New arylacetic acid N-phenylamide or arylcarboxylic acid N-benzylamide derivatives, used as antithrombotic agents in treatment of e.g. deep leg vein thrombosis, are Factor Xa and thrombin inhibitors

摘要

Amidino- or cyano-substituted arylacetic acid N-phenylamide or arylcarboxylic acid N-benzylamide derivatives (I) are new. Amidino- or cyano-substituted arylacetic acid N-phenylamide or arylcarboxylic acid N-benzylamide derivatives of formula (I) and their isomers and salts are new. m = 0 and; n = 1; or m = 1; and n = 0; Ar' = phenylene or naphthylene (both optionally substituted (os) by F, Cl, Br, CF3, T', OH, OT', phenyl-(1-3C)alkoxy, NH2, NHT' or NT'2, phenyl being further os by F, Cl, Br or T), or thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene (all os on C by T'); T' = 1-3C alkyl; R1 = T' (os by NH2, NHT', NT'2, phenyl, naphthyl, heteroaryl or 4-7 membered cycloalkyleneimino), 3-7C cycloalkyl substituted in the 1-position by 5-7 membered cycloalkyleneiminocarbonyl, NH2, 1-5C alkylamino, 5-7C cycloalkylamino or phenyl-(1-3C) alkylamino (all os on N by benzoyl or phenylsulfonyl or by T' or COT' (both os by COOH), 4-7 membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl (both os by T), phenyl (os by F, Cl, Br, CF3, SO2NH2, T' or OT'; and further os by F, Cl, Br, CF3, T' or OT'), OT', phenyl-(1-3C) alkoxy, heteroaryloxy or heteroaryloxy-(1-3C) alkoxy (all os in the 2- or 3-position of the alkoxy moiety by NH2, NHT' or NT'2) or 3-7C cycloalkoxy (optionally having CH2 in the 2- or 3-position replaced by NH or NQ); Q = T' (os in the 2- or 3-position by NH2, NHT' or NT'2), COT', arylcarbonyl, arylsulfonyl, CONH2, CONHT', CONT'2, C(=NH)NH2, C(=NH)NHT' or C(=NH)NT'2; R2 = H, F, Cl, Br, T', OH or OT'; R3 = H or T'; R4 = H or T' (os by COOH); R5 = CN or amidino (os by 1 or 2 T'); and heteroaryl = 5-membered heteroaryl (os by T' and containing NH, NT', O or S, NH or NT' plus O, S or N, NH or NT' plus two N or O or S plus two N) or 6-membered heteroaryl (os by T and containing 1 or 2 N) COOH moieties may be replaced by groups convertible into COOH in vivo or groups which are negatively charged under physiological conditions; amino or imino moieties are os by in vivo cleavable groups. An Independent claim is included for the preparation of (I).