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] have been unequivocally synthesized via separate ten-step reaction sequences starting from isovanillin and vanillin, respectively. The 6-O-demethyl derivative was found to be 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 four 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. © 1977, American Chemical Society. All rights reserved.