1.80−0.70 (m, 11H), 1.15 (t, 6H, J=7.3 Hz).
EXAMPLE 42[0215] Synthesized According to Scheme 3.
[0216] N-[4-([4,6-di(ethylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methylmethanesulfonamide: 55% yield; 386 (MH+, ESI); Anal. Calc. for C16H31N7O2S1+0.5CH3OH: C, 49.35; H, 8.28; N, 24.42. Found: C, 49.10; H, 7.78; N, 24.81; 1H NMR (CDCl3) &dgr;5.20−4.60 (broad, 5H), 3.50−3.00 (m, 8H), 2.95 and 2.93 (two s, 3H), 1.90−0.70 (m, 11H), 1.18 (t, 6H).
[0217] Compounds in Table 3 (Dioxane as Solvent):
Example 43[0218] Synthesized According to Scheme 4A.
[0219] N1-[4-([4-(isopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-pyrrolidinesulfonamide: 35% yield; Anal. Calc. For C22H40N8SO2+0.10 CH2Cl2: C, 54.26; H, 8.28; N; 22.91. Found: C, 53.93; H, 8.25; N, 22.86; 481 (MH+, ESI); 1H NMR (CDCl3) &dgr;5.00−4.80 (m, 1H), 4.80−4.60 (m, 1H), 4.60−4.40 (m, 1H , 3.60−3.40 (m, 6H), 2.95−2.80 (m, 3H), 1.90−1.80 (m, 8H), 1.50−1.30 (m, 8H), 1.20−1.050 (m, 6H), 0.90−0.80 (m, 2H)
EXAMPLE 44[0220] Synthesized According to Scheme 4B.
[0221] N4-[4-([4-(isopropylamino)-6-morpholino-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-morpholinesulfonamide: 30% yield; Anal. Calc. For C22H40N8SO2+1.10 CH2Cl2: C, 48.30; H, 7.40; N, 19.60. Found: C, 48.16; H, 7.28; N, 20.01; 513 (MH+, ESI); 1H NMR (CDCl3) &dgr;5.05−4.60 (m, 3H), 3.80−3.60 (m, 12H), 3.35−3.10 (m, 6H), 3.05−2.80 (m, 3H), 1.80−1.30 (m, 8H), 1.20−1.05 (m, 6H), 1.00−0.80 (m, 2H).
EXAMPLE 45[0222] Synthesized According to Scheme 4B.
[0223] N1-[4-([4-(isopropylamino)-6-piperidino-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-1-piperidinesulfonamide: 30% yield; Anal. Calc. For C24H44N8SO2+0.3 CH2Cl2: C, 54.64; H, 8.41; N, 20.98. Found: C, 54.53; H, 8.24; N, 20.94; 509 (MH+, ESI); 1H NMR (CDCl3) &dgr;4.80−4.60 (m, 1H), 4.60−4.50 (m, 1H), 4.20−4.10 (m, 1H), 3.80−3.60 (m, 4H), 3.40−3.30 (m, 2H), 3.20−3.10 (m, 4H), 3.00−2.90 (m, 3H), 1.80−1.40 (m, 20H), 1.20−1.050 (m, 6H), 0.90−0.80 (m, 2H).
EXAMPLE 46[0224] Synthesized According to Scheme 2.
[0225] N1-[(4-[(4,6-ditetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl)amino]methylcyclohexyl)methyl]-4-(tert-butyl)-1-benzenesulfonamide: 30% yield; Anal. Calc. For C29H45N7SO2+0.2 CH2Cl2: C, 61.20; H, 8.00; N, 17.10. Found: C, 61.60; H, 8.12; N, 16.41; 556 (MH+, ESI); 1H NMR (CDCl3) &dgr;7.75 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.7 Hz), 4.85 (broad, 1H), 4.70-650 (broad, 1H), 3.60−3.50 (broad, 8H), 3.20 (t, 2H, J=7.5 Hz), 2.75 (t, 2H, J=7.5 Hz), 1.95−1.15 (m, 16H), 1.15 (s, 9H), 0.90−0.80 (m, 2H)
EXAMPLE 47[0226] Synthesized According to Scheme 4C and 4D.
[0227] N-cyclopropyl-N′-[4-([4-(cyclopropylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methylsulfamide: 20% yield; Anal. Calc. For C20H36N8SO2+0.15 CH2Cl2: C, 52.00; H, 7.86; N; 24.08. Found: C, 51.87; H, 7.83; N, 23.74; 453 (MH+, ESI); 1H NMR (CDCl3) &dgr;5.40−5.00 (m, 3H), 4.95−4.60 (m, 2H), 3.30−3.20 (m, 2H), 2.90−2.60 (m, 3H), 2.50−2.40 m, 2H), 1.80−1.30 (m, 8H), 1.25−1.10 (m, 6H), 0.90−0.80 (m, 2H), 0.70−0.60 (m, 4H), 0.50−0.40 (m, 4H).
EXAMPLE 48[0228] Synthesized According to Scheme 2.
[0229] N′-[4-([4-(cyclopropylamino)-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-N,N-dimethylsulfamide: 28% yield; Anal. Calc. For C19H36N8SO2+0.60) CH3COOC2H5+0.10 CH2Cl2: C, 50.90; H, 7.95; N, 22.30. Found: C, 50.42; H, 7.52; N, 22.87; 441 (MH+, ESI); 1H NMR (CDCl3) &dgr;4.90−4.80 (m, 1H), 4.70−4.60 (m, 1H), 4.50−4.40 (m, 1H), 4.20−4.10 (m, 1H), 3.40−3.20 (m, 3H), 3.10 (s, 6H), 3.00−2.80 (m, 3H), 1.90−1.30 ;m, 8H), 1.15−1.05 (m, 6H), 0.95−0.85 (m, 9H), 0.70−0.50 (m, 4H)
EXAMPLE 49[0230] Synthesized According to Scheme 2.
[0231] N1-{[4-({[4-chloro-6-(isopropylamino)-1,3,5-triazin-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonamide: 60% yield; 503.08 and 505.09 (MH+, ESI): 60% yield; 1H NMR (CDCl3) &dgr;8.62 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.95 (dd, J=8.0, 0.9 Hz), 7.72−7.50 (m, 3H), 5.203.95 (m, 4H), 4.04 (septet, 1H, J=6.6 Hz), 3.21 and 3.06 (two t, 2H, J=6.6 Hz), 2.72 (t, 2H, J=6.6 Hz), 1.80−0.65 (m, 7H), 1.19 (d, 6H, J=6.6 Hz).
EXAMPLE 50[0232] Synthesized According to Scheme 3.
[0233] N′-[(4-[(4,6-dimorpholino-1,3,5-triazin-2-yl)amino]methylcyclohexyl)methyl]-N,N-dimethylsulfamide: 40% yield; Anal. Calc. For C21H38N8SO2+0.70 CH2Cl2: C, 46,80; H, 6.75; N, 19.90. Found: C, 46.68; H, 6.75; N, 19.98; 1H NMR (CDCl3) &dgr;4.90−4.80 (m, 1H), 4.60−4.50 (m, 1H), 3.80−3.60 (m, 16H), 3.20 (t, 2H, J=4.5 Hz), 2.75 (t, 2H, J=4.5 Hz), 2.8 (s, 6H), 1.8−1.3 (m, 8H). 1.1−0.9 (m, 2H).
EXAMPLE 51[0234] Synthesized According to Scheme 2.
[0235] N1-[4-([4-chloro-6-(isopropylamino)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-(tert-butyl)-1-benzenesulfonamide: 30% yield; 509 (MH+, ESI); 1H NMR (CDCl3) &dgr;7.80 (d, 2H, J=8.80 Hz), 7.50 (d, 2H, J=8.80 Hz) 5.30−5.20 (m, 1H), 4.70−4.50 (m, 2H), 3.35−3.25 (m, 2H), 2.90−2.75 (m, 3H), 1.80−1.30 (m, 8H), 1.35 (s, 9H), 1.25−1.15 (m, 6H), 0.90−0.85 (m, 2H).
EXAMPLE 52[0236] Synthesized According to Scheme 2.
[0237] N1-[4-([4-(cyclopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide: 504 (MH+, ESI); 1H NMR (CDCl3) &dgr;7.65 (d, 2H, J=8.7 Hz), 6.63 (d, 2H, J=8.7 Hz), 4.95−4.70 (m, 2H), 4.30 (m, 1H), 3.50 (m, 3H), 3.40−3.20 (m, 4H), 2.85 (t, 2H, J=5.5 Hz), 1.90 (m, 4H) 1.80−1.30 (m, 8H), 0.90 (m, 2H), 0.70 (m, 2H), 0.50 (m, 2H)
EXAMPLE 53[0238] Synthesized According to Scheme 2.
[0239] N′-((4-(((4,6-dichloro-1,3,5-triazin-2-yl)amino)methyl)cyclohexyl)methyl)-N,N-dimethylsulfamide: 35% yield; 397 (MH+, ESI); 1H NMR (CDCl3) &dgr;6.40 (m, 1H), 4.65−4.55 m, 1H), 3.40 (t, 2H, J=5.20 Hz), 3.0 (t, 2H, J=5.20 Hz), 2.80 (s, 6H), 1.85−1.30 (m, 8H) 0.950−0.85 (m, 2H)
EXAMPLE 54[0240] Synthesized According to Scheme 2.
[0241] N1-[(4-[(4,6-ditetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl)amino]methylcyclohexyl)methyl]-2-methoxy-5-methyl-1-benzenesulfonamide: 35% yield; Anal. Calc. For C27H41N7SO3+0.35 CH2Cl2: C, 57.30; H, 7.35; N, 17.10. Found: C, 57.72; H, 7.43; N, 16.43; 1H NMR (CDCl3) &dgr;7.7 (s, 1H), 7.40−7.30 (dd, 1H), 6.90 (d, 1H), 4.90−4.80 (m, 2H), 3.95 (s, 3H), 3.60−3.40 (broad s, 8H), 3.25 (t, 2H, J=5.5 Hz), 2.75 (t, 2H, J=5.5), 2.30 (s, 3H), 1.95−1.85 (broad, s, 8H), 1.80−1.20 (m, 8H), 0.95−0.8 (m, 2H).
EXAMPLE 55[0242] Synthesized According to Scheme 5.
[0243] N1-([4-([4-(cyclopropylamino)-6-(2-pyridyl)-1,3,5-triazin-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide
[0244] N1-[4-(aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide: A solution of 2.37 g of 4-fluorophenylsulfonyl chloride (12.2 mmol) in 30 ml of dichloromethane was added over 10 minutes to a stirred solution of 5.20 g of 1,4-bis-aminomethylcyclohexane (36.6 mmol) and 3.15 g of diisopropylethylamine (24.4 mmol) in 100 ml of dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 16 hours, concentrated, and chromatographed on 200 g of silica packed with 5% MeOH. (containing 2M NH3)—CHCl3, eluted with 5%, 7.5%, 10% (1 liter each) to give 3.63 g of the desired product.
[0245] A mixture of 564 mg
[0246] N1-[4-(aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzenesulfonamide (2.0 mmol) in MeOH was triturated with 1M HCl in ether. The precipitate was filtered and heated with 248 mg of cyclopropylcyanoguanidine (2.00 mmol) in 5 ml of 1-butanol for 16 hours. The solvent was removed in vacuo and the product was used in the next step.
[0247] Piconinyl chloride (67.7 mg, 0.38 mmol) was added to a stirred mixture of 175 mg of biguanide (0.38 mmol) in acetone-5% aqueous NaOH (3 mL, 2:1) at 0° C. (ice bath). After five minutes, the ice bath was removed and the mixture was stirred for 1 hour at room temperature. The solvent was removed and chromatographed on silica to give the desired compound: 11% yield; 512 (NH+, ESI); 1H NMR (CDCl3) &dgr;8.75 (m, 1H), 7.90−7.70 (m, 7H), 7.20 (m, 1H), 7.10 (m, 1H), 5.60 (broad, 1H, 5.40 (broad, 2H), 4.50 (broad, 1H), 3.45 (m, 2H), 3.00−2.60 (m, 4H), 1.90−1.00 (m, 11H), 1.00−0.50 (m, 4H).
[0248] Compounds in Table 4 (Dioxane as Solvent):
EXAMPLE 56[0249] Synthesized According to Scheme 2.
[0250] N2,N4-diethyl-N6-[5-(1H-1-pyrazolyl)pentyl]-1,3,5-triazine-2,4,6-triamine: 1H NMR (CDCl3) &dgr;7.54 (d, 1H, J=1.8 Hz), 7.32 (d, 1H, J=2.1 Hz), 6.19 (dd, 1H, J=1.8, 2.1 Hz), 5.10 (b, 3H), 4.08 (t, 2H, J=6.9 Hz), 3.32 (m, 6H), 1.85 (p, 2H, J=6.9 Hz), 1.54 (p, 2H, J=6.9 Hz), 1.31 (p, 2H, J=6.9 Hz), 1.12 (t, 6H, J=7.2 Hz).
EXAMPLE 57[0251] Synthesized According to Scheme 2.
[0252] N2,N4-diethyl-N6-[3-(1H-1-imidazolyl)propyl]-1,3,5-triazine-2,4,6-triamine: 1H NMR (CDCl3) &dgr;7.45 (s, 1H) 6.99 (s, 1H), 6.86 (s, 1H), 5.42 (broad, 1H), 5.15 (broad, 2H), 3.92 (t, 2H, J=6.9 Hz), 3.55 (broad, 1H), 3.31 (m, 6H), 1.98 (p, 2H, J=6.9 Hz), 1.10 (t, 6H, J=7.2 Hz).
Example 58[0253] Synthesized According to Scheme 2.
[0254] N2,N4-diethyl-N6-(2-pyridylmethyl)-1,3,5-triazine-2,4,6-triamine: 1H NMR (CDCl3) &dgr;8.44 (d, 1H, J=4.8 Hz), 7.55 (apparent dt, 1H, J=7.8, 1.3 Hz), 7.32 (d, 1H, J=7.8 Hz), 7.07 (dd, 1H, J=1.3, 4.8 Hz), 6.00 (broad, 1H), 4.63 (m, 2H), 3.32 (m, 4H), 1.08 (t, 6H, J=7.2 Hz).
[0255] II. Synthetic Methods for General Structures
[0256] The examples described in Section I are merely illustrative of the methods used to synthesize triazine derivatives. Further derivatives may be obtained utilizing methods shown in Schemes 1-5. The substituents in Schemes 1-5 are described in the Detailed Description.
[0257] It may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid, and hydroxyl groups in the synthetic methods described above to form triazine derivatives. Methods for protection and deprotection of such groups are well-known in the art, and may he found, for example in Green, T. W. and Wuts, P. G. M. (1991) Protection Groups in Organic Synthesis, 2nd Edition John Wiley & Sons, New York.
[0258] III. Oral Compositions
[0259] As a specific embodiment of an oral composition of a compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
[0260] IV. Pharmacological Evaluation of Compounds at Cloned Neuropeptide Y-Type Receptors
[0261] The pharmacological properties of the compounds of the present invention were evaluated at one or more of the cloned human neuropeptide Y-type receptors Y1, Y2, Y4, and Y5, using protocols described below.
[0262] Cell Culture
[0263] COS-7 cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 &mgr;g/ml streptomycin) at 37° C., 5% CO2. Stock plates of COS-7 cells were trypsinized and split 1:6 every 3-4 days. Human embryonic kidney 293 cells were grown on 150 mm plates in D-MEM with supplements (minimal essential medium) with Hanks' salts and supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 &mgr;g/ml streptomycin) at 37° C., 5% CO2. Stock plates of 293 cells were trypsinized and split 1:6 every 3-4 days. Mouse fibroblast LM(tk-) cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin/100 &mgr;g/mL streptomycin) at 37° C., 5% CO2. Stock plates of LM(tk-) cells were trypsinized and split 1:10 every 3-4 days.
[0264] LM(tk-) cells stably transfected with the human Y5 receptor were routinely converted from an adherent monolayer to a viable suspension. Adherent cells were harvested with trypsin at the point of confluence, resuspended in a minimal volume of complete DMEM for a cell count, and further diluted to a concentration of 106 cells/ml in suspension media (10% bovine calf serum, 10% 10× Medium 199 (Gibco), 9 mM NaHCO3, 25 mM glucose, 2 mM L-glutamine, 100 units/ml penicillin/100 &mgr;g/ml streptomycin, and 0.05% methyl cellulose). The cell suspension was maintained in a shaking incubator at 37° C., 5% CO2 for 24 hours. Membranes harvested from cells grown in this manner may be stored as large, uniform batches in liquid nitrogen. Alternatively, cells may be returned to adherent cell culture in complete DMEM by distribution into 96-well microtiter plates coated with poly-D-lysine (0.01 mg/ml) followed by incubation at 37° C., 5% CO2 for 24 hours. Cells prepared in this manner yielded a robust and reliable NPY-dependent response in cAMP radio-immunoassays as further described hereinbelow.
[0265] Mouse embryonic fibroblast NIH-3T3 cells were grown on 150 mm plates in Dulbecco's Modified Eagle Medium (DMEM) with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 &mgr;g/ml streptomycin). at 37° C., 5% CO2. Stock plates of NIH-3T3 cells were trypsinized and split 1:15 every 3-4 days. Sf9 and Sf21 cells were grown in monolayers on 150 mm tissue culture dishes in TMN-FH media supplemented with 10% fetal calf serum, at 27° C., no CO2. High Five insect cells were grown on 150 mm tissue culture dishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27° C., no CO2.
[0266] Transient Transfection
[0267] All receptor subtypes studied (human and rat Y1, human and rat Y2, human and rat Y4, human and rat Y5) were transiently transfected into COS-7 cells by the DEAE-dextran method, using 1 &mgr;g of DNA /106 cells (Cullen, 1987) The human Y1 receptor was prepared using known methods (Larhammar, et al., 1992).
[0268] Stable Transfection
[0269] Human Y1, human Y2, and rat Y5 receptors were co-transfected with a G-418 resistant gene into the human embryonic kidney 293 cell line by a calcium phosphate transfection method (Cullen, 1987). Stably transfected cells were selected with G-418. Human Y4 and human Y5 receptors were similarly transfected into mouse fibroblast LM(tk-) cells and NIH-3T3 cells.
[0270] Binding of the compounds of the present invention to human Y1, Y2, Y4, and Y5 receptors was evaluated using stably transfected 293 or LM(tk-) cells as described above, Stably transfected cell lines which may be used for binding assays include, for example, for the human Y1 receptor, 293-hY1-5 (deposited Jun. 4, 1996, under ATCC Accession No. CRL-12121), for the human Y2 receptor, 293-hY2-10 (deposited Jan. 27, 1994, under ATCC Accession No. CRL-11537), for the human Y4 receptor, L-hY4-3 (deposited Jan. 11, 1995, under ATCC Accession No. CRL-11779), and for human Y5 receptor, L-hY5-7 (deposited Nov. 15, 1995, under ATCC Accession No. CRL-11995). These cell lines were deposited with the American Type Culture Collection (ATCC), 10801 University Blvd.; Manassas, Va. 20110-2209, U.S.A. under the provisions or the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
[0271] Membrane Harvest
[0272] Membranes were harvested from COS-7 cells 48 hours after transient transfection. Adherent cells were washed twice in ice-cold phosphate buffered saline (138 mM NaCl, 8.1 mM Na2HPO4, 2.5 mM KCl, 1.2 mM KH2PO4, 0.9 mM CaCl2, 0.5 mM MgCl2, pH 7.4) and lysed by sonication kin ice-cold sonication buffer (2:0 mM Tris-HCl, 5 mM EDTA, pH 7.7). Large particles and debris were cleared by low speed centrifugation (200×g, 5 min, 4° C.). Membranes were collected from the supernatant fraction by certrifugation (32,000×g, 18 min. 4° C.), washed with Ice-cold hypotonic buffer, and collected again by centrifugation (32,000×g, 18 min, 4° C.). The final membrane pellet was resuspended by sonication into a small volume of ice-cold binding buffer (˜1 ml for every 5 plates: 10 mM NaCl, 20 mM HEPES, 0.22 mM KH2PO4, 1.26 mM CaCl2, 0.81 mM MgSO4, pH 7.4). Protein concentration was measured by the Bradford method (Bradford. 1976) using Bio-Rad Reagent, with bovine serum albumin as a standard. Membranes were held on ice for up to one hour and used fresh, or flash-frozen and stored in liquid nitrogen.
[0273] Membranes were prepared similarly from 293, LM(tk-) and NIH-3T3 cells. To prepare membranes from baculovirus infected cells, 2×107 Sf21 cells were grown in 150 mm tissue culture dishes and infected with a high-titer stock of hY5BB3. Cells were incubated for 2-4 days at 27° C., no CO2 before harvesting and membrane preparation as described above.
[0274] Membranes were prepared similarly from dissected rat hypothalamus. Frozen hypothalami were homogenized for 20 seconds in ice-cold sonication buffer with the narrow probe of a Virtishear homogenizer at 1000 rpm (Virtis, Gardiner, N.Y.). Large particles and debris were cleared by centrifugation (200×g, 5 min, 4° C.) and the supernatant fraction was reserved on ice. Membranes were further extracted from the pellet by repeating the homogenization and centrifugation procedure two more times. The sunernatant fractions were pooled and subjected to high speed centrifugation (100,000×g, 20 min. 4° C.). The final membrane pellet was resuspended by gentle homogenization into a small volume of ice-cold binding buffer (1 mL/gram wet weight tissue) and held on ice for up to one hour, or flash-frozen and stored in liquid nitrogen.
[0275] Radioligand Binding to Membrane Suspensions
[0276] Membrane suspensions were diluted in binding buffer supplemented with 0.1% bovine serum albumin to yield an optimal membrane protein concentration so that 125I-PYY (or alternative radioligand such as 125I-NPY, 125I-PYY3-36 or 125I-[Leu31Pro34]PYY) bound by membranes in the assay was less than 10% of 125I-PYY (or alternative radioligand) delivered to the sample (100,000 dpm/sample=0.08 nM for competition binding assays). 125I-PYY (or alternative radioligand) and peptide competitors were also diluted to desired concentrations in supplemented binding buffer. Individual samples were then prepared in 96-well polypropylene microtiter plates by mixing 125I-PYY (25 &mgr;L) (or alternative radioligand), competing peptides or supplemented binding buffer (25 &mgr;L), and finally, membrane suspensions (200 &mgr;l). Samples were incubated in a 30° C. water bath with constant shaking for 120 min. Incubations were terminated by filtration over Whatman GF/C filters (pre-coated with 1% polyethyleneimine and air-dried before use), followed by washing with 5 mL of ice-cold binding buffer. Filter-trapped membranes were impregnated with MeltiLex solid scintillant (Wallac, Turku, Finland) and counted for 125I in a Wallac Beta-Plate Reader. Alternatively, incubations were carried out in GF/C filter plates (pre-coated with 1% polyethyleneimine and air-dried before use), followed by vacuum filtration and three washes of 300 &mgr;L of ice-cold binding buffer. 50 &mgr;L of UltimaGold (Packard) scintillant were added and counted for 125I in a Wallac MicroBeta Trilux. Non-specific binding was defined by 300 nM human NPY for all receptors except the Y4 subtypes; 100 nM human PP was used for the human Y4 and 100 nM rat PP for the rat Y4. Specific binding in time course and competition studies was typically 80%; most non-specific binding was associated with the filter. Binding data were analyzed using nonlinear regression and statistical techniques available in the GraphPAD Prism package (San Diego, Calif.)
[0277] Functional Assay: Radioimmunoassay of cAMP
[0278] Stably transfected cells were seeded into 96-well microtiter plates and cultured until confluent. To reduce the potential for receptor desensitization, the serum component of the media was reduced to 1.5% for 4 to 16 hours before the assay. Cells were washed in Hank's buffered saline, or HBS (150 mm NaCl, 20 mM HEPES, 1 mM CaCl2, 5 mM KCl, 1 mM MgCl2, and 10 mM glucose) supplemented with 0.1% bovine serum albumin plus 5 mM theophylline and pre-equilibrated in the same solution for 20 min at 37° C. in 5% CO2. Cells were then incubated 5 min with 10 &mgr;M forskolin and various concentrations of receptor-selective ligands. The assay was terminated by the removal of HBS and acidification of the cells with 100 mM HCl. Intracellular cAMP was extracted and quantified with a modified version of a magnetic bead-based radioimmunoassay (Advanced Magnetics, Cambridge, Mass.). The final antigen/antibody complex was separated from free 125I-cAMP by vacuum filtration through a PVDF filter -n a microtiter plate (Millipore, Bedford, Mass.) Filters were punched and counted for 125I in a Packard gamma counter. Binding data were analyzed using nonlinear regression and statistical techniques available in the GraphPAD Prism package (San Diego, Calif.).
[0279] Functional Assay: Intracellular Calcium Mobilization
[0280] The intracellular free calcium concentration was measured by microspectreflourometry using the fluorescent indicator dye Fura-2/AM. Stably transfected cells were seeded onto a 35 mm culture dish containing a glass coveslip insert. Cells were washed with HBS and loaded with 100 &mgr;l of Fura-2/AM (10 &mgr;M) for 20 to 40 min. After washing with HBS to remove the Fura-2/AM solution, cells were equilibrated in HBS for 10 to 20 min. Cells were then visualized under the 40× objective of a Leitz Fluovert FS microscope and fluorescence emission was determined at 510 nM with excitation wave lengths alternating between 340 nM and 380 nM. Raw fluorescence data were converted to calcium concentrations using standard calcium concentration curves and software analysis techniques.
[0281] Materials
[0282] Cell culture media and supplements were from Specialty Media (Lavallette, N.J.). Cell culture plates (150 mm and 96-well microtiter) were from Corning (Corning, N.Y.). Sf9, Sf21, and High Five insect cells, as well as the baculovirus transfer plasmid, pBlueBacIII™, were purchased from Invitrogen (San Diego, Calif.) TMN-FH insect medium complemented with 10% fetal calf serum, and the baculovirus DNA, BaculoGold™, was obtained from Pharmingen (San Diego, Calif.). Ex-Cell 400™ medium with L-Glutamine was purchased from JRH Scientific. Polypropylene 96-well microtiter plates were from Co-star (Cambridge, Mass.). All radioligands were from New England Nuclear (Boston, Mass.). Commercially available NPY and related peptide analogs were either from Bachem Calif. (Torrance, Calif.) or Peninsula (Belmont, Calif.); [D-Trp32]NPY and PP C-terminal fragments were synthesized by custom order from Chiron Mimotopes Peptide Systems (San Diego, Calif.). Bio-Rad Reagent was from Bio-Rad (Hercules, Calif.). Bovine serum albumin (ultra-fat free, A-7511) was from Sigma (St. Louis. Mo.). All other materials were reagent grade.
[0283] Radioligand Binding Assay Results
[0284] The compounds described above were assayed using cloned human NPY receptors. The preferred compounds were found to be selective NPY (Y5) antagonists. Example 49 has been assayed using the cloned human NPY receptors and a Ki (nM)>100000 was determined for NPY (Y1), NPY (Y2), and NPY (Y4). The binding affinities of several compounds for NPY (Y5) are illustrated in Tables 1-4. 1 TABLE 1 11 Ki (nM) Example # R hNPY-5 1 CH3NH— 13 2 CH3CH2NH— 7 3 CH2═CH2CH2NH— 12 4 (CH3)2CHNH— 23 5 CH3CH2CH2NH— 18 6 CH3CH2CH2CH2NH— 22 7 12 22 8 13 9 9 CH3CH2CH2CH2CH2NH— 6 10 NCCH2CH2NH— 81 11 HOCH2CH2NH— 35 12 CH3OCH2CH2NH— 18 13 CH3OCH2CH2CH2NH— 22 14 (CH3)2NCH2CH2NH— 194 15 14 83 16 15 313 17 (CH3)2N— 27 18 CH3CH2(CH3)N— 32 19 (CH3CH2)2N— 53 20 16 19 21 17 71 22 18 38 23 19 68 24 20 40 25 21 135 26 HOCH2CH2(CH3)N— 86 27 22 31 28 23 22
[0285] 2 TABLE 2 24 Ki (nM) Example # R hNPY-5 29 4-t-butylphenyl 50 30 4-fluorophenyl 40 31 2-methoxy-5-methylphenyl 25 32 2-fluorophenyl 35 33 2-methylphenyl 22 34 25 427 35 4-methoxyphenyl 82 36 26 71 37 thiophen-2-yl 55 38 27 313 39 4-methylphenyl 28 40 28 5 41 29 13 42 Methyl 3067
[0286] 3 TABLE 3 30 Ki (nM) Example # R1 R2 R3 hNPY-5 43 31 32 33 43 44 34 35 36 295 45 37 38 39 59 46 40 41 4-t-butylphenyl 68 47 42 43 44 359 48 45 46 47 192 49 48 chloro 1-naphthyl 138 50 49 50 51 3508 51 52 chloro 4-t-butylphenyl 3544 52 53 54 4-fluorophenyl 101 53 chloro chloro 55 20654 54 56 57 2-methoxy-5- methylphenyl — 55 58 2-pyridyl 4-fluorophenyl 209
[0287] 4 TABLE 4 59 Ki (nM) Example # R1 R2 R3 hNPY-5 56 60 61 62 94406 57 63 64 65 >100000 58 66 67 68 >100000
[0288] Functional Assay Results
[0289] The functional in vitro activity of several compounds were characterized using a radioimmunoassay of cAMP, the results of which are summarized in Table 5. 5 TABLE 5 Functional Antagonism Data Example 4 Ki (h NPY-5). nM pKb 1 13 6.7 37 55 6.8 49 138 6.0
[0290] 69
[0291] i)BOC2O, CH2Cl2, DIEA; ii) R16SO2Cl, DIEA; iii) TFA, CH2Cl2; iv) R16SO2Cl, DIEA
[0292] R14, R15, R16, X, m, p, and s are described herein 70 71 72
[0293] i)BOC2O, CH2Cl2, DIEA; ii) R16SO2Cl, DIEA; iii) TFA, CH2Cl2; iv) R16SO2Cl, DIEA
[0294] R16, q, and r are described herein 73 74
[0295] i)BOC2O, CH2Cl2, DIEA; ii) R16SO2Cl, DIEA; iii) TFA, CH2Cl2; iv) R16So2Cl, DIEA
[0296] R16, R10, m, and p are described herein 75 76
[0297] i)BOC2O, CH2Cl2, DIEA; ii) R16SO2Cl, DIEA; iii) TFA, CH2Cl2; iv) R16SO2Cl, DIEA
[0298] R16, R9, p, and m are described herein 77 78
[0299] i) BOC2O, CH2Cl2, DIEA; ii) acid chloride followed by reduction with B2H6; DIEA; iii) A formylating agent such as 1H-benzotriazole-1-carboxaldehyde; iv) TFA, CH2Cl2 79
[0300] R13, m, and p are substitutents described herein 80
[0301] i) A protecting group such as BOC (using BOC2O) or benzyl (Bn) using benzoyl chloride followed by reduction of the amide; ii) acid chloride followed by reduction with B2H6; iii) A formylating agent such as 1H-benzotriazole-1-carboxaldehyde; iv) H2, Pd/C 81
[0302] R13, m, and p are substitutents described herein 82 83 84
[0303] R3 and R4 are substituents described herein
[0304] —NHR is a subset of the substituent R8 described herein 85 86
[0305] R3 and R4 are substituents described herein
[0306] —N(R9)R and —NH—L—NHSO2—R are independently subsets of the substituent R8 described herein 87 88
[0307] (R)(R′)NH=morpholine, piperidine, pyrrolidine, cyclopropylamine, etc.
[0308] —NH—L—NH—SO2—N(R)(R′) is a subset of the R8 substituent described herein 89
[0309] R3 and R4 are substituents described herein
[0310] (R)(R′)NH=morpholine, piperidine, pyrrolidine, cyclopropylamine, etc.
[0311] (R)(R′)N—=morpholinyl, piperidinyl, pyrrolidinyl, cyclopropylamine, etc.
[0312] —NH—L—NH—SO2—N(R)(R′) and
[0313] —NH—L—NH—SO2—N(CH3)2 are independently subsets of the R8 substituent described herein 90 91
[0314] R3 and R4 are sutstituents described herein
[0315] (R)(R′)NH=morpholine, piperidine, pyrrolidine, cyclopropylamine, etc.,
[0316] —N(R)(R′), —NH—L—NHSO2NR(R′), and
[0317] —NH—L—NHSO2N (CH3)2 are subsets of the R8 substituent described herein 92
[0318] R2 and R3 are substituents described herein
[0319] —NH—R is a subset of the R8 substituent described herein 93
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Claims
1. A compound having the structure
- 94
- wherein R1 is F; Cl; Br; I; NR3R4; or phenyl or heteroaryl; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- wherein R2 is NR3R4;
- wherein R1 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl, C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- wherein R4 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, C1, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- or R3 and R4 taken together with the nitrogen atom to which they are attached are 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl, wherein the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1H-azepanyl is substitute, with one or more of F, —CN, —(CH2)nNR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R7, —(CH2)nCO2R5, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, a C3-C7 cycloalkyl or cycloalkenyl, or phenyl or heteroaryl; wherein if —(CH2)nNR5R6, —(CH2)nYR5, or —(CH2)nNR5C(Y)R5 are in the 2-position, then n is not 0; wherein the phenyl or heteroaryl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl, wherein the morpholinyl, thiomorpholinyl, [1,4]oxazepanyl, [1,4]thiazepanyl, piperazinyl, or [1,4]diazepanyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl or [1,4]diazepanyl ring is substituted with —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl; wherein the phenyl C1-C6 phenylalkyl, or C1-C6 heteroarylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- wherein each of R5, R6 and R7 is independently H; or straight chained or branched C1-C7 alkyl;
- wherein each n is independently an integer from 0 to 6 inclusive;
- wherein each t is independently an integer from 1 to 4 inclusive;
- wherein each u is independently an integer from 2 to 4 inclusive;
- wherein Y is O or S;
- wherein R8 is
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- provided teat if R8 contains a piperidinyl group and m is O, then the compound is not an &agr;-aminal-containing compound;
- wherein each of R9 and R10 is independently H; straight chained or branched C1-C4 alkyl;
- wherein R11 is H or
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- wherein R12 is H;
- wherein R13 is independently H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; C1-C7 alkyl substituted with one or more F or Cl; C3-C7 cycloalkyl-C1-C7 alkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or cycloalkenyl; phenyl or C1-C6 phenylalkyl; wherein the phenyl or C1-C6 phenylalkyl may be substituted with one or more of F, Cl, —CN, —NO2, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, a straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, a C2-C7 alkenyl or C2-C7 alkynyl, or a C3-C7 cycloalkyl or cycloalkenyl;
- or R12 and R13 together with the amide linkage to which they are attached are pyrrolidinonyl or piperidonyl;
- wherein R14 is H; straight chained or branched C1-C7 alkyl; F; or —(CH2)nOR5;
- wherein R15 is H, straight chained or branched C1-C7 alkyl, or F;
- wherein R16 is NR3R4, unsubstituted straight chained or branched C2-C7 alkyl, substituted straight chained or branched C1-C7 alkyl, wherein the C1-C7 alkyl may be substituted with one or more of F, Cl, —CN, —NR5R6, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nNR5C(Y)R5, —(CH2)nCO2R5, —(CH2)—OCF3, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or C2-C7 alkynyl, or C3-C7 cycloalkyl or cycloalkenyl, phenyl, heteroaryl, or C1-C7 phenylalkyl, wherein the phenyl, heteroaryl, or C1-C7 phenylalkyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; quinolinyl, 1-naphthyl, 2-naphthyl, or 2,1,3-benzothiadiazolyl; with the provisos that when R1 is F, Cl, Br, or I, then R16 is 1-naphthyl; and when R1 and R2 are morpholinyl, then R16 is not NR3R4;
- wherein each m is independently an integer from 0 to 3 inclusive;
- wherein each s is independently an integer from 1 to 6 inclusive;
- wherein each p is independently an integer from 0 to 2 inclusive;
- wherein each q is independently an integer from 1 to 2 inclusive;
- wherein each r is independently an integer from 1 to 2 inclusive;
- wherein X is N or C;
- or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the (+) enantiomer.
3. The compound of claim 1, wherein the compound comprises the (−) enantiomer.
4. The compound of claim 1, wherein R8 is
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5. The compound of claim 1, wherein R1 is F, Cl, Br, I, or NR3R4.
6. The compound of claim 1, wherein R1 and R2 are both NR3R4 where R3 and R4 are independently H;
- straight chained or branched C1-C7 alkyl;
- straight chained or branched C2-C7 alkenyl or alkynyl; or R3 and R4 taken together with the nitrogen atom to which on they are attached are morpholinyl, piperazinyl, or 1-pyrrolidinyl, wherein the morpholinyl, piperazinyl, or 1-pyrrolidinyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl ring is substituted with H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl.
7. The compound of claim 1, wherein R16 is phenyl, 1-naphthyl, quinolinyl, or 2,1,3-benzothiadiazolyl; wherein the phenyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6 ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl.
8. The compound of claim 1, wherein R9 is H, R10 is H, p is 1, and m is 1.
9. The compound of claim 4, wherein R1 is F, Cl, Br, I, or NR3R4.
10. The compound of claim 9, wherein R1 and R2 are both NR3R4, where R3 and R4 are independently H; straight haired or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; or R3 and R4 taken together with the nitrogen atom to which they are attached are morpholinyl, piperazinyl, or 1-pyrrolidinyl, wherein the morpholinyl, piperazinyl, or 1-pyrrolidinyl is substituted with one or more straight chained or branched C1-C7 alkyl or C1-C7 phenylalkyl; and wherein the nitrogen atom of the piperazinyl ring is substituted with H; —(CH2)uYR5; —(CH2)tC(Y)NR5R6; —(CH2)uNR5C(Y)R5; —(CH2)tC(Y)R7; —(CH2)tCO2R5; —(CH2)uNR5R6; —(CH2)uCN; —C(Y)R5; —C(Y)NR5R6; —CO2R5; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl; C1-C6 phenylalkyl; or C1-C6 heteroarylalkyl.
11. The compound of claim 10, wherein R16 is phenyl:, 1-naphthyl, quinolinyl, or 2,1,3-benzothiadiazolyl; wherein the phenyl may be substituted with one or more of F, Cl, Br, I, —CN, —NO2, —NR5R6, —(CH2)nNR5C(Y)R5, —SO2R5, —(CH2)nC(Y)R7, —(CH2)nYR5, —(CH2)nC(Y)NR5R6, —(CH2)nCO2R5, —(CH2)nSO2NR5R6, ethylenedioxy, methylenedioxy, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl.
12. The compound of claim 11, wherein R9 is H, R10 is H, p is 1, and m is 1.
13. The compound of claim 1, selected from the group consisting of:
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14. The compound of claim 1, selected from the group consisting of:
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15. The compound of claim 1, selected from the group consisting of:
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16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition of claim 16, wherein the amount of he compound is an amount from about 0.01 mg to about 800 mg.
18. A pharmaceutical composition of claim 17, wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg.
19. A pharmaceutical composition of claim 18, wherein the amount of the compound is an amount from about 0.01 mg to about 250 mg.
20. A pharmaceutical composition of claim 19, wherein the amount of the compound is an amount from about 0.1 mg to about 60 mg.
21. A pharmaceutical composition of claim 20, wherein the amount of the compound is an amount from about 1 mg to about 20 mg.
22. The pharmaceutical composition of claim 16, wherein them carrier is a liquid and the composition is a solution.
23. The pharmaceutical composition of claim 16, wherein the carrier is a solid and the composition is a tablet.
24. The pharmaceutical composition of claim 16, wherein the carrier is a gel and the composition is a suppository.
25. A pharmaceutical composition made by combining a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
26. A process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
Type: Application
Filed: Apr 22, 2003
Publication Date: Jan 29, 2004
Applicant: Synaptic Pharmaceutical Corporation
Inventors: Mohammad R. Marzabadi (Ridgewood, NJ), Stewart A. Nobel (Upper Saddle River, NJ), Mahesh N. Desai (Clifton, NJ)
Application Number: 10420238
International Classification: A61K031/53; C07D251/18; C07D251/48; C 07D 4 3/02;
