Synthesis and identification of the major metabolites of prazosin formed in dog and rat

Abstract

The 6-O-demethyl and 7-O-demethyl analogues of the new antihypertensive drug prazosin [2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride] were unequivocally synthesized via separate 10-step reaction sequences starting from isovanillin and vanillin, respectively. The 6-O-demethyl derivative was identical with the major prazosin metabolite formed in dog and rat, while the 7-O-demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline and 2,4-diamino-6,7-dimethoxyquinazoline, are also described. All 4 metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect since they account for a major portion of the administered dose.