New 1-phenyl:benzyl -benzimidazole derivs. with alkylene-bridged heterocyclic gp. - used as angiotensin II antagonists e.g. for treating cardiovascular, pulmonary or CNS disorders

摘要

Benzimidazoles of formula (I), and their 1-, 3-isomer mixts., N-alkyl quat. salts and salts are new: R1 = H, F, Cl, Br, CF2F, CHF2, CF3 or alkyl; R2 = (i) oxazol-2-yl, thiazol-2-yl or imidazol-2-yl, all with the 4,5-positions linked by an n-propylene or n-butylene bridge, where the NH in the imidazole ring is opt. substd. by 1-6C alkyl (itself opt. substd. by a gp. metabolised in vivo to COOH or by CF3, COOH, alkoxycarbonyl, aminocarbonyl or mono- or di-alkylaminocarbonyl); or (ii) 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl; R4 = H or a 4-phenyl-benzyl gp. of formula (a): R5 = gp. metabolisable in vivo to COOH, COOH, CN, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl; R3 = 1-5C alkyl, 3-5C cycloalkyl, 1-4C alkoxy or 1-4C alkylthio; all alkyl and alkoxy gps. have 1-3C unless otherwise specified; gp. metabolisable to COOH = e.g. COOR1,-COOCHR11 OCOR111 or -COOCHR"OCOOR"'; R1 = 1-6C alkyl, 5-7C cycloalkyl, benzyl, 1- or 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl; R11 = H or Me; R111 = 1-6C alkyl, 5-7C cycloalkyl, phenyl, benzyl, 1- or 2-phenylethyl or 3-phenylpropyl. USE/ADVANTAGE - Cpds. (I; R5 = gp. metabolisable to COOH, COOH or 1H-tetrazolyl) are angiotensin antagonists, esp. angiotensin II antagonists. (I; R4 = H or R5 = CN or triphenylmethyl-triazolyl) are intermediates for the active cpds. The angiotensin II antagonists are useful for treatment of hypertension, cardiac insufficiency, ischaemic peripheral blood flow disorders, myocardial ischaemia (angina), diabetic nephropathy; glaucoma and gastrointestinal or bladder disorders; for prevention of cardiac insufficiency progression after myocardial infarct, atherosclerotic vascular changes or restenosis after operations to widen vascular stenoses; for treating pulmonary diseases; and CNS disorders such as depression, Alzheimer's disease, Parkinson's disease, bulimia and cognitive function disorders. (I) show not toxic side-effects (e.g. negative isotropic action or arrhythmia) at up to 30 mg/kg i.v. Dose for adults is 20-100 (pref. 30-70) mg i.v. or 50-200 (pref. 75-50) mg p.o., each 1-3 times daily.