Patent DE-19816983-A1 (DE)
Title: New bicyclic heteroaromatic amidine or nitrile compounds, used as thrombin inhibitors, antithrombotic agents or intermediates
Inventor: RIES UWE
IPC: C07D239/96
Filed: 1998-04-17
Abstract: Bicyclic heteroaryl-substituted aromatic amidine or nitrile derivatives (I) are new. Bicyclic heteroaromatic compounds of formula Ra-Het-A-Ar-Rb (I) and their tautomers, stereoisomers, mixtures and salts are new. A  = O, S, CF2, CO, SO, SO2, NH, NT or CH2 (optionally substituted (o/s) by 1 or 2 T'COOT'');  T  = 1-3C alkyl;  T'  = 1-3C alkylene;  T''  = H or T;  Ar  = phenylene or naphthylene (both o/s by F, Cl, Br, CF3, T or OT); or thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene (all o/s on C by T);  Het  = (i) quinolinylene, isoquinolinylene, quinazolinylene, phthalazinylene, cinnolinylene or quinoxazolinylene (all o/s in the aromatic heterocyclic part by T or N(T'')2); or (ii) quinolinylene, isoquinolinylene, quinazolinylene, phthalazinylene, cinnolinylene or quinoxazolinylene in which the heterocyclic part is di- or tetrahydrogenated, dihydro rings have a CH2 adjacent to N replaced by CO or CS and are o/s by T and  tetrahydro rings have two CH2 groups adjacent to N replaced by CO and are o/s by 1 or 2 T; the phenyl part (in which one CH is optionally replaced by N) of all Het ring systems is bonded to Ra;  Ra  = H, F, Cl,  Br or NO2; T, alkenyl or alkynyl (all o/s by CH2OH or COOT''); T substituted by NHCOT or NHCOT'COOT''; T substituted by 1 or 2 COOT'' or by one pyrrolidinocarbonyl or piperidinocarbonyl (both o/s by 1 or 2 T) and by one COOT'' or NHCOT'COOT''; NH2 (o/s by COT, carboxyalkyl, or (1-3C) alkoxycarbonylalkyl); hydroxyimino-(1-3C) alkylene (o/s on O by T'COOT''); cycloalkyl or 5-6C cycloalkenyl; phenyl (o/s by T, alkenyl, COOT'', NO2 or NH2 (itself o/s by COT, T'COOT'', COT'COOT'' or CONHT'COOT''); phenyl substituted by T and by COOT'' or CONHT'COOT''; COQ; NHSO2T'COOT'', NHSO2Ph, NHSO2-naphthyl, NHSO2-quinolyl or NHSO2-isoquinolyl (all o/s on the amido N by T'COOT'', or T'N(T'')2); 1-6C alkylamino or cycloalkylamino, both N-substituted by COT'COOT'', COT'-tetrazolyl or CONHT'COOT''; piperidino in which the 2-CH2 moiety is replaced by CO or SO2; tetrazolyl (o/s by 1-5C alkyl); 1-(T'COOT'')-imidazolyl (o/s by 1-5C alkyl); PhSO2; 1-5C alkylsulfonyl (o/s by N(T'')2); imidazolidin-2-on-1-yl (o/s in the 3-position b y T'COOT''); 1-(4-7C cycloalkylamino or alkylamino)-cycloalkyl (o/s on N by T'COOT''); or R1COCH2, R1COCHT, R1COC(T)2 or 1-(R1CO)-(1-6C) (sic) cycloalkylene; Q  = 1-6C alkyl, 5-7C cycloalkyl (o/s by T), 1-6C alkylamino, phenylamino or pyridylamino (where amino moieties are o/s on N by T'COOT'' or T'-tetrazolyl);  R1  = OH, OT, NHT'', pyrrolidino, piperidino, morpholino, piperazino or N-(T)-piperazino (where NHT'', pyrrolidino and piperidino are o/s by T, T'COOT'' or CONHT'COOT''; and pyrrolidino and piperidino may carry a fused benzene ring);  Rb = CN or amidino (o/s by OH, T, (T)2 or 1-16C alkoxycarbonyl);  unless specified otherwise alkyl moieties have 1-4C, alkenyl or alkynyl moieties 2-3C and cycloalkyl moieties 3-7C; all COOH moieties are optionally replaced by groups convertible into COOH in vivo; and all amino or imino moieties are o/s by in vivo cleavable groups. An Independent claim is included for the preparation of (I).