METHOD FOR PRODUCING 4-(BENZIMIDAZOLYLMETHYLAMINO)-BENZAMIDINES

摘要

Production of optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidines (I) involves: (a) condensing an optionally substituted diaminobenzene (II) with 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino)-acetic acid (III); (b) hydrogenating the product (IV); and (c) optionally carbonylating the amidino group. The intermediates (III), 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-aniline (V) and benzimidazole derivatives (IV') are new compounds. Independent claims are included for the following new intermediates: 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino)-acetic acid of formula (III), 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-phenylaminomethyl)-benzimidazoles of formula (IV') and 2-(4-(1,2,4-oxadiazol-5-on-3-yl)-aniline of formula (V). R 1> : alkyl or cycloalkyl; R 2> : alkyl (optionally substituted (os) by cycloalkyl-(1-3C) alkyl, where the 1-3C alkyl is os by COOH or a group convertible in vivo to COOH); or NR 21>R 22>; R 21> : alkyl (os by COOH, alkoxycarbonyl, COOCH 2Ph, CONHSO 2T, CONHSO 2Ph, 'trifluorosulfonylamino' (sic), trifluorosulfonylaminocarbonyl' (sic), or 1H-tetrazolyl); 2-4C alkyl substituted (but not on the alpha -C adjacent to the N) by OH, -O-T-Ph, -NH-T-COOH, -NH-T-COOT, -N(T)-T-COOH or -N(T)-T-COOT; or piperidinyl (os by T); R 22> : H; alkyl; cycloalkyl (os by T); 3-6C alkenyl or 3-6C alkynyl (both with the unsaturated part not bonded directly to N); phenyl (os by F, Cl, Br, T or OT); or benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl (all os by T); or NR 21>R 22> : 5-7 membered cycloalkyleneimino (os by COOH or (1-4C) alkoxycarbonyl and optionally fused with a benzene ring); T : 1-3C alkyl; alkyl groups have 1-6C and cycloalkyl groups 3-7C unless specified otherwise. [Image] ACTIVITY : Anticoagulant. MECHANISM OF ACTION : Thrombin inhibitor.