Disubstituted bicyclic heterocycles with thrombin inhibiting effect against related serine proteases

摘要

Disubstituted bicyclic heterocycles of the Formula (I) in particular for inhibiting thrombin and prolonging thrombin time. The disclosed compounds relates to the tautomers, stereoisomers, mixtures, and salts, which have valuable properties. The compounds of the above general formula (I), in which E is a cyano group, represent valuable intermediate products for the production of the other compounds of the general formula (I). Furthermore, the compounds of the above general formula (I), in which E stands for a RbNH-C(=NH)-group, have valuable pharmacological properties. Wherein; A denotes a carbonyl or sulphonyl group linked to benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het. B denotes an ethylene group, in which a methylene group, linked to either to the group Het or Ar, may be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, carbonyl or -NR1- group, wherein R1 denotes a hydrogen atom or C1-5alkyl group; E denotes an RbNH-C(=NH)-group wherein Rb denotes a hydrogen atom, hydroxy group, C1-3alkyl or C1-3alkoxy group; Ar denotes a phenylene group optionally substituted by fluorine, chlorine or bromine atom or by trifluoromethyl, C1-3alkyl or C1-3alkoxy group; a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted by C1-3alkyl group; Het denotes a bicyclic heterocycle of the formula (II), (III), (IV), (V), (VI), (VII) or (VIII); Ra denotes C1-6alkyl group, C3-7cycloalkyl group optionally substituted by C1-3alkyl group. Ra is further described as disclosed.