Synthesis of N-(2,3-dihydro-1-~14Cmethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-benzamide and N-(2,3-dihydro-l-~14Cmethyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) - N -~14C methyl-benzamide as novel carbon-14 labelled CCK Antagonists

摘要

Introduction: Dealkylayion and 3- hydroxylation are the most important metabolic routes for several 1,4-benzodiazepine derivatives. Isotopic substitution at the site of metabolic transformation is one of the best methods for elucidating the mechanism of the metabolic process and several carbon 14 labelled benzo diazepine derivatives have been synthesized and there metabolic fates studied in human and animal models. Since the isolation of the non-pep tidal cholecystokinin (CCK) antagonist Asperlicin, the 1,4-benzodiazepin ring system has served as a useful tool for delineating the pharmacologic action of CCK. In order to study the rate of 1-dealkylation of benzodiazepine CCK antagonist and its influence on the pharmacologic profile of this compounds it became necessary to synthesis a CCK antagonist derivate labeled with carbon-14 at the N-1 position. Furthermore in order to determine the rate of chain N-methyl dealkylation, synthesis of a ligand, N-methylated both in N-1 and the amide chain appeared of interest.