Patent EA-003674-B1 (EA)
Title: Bispiperidines as antithrombotic agents, use thereof, method for preparing thereof, intermediate products and therapeutical composition
Inventor: YUE CHRISTOPHE
IPC: A61K31/4427
Filed: 1999-07-16
Abstract: 1. Compounds of formula: formula I in which: i) either R1 is chosen from: C1-C4 alkyl, C3-C12 mono- or bicyclic cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, these groups optionally being substituted with groups chosen from halogens and the hydroxyl group; mono-, bi- or tricyclic C6-C14 aryl groups; heteroaryl groups chosen from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; phenyl (C1-C4)alkyl and naphthyl(C1-C4)alkyl groups optionally substituted on the aryl nucleus; the aryl and heteroaryl groups possibly being substituted with one or more groups chosen independently from halogens, C1-C4 alkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C1-C4 alkyloxy, nitro and groups -COOR, -CH2COOR or -O-CH2-COOR, R being a C1-C4 alkyl group; the groups of formula: in which R4 and R'4 are chosen from C1-C8 alkyl and mono- or polycyclic C3-C12 cycloalkyl groups, these groups optionally being substituted with groups chosen from halogens and the hydroxyl group, R'4 also possibly being hydrogen, or alternatively R4 and R'4 together form a tetramethylene or pentamethylene group, these last two groups themselves possibly being substituted, in particular with a C6-C14 aryl or (C6-C14)aryl(C1-C4)alkyl residue; the groups of formula: in which m=1 to 4 and R5 is chosen from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups; and R2 is hydrogen, ii) or R1 is hydrogen and R2 is chosen from the groups of formula: -NH-CO-R6, R6 being chosen from C1-C4 alkoxy, C3-C7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, and the groups of formula: -NH-SO2-R7, R7 being chosen from: C1-C5 alkyl groups optionally substituted with one or more groups chosen from halogens, hydroxyl groups and the trifluoromethyl group; C2-C5 alkenyl groups; mono- or bicyclic C3-C12 cycloalkyl groups; mono-, bi- or tricyclic C6-C14 aryl groups; heteroaryl groups chosen from pyridyl, furyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl, benzofuryl and benzothiazolyl groups; phenyl(C1-C4)alkyl and naphthyl(C1-C4)alkyl groups; and the groups of formula: in which n=1, 2 or 3 and B is chosen from -CH2-, O or S and -NH-, the aryl or heteroaryl groups optionally being substituted with one or more groups chosen independently from halogens, C1-C4 alkyl, C3-C7 cycloalkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyloxy, C1-C4 alkylsulfonyl, nitro, di((C1-C4)alkyl)amino and groups -COOR, -CH2-COOR or -O-CH2COOR, R being a C1-C4 alkyl group, phenyl and naphthyl groups and heteroaryl groups chosen from thienyl, furyl and pyridyl groups; iii) R3 is chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4) alkyl group; iv) A is chosen from groups -NH-CHR10-, -NH-CHR10-CH2- and with p=1 or 2, R10 being chosen from hydrogen, a C1-C4 alkyl group and a C6-C14 aryl group; v) and Z1 and Z2 are hydrogen or an amine-protecting group, and the addition salts thereof with pharmaceutically acceptable acids. 2. Compounds according to claim 1, of formula formula Ia in which: i) either R1 is chosen from: C1-C4 alkyl, C3-C12 mono- or bicyclic cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl groups, these groups optionally being substituted with groups chosen from halogens and the hydroxyl group; mono-, bi- or tricyclic C6-C14 aryl groups; heteroaryl groups chosen from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; phenyl(C1-C4)alkyl and naphthyl (C1-C4)alkyl groups optionally substituted on the aryl nucleus; the aryl and heteroaryl groups possibly being substituted with one or more groups chosen independently from halogens, C1-C4 alkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C1-C4 alkyloxy, nitro and groups -COOR, -CH2OOR or -OH2-COOR, R being a C1-C4 alkyl group; the groups of formula: in which R4 and R'4 are chosen from C1-C8 alkyl and mono- or polycyclic C3-C12 cycloalkyl groups, these groups optionally being substituted with groups chosen from halogens and the hydroxyl group, R'4 also possibly being hydrogen, or alternatively R4 and R'4 together form a tetramethylene or pentamethylene group, these last two groups themselves possibly being substituted, in particular with C6-C14 aryl or (C6-C14)aryl(C1-C4)alkyl residue; the groups of formula: in which m=1 to 4 and R5 is chosen from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups; and R2 is hydrogen, ii) or R1 is hydrogen and R2 is chosen from the groups of formula: -NH-CO-R6, R6 being chosen from C1-C4 alkoxy, C3-C7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups; and the groups of formula: -NH-SO2-R7, R7 being chosen from: C1-C5 alkyl groups optionally substituted with one or more groups chosen from halogens, hydroxyl groups and the trifluoromethyl group; mono- or bicyclic C3-C12 cycloalkyl groups; mono-, bi- or tricyclic C6-C14 aryl groups; heteroaryl groups chosen from pyridyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl and isoxazolyl groups; phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups; and the groups of formula: in which n=1, 2 or 3; the aryl or heteroaryl groups optionally being substituted with one or more groups chosen independently from halogens, C1-C4 alkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyloxy, C1-C4 alkylsulfonyl, nitro, di((C1-C4)alkyl)amino and groups -COOR, -CH2-COOR or -O-CH2COOR, R being a C1-C4 alkyl group; iii) R3 is chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl(C1-C4)alkyl group; iv) and Z1 and Z2 are hydrogen or an amine-protecting group; and the addition salts thereof with pharmaceutically acceptable acids. 3. Compounds according to claim 1, in which R1 =H and R2 is a group of formula -NH-SO2-R7. 4. Compounds according to claim 3, in which R7 is chosen from naphthyl, substituted naphthyl, phenylthienyl and biphenyl groups. 5. Compounds according to claim 1, which are: ethyl (2S)-2-[(2-naphthylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoate; 3-(1,3-benzodioxol-5-yl)-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(phenylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl] butanoyl}amino)acetyl]amino}propanoic acid; (2S)-2-[(2-naphthylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[([1,1'-biphenyl]-4-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(1-naphthylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(2-thienylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; (2S)-2-{[(6-methoxy-2-naphthyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[ 2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(mesitylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-{[(4-methylphenyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-{[(3-nitrophenyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}-propanoic acid; 2-{[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[ 2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-({[5-(dimethylamino)-1-naphthyl)sulfonyl}amino)-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-{[(6,7-dimethoxy-2-naphthyl)sulfonyl]amino)-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(3-pyridylsulfonyl)amino]3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(1,3-benzodioxol-5-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl )-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(1-benzothiophen-2-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-{[(2,5-dimethyl-3-furyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-{[(4-fluoro-1-naphthyl)sulfonyl]amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)-acetyl]amino}propanoic acid; 2-{[(4-chloro-1-naphthyl)sulfonyl]-amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(1-benzofuran-2-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(2,3-dihydro-1H-inden-5-ylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)-acetyl]amino}propanoic acid; 2-{[(5-phenyl-2-thienyl))sulfonyl]-amino}-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(5,6,7,8-tetrahydro-2-naphthalenylsulfonyl)amino]3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid; 2-[(2-naphthylsulfonyl)amino]-3-{[3-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)propanoyl]amino}propanoic acid; (2R)-2-[(2-naphthylsulfonyl)amino]-3-{[2-({4-(4-piperidyl)-2-[2-(4-piperidyl)ethyl]butanoyl}amino)acetyl]amino}propanoic acid and the addition salts thereof with pharmaceutically acceptable acids. 6. A method of preparing compounds of formula (I) according to claim 1 a) by reacting an acid of formula: formula II in which R8 and