NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF POTENTIAL PRODRUGS OF BENZIMIDAZOLE-7-CARBOXYLIC ACIDS

In order to improve the oral bioavailability (BA) of iphenyl-4-yl]meth yl]-1H-benzimidazole-7-carboxylic acid (3: CV-111940 and iphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid(4: CV-11974), novel angiote nsin II (AII) receptor antagonists, chemical modification to yield pro drugs has been examined. After selective tritylation of the tetrazole rings in 3 and 4, treatment of N-tritylated benzimidazole-7-carboxylic acids (6, 7) with a variety of alkyl halides, followed by deprotectio n with hydrochloric acid, afforded esters of 3 and 4. Mainly 1-(acylox y)alkyl esters and 1-[(alkoxycarbonyl)oxy]alkyl esters, double ester d erivatives, were synthesized. Their inhibitory effect on AII-induced p ressor response in rats and oral BA were investigated. (Pivaloyloxy)me thyl and (+/-)-1-[[(cyclohexyloxy)-carbonyl]oxy]ethyl esters of 3 and 4 showed marked increases in oral bioavailability which significantly potentiated the inhibitory effect of the parent compounds on AII-induc ed pressor response. Among them, (+/-)-1-[[(cyclohexyloxy)carbonyl]oxy ]ethyl phenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (10s, TCV-11 6) was selected as a candidate for clinical evaluation.