Patent EA-004986-B1 (EA)
Title: N-(heterocyclyl)benzene or pyridine sulphonamides as antithrombotic agents and anticoagulants
Inventor: ALTENBURGER JEAN-MICHEL
IPC: C07D213/73
Filed: 2001-03-22
Abstract: 1. A compound of formula (I): wherein: X is a nitrogen atom or (CR4; W is -CH2)2-, -(CH2)3-, -CH2-C [triple bond] C- or -CH2-CH(CH- (double bond in cis- or trans-configuration), R2 is either piperidyl optionally substituted: with one or two groups chosen from hydroxyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl and (C3-C6)cycloalkyl, with a group (CYZ in which Y and Z are independently hydrogen, halogen or (C1-C4)alkyl optionally substituted with 1 to 3 halogen atoms, with a group in which r is 1 to 3, or with a spiro (C3-C6)cycloalkane group; or 1,2,3,6-tetrahydropyridyl optionally substituted with a (C1-C4)alkyl group, said (C1-C4)alkyl group being optionally substituted with 1 to 3 halogen atoms or a (C3-C6)cycloalkyl group; or hexahydro-1H-azepinyl optionally substituted in position 4 with a trifluoromethyl or difluoromethylene group; or heptahydroazocin-1-yl; or octahydro-1H-azonin-1-yl; or a group in which a-b is -CONR'-, m=1 to 2, p=1 to 2 and R' is hydrogen or (C1-C4)alkyl; or a group in which R12 is (C1-C4)alkyl, carboxy(C1-C4)alkyl or (C1-C44)alkoxycarbonyl(C1-C4)alkyl and R13 (C1-C4)alkoxy or (C1-C4)alkyl, or R12 is (C1-C4)alkyl or CH2CF3 and R13 is a group in which Q is a carbon or nitrogen atom and r is 1 to 3; piperazinyl optionally substituted with (C1-C4)alkyl or (C1-C4)alkylsulphonyl; or morpholinyl; R3 is: either (C1-C5)alkyl; or -COR1, in which R1 is either hydrogen, or (C1-C4)alkyl, -(CH2)nOCH3, -CH2O(C2H4O)nCH3, -(CH2)nCF3 or -(CH2)nOH and n is 1 to 4; or -SO2R5; or -CONHR5; or or -SO2N(R5)2, in which R5 is (C1-C4)alkyl; A is: either phenyl optionally substituted with 1 to 3 substituents chosen from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, trifluoromethyl, trifluoromethoxy, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, -NR10R11, -NHCOR10 and -H(CH2)qqOR10, in which R10 and R11 are independently hydrogen or (C1-C4)alkyl and q is from 0 to 6; or heterocycle chosen from pyridyl, thienyl, furyl, pyrimidinyl or thiazolyl, said groups optionally substituted with similar phenyl, or C5-C8)cycloalkyl; and B is: either pyridyl optionally substituted with 1 or 2 substituents chosen from (C1-C4)alkyl, hydroxyl and (C1-C4)alkoxy; or aminopyrazinyl; or aminopyridazinyl; or pyrimidinyl optionally substituted with an amino group; or piperidyl; or aminopyridyl optionally substituted on the pyridine with (C1-C4)alkyl, (C1-C4)alkoxy or halogen and optionally substituted on the amino group with (C1-C4)alkyl; or aminophenyl optionally substituted on the amino group with (C1-C4)alkyl and on the phenyl group with (C1-C4)alkyl or halogen; or in the form of racemates or pure enantiomers or alternately in the form of acids or free bases, or a pharmaceutically acceptable acid-addition salt thereof. 2. A compound according to claim 1, wherein X, W, R4, A and B are as defined in claim 1, R2 is either piperidyl optionally substituted: with one or two groups chosen from hydroxyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl and (C3-C6)cycloalkyl, with a group (CYZ in which Y and Z are independently hydrogen, halogen or (C1-C4)alkyl optionally substituted with 1 to 3 halogen atoms, or 1,2,3,6-tetrahydropyridyl optionally substituted with a (C1-C4)alkyl group, said (C1-C4)alkyl group being optionally substituted with 1 to 3 halogen atoms or a (C3-C6)cycloalkyl group; or hexahydro-1H-azepinyl optionally substituted in position 4 with a trifluoromethyl or difluoromethylene group; or a group in which R12 is (C1-C4)alkyl, carboxy(C1-C4)alkyl or (C1-C4)alkoxycarbonyl(C1-C4)alkyl and R13 (C1-C4)alkoxy or (C1-C4)alkyl, or piperazinyl optionally substituted with (C1-C4)alkyl or (C1-C4)alkylsulphonyl; or morpholinyl; R3 is: either (C1-C5)alkyl; or -COR1, in which R1 is either hydrogen, or (C1-C4)alkyl, -(CH2)nOCH3, -CH2O(C2H4O)nCH3, -(CH2)nCF3 or -(CH2)nOH and n is 1 to 4; in the form of racemates or pure enantiomers or alternately in the form of acids or free bases, or a pharmaceutically acceptable acid-addition salt thereof. 3. A compound according to claim 1 wherein X, R4, and B are as defined in claim 1, W is -(CH2)3 - or -CH2-CH(CH-; (double bond in cis- or trans-configuration), R2 is either piperidyl optionally substituted: with one or two groups chosen from hydroxyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, with a group (CYZ in which Y and Z are independently hydrogen, halogen or (C1-C4)alkyl optionally substituted with 1 to 3 halogen atoms, or 1,2,3,6-tetrahydropyridyl optionally substituted with a (C1-C4)alkyl group, said (C1-C4)alkyl group being optionally substituted with 1 to 3 halogen atoms, or hexahydro-1H-azepinyl, or piperazinyl optionally substituted with (C1-C4)alkylsulphonyl; or morpholinyl; R3 is -COR1, in which R1 is (C1-C4)alkyl, -(CH2)nOCH3, or -(CH2)nCF3 and n is 1 to 4; A is: either phenyl optionally substituted with 1 to 3 substituents chosen from halogen and (C1-C4)alkyl, (C1-C4)alkoxy, or heterocycle chosen from pyridyl and thienyl groups, or C5-C8)cycloalkyl, in the form of racemates or pure enantiomers or alternately in the form of acids or free bases, or a pharmaceutically acceptable acid-addition salt thereof. 4. Compounds according to any one of claims 1-3 wherein they are chosen from N-[2-[[[(1S)-4-(5-amino-3-methylpyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide, N-[2-[[[(1S)-4-(6-amino-4-ethylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6cyclopentylphenyl]acetamide, N-[3-[[[(1S)-4(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3'-fluoro[1,1'-diphenyl]-2-yl]propanamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3'-fluoro[1,1'-diphenyl]-2-yl]acetamide, N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-piperid-1-ylcarbonyl)butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide, N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1'-diphenyl]-2-yl]acetamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]acetamide, N-[2-[[[(1S)-4-(6-amino-4-methylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide, N-[2-[[[(1S)-4(aminopyrid-3-yl)-1-[[4-(trifluoromethyl)-1,2,3,6-tetrahydropyrid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1'-diphenyl]-2-yl]propanamide, N-[2-[[[(1S)-4-(6-amino-4-methylpyrid-3-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide, N-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3'-fluoro[1,1'-diphenyl]-2-yl]propanamide, N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]acetamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide, N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3'-methyl[1,1'-diphenyl]-2-yl]acetamide, N-[3-[[[(1S)-4-(6amino-4-methoxypyrid-3-yl-1-[[4-(difluoromethylene)piperidyl-1-yl]carbonyl]butyl]amino]sulphonyl][1,1'-diphenyl]-2-yl]propanamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3'-methyl[1,1'-diphenyl]-2-yl]propanamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl] amino]sulphonyl]-3'-fluoro[1,1'-diphenyl]-2-yl]acetamide, N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl] amino]sulphonyl]-3'-methoxy[1,1'-diphenyl]-2-yl]propanamide, N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3'-methyl[1,1'-diphenyl]-3-sulphonamide, N-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl ]carbonyl]-3-butenyl]amino]sulphonyl][1,1'-diphenyl]-2-yl]acetamide, and N-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[(4-methyl-1-piperidyl)carbonyl]-3-butenyl]amino]sulphonyl][1,1'-diphenyl]-2-yl]acetamide in the form of racemates or pure enantiomers or alternately in the form of acids or free bases, or a pharmaceutically acceptable acid-addition salt thereof. 5. A compound according to any one of claims 1-4 wherein the preferable configuration of central aminoacid part is [S] 6. A process for preparing a compound of formula (I) according to claim 1 in which X is CR4-, where R4 is as defined in claim 1, which comprises reacting a compound of formula (V) in which P1 is a protecting group for an amine function, B and W are as defined in claim 1and P is a protecting group or hydrogen with a compound of formula (VI) R2H			 (VI) in which R2 is as defined in claim 1 to give a compound of formula (IV) which is then treated in step (ii) with hydrogen chloride to give a compound of