New (hetero)aryl-alkanoic acid anilide derivatives, are thrombin and factor Xa inhibitors useful as antithrombotic agents, e.g. for treating deep vein thrombosis or preventing reocclusion after angioplasty

摘要

2-(Aryl or heteroaryl)-alkanoic acid anilide derivatives (I), their stereoisomers and salts, are new. 2-(Aryl or heteroaryl)-alkanoic acid anilide derivatives of formula (I), their stereoisomers and salts, are new: [Image] R1cycloalkylcarbonyl, where the CH2 in the 3- or 4-position is optionally replaced by NQ; 1-6C alkylcarbonyl (optionally substituted (os) terminally in the alkyl by NH2,or mono- or dialkylamino); -CO-N(Rh)-(CH2)m-NRfRg; phenyl-, naphthyl- or hetero-carbonyl; 1-3C hydroxyalkyl (os terminally by phenyl, itself os by amidino, mono- or dialkylamidino, F, Cl, Br, CF3, alkyl or alkoxy); 4-7 membered cycloalkyleneimino-carbonyl or -sulfonyl, substituted by aminoalkyl, mono- or dialkylaminoalkyl, CONH2 or mono- or dialkylaminocarbonyl; cycloalkylamino, N-substituted by mono- or dialkylaminoalkyl; or unsubstituted 4-7 membered cycloalkyleneimino-carbonyl or -sulfonyl, cycloalkylamino or N-alkyl-cycloalkylamino; Q : H, alkyl(carbonyl), phenylcarbonyl or phenylsulfonyl; Rf, Rg, Rh, R3H or alkyl; m : 2 - 6; R2H, F, Cl, Br, alkyl (os by one or more F), OH or alkoxy; R4H or alkyl (os by COOH or a group convertible into COOH in vivo); Ar : phenyl or naphthyl, both substituted by R5, R6 and R7; or thienyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, all os on C by alkyl; R5CN, amidino, mono- or dialkylamidino, aminoalkyl or mono- or dialkylaminoalkyl; R6H, F, Cl, Br, CF3, alkyl, OH, hydroxyalkyl, alkoxy, alkoxyalkyl, COOH, carboxyalkyl, carboxyalkoxy, 1-4C alkoxycarbonylalkoxy, phenylalkoxy, NH2 or mono- or dialkylamino; R7H, F, Cl, Br or alkyl; R8, R9H, alkyl (os by phenyl or heteroaryl) or amino (os by 1 or 2 alkyl or alkylcarbonyl); heteroaryl : (i) C- or N-bonded 5-membered heteroaryl in which the heteroatoms are one NH, N(Q'), N(COQ'), O or S, one NH, N(Q'), O or S plus one N or one NH, NQ', O or S plus two N; (ii) 6-membered heteroaryl in which the heteroatoms are one or two N; or (iii) a ring as in (i) or (ii) fused with phenyl and bonded via the heterocyclic or carbocyclic ring; Q' : 1-4C alkyl; and provided that provided that R2 is CF3, R5 is aminoalkylamino or mono- or dialkylaminoalkylamino, R6 is carboxyalkoxy or 1-4C alkoxycarbonylalkoxy and/or at least one of R8 and R9 is other than H. Phenyl, naphthyl or heteroaryl moieties are os (or additionally os if already monosubstituted) on C by F, Cl, Br, CF3, alkoxy, alkoxy or alkoxycarbonyl; all COOH groups are optionally replaced by a group convertible into COOH in vivo or a group which is negatively charged under physiological conditions; amino or imino moieties are os by a group cleavable in vivo; alkyl moieties have 1-3C and 3-7C cycloalkyl moieties unless specified otherwise; (I) additionally include the following compounds: 2-(5-carbamimidoyl-2-hydroxyphenyl)-N-(3-chloro-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-acetamide, 2-(5-carbamimidoyl-2-hydroxyphenyl)-N-(3-chloro-4-(pyrrolidin-1-ylsulfonyl)-phenyl)-acetamide, 2-(5-carbamimidoyl-2-hydroxyphenyl)-N-(3-methyl-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-acetamide, 2-(5-carbamimidoyl-2-hydroxyphenyl)-N-(3-bromo-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-acetamide and 2-(5-carbamimidoyl-2-hydroxyphenyl)-N-(3-methoxy-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-acetamide. An independent claim is also included for the preparation of (I). ACTIVITY : Thrombolytic; Anticoagulant; Vasotropic; Cerebroprotective; Cardiant; Cytostatic; Antiinflammatory; Antirheumatic; Antiarthritic; Vulnerary. MECHANISM OF ACTION : Serine protease inhibitor; Thrombin inhibitor; Factor Xa inhibitor; Trypsin inhibitor; Urokinase inhibitor; Factor VIIa inhibitor; Factor IX inhibitor; Factor XI inhibitor; Factor XII inhibitor. 2-(5-Carbamimidoyl-2-hydroxyphenyl)-N-(3-trifluoromethyl-4-(pyrrolidin-1-ylcarbonyl)-phenyl)-acetamide (Ia) had IC50 0.11 MicroM for inhibition of Factor Xa.