Study On Metabolism Of Benproperine And Its Enantiomers

Benproperine, 1-[1-methyl-2-[2-(phenylmethyl)phenoxy]ethyl]piperidine, is widely used as a cough suppressant in non-productive cough. It was reported to have a peripheral and central action and be given to humans orally as the embonate or the phosphate. But there was little report about the metabolism of the drug. In the previous research of our laboratory, five mono-hydroxylated metabolites of benproperine and their conjugates were detected in human urine; and the plasma concentration of (S)-enantiomer was found to be higher than that of (R)-enantiomer in health volunteers. The purposes of this study are to prepare the authentic reference of metabolites of benproperine, to obtain the rule of fragmentation pathway of benproperine derivatives in ESI-MS, to investigate the metabolism pathway of benproperine in humans and animals, to study the pharmacokinetics and pharmacology of benproperine and its metabolites, and to discover the stereoselectivity of benproperine enantiomers in metabolism and in pharmacodynamics. The farther purposes are to give the advices to the clinics for safety and rational administration, to give the evidences and materials for drug discovery on benproperine derivatives, and to give the ideas and procedures for drug discovery on metabolism and chiral shift.1. Preparation and mass spectral character of benproperine derivativesTwelve beproperine derivatives were prepared by chem-synthesis, microbial transformation and isolation from rat feces. Eleven novel compounds were obtained. Their structures were identified by NMR and ESI-MS.The metabolites of benproperine were synthesized by self-designed procedure. Two mono-hydroxylates of benproperine, 10 and 11, were prepared from o-benzylphenol and epoxypropane in 3 steps, which reacted with methyl (2,3,4-tri-Oacetyl-1-O-trichloro-acetimidoyl)-α-D-glucopyranuronate (26) to obtain protected glucuronides 36 and 42, respectively. The basic group, the reaction promoter and the order of addition are all important variables in the glucuronidation. The glucuronides of mono-hydroxylates of benproperine, 21 and 22, were obtained by hydrolysis of 36 and 42. Benproprine lactam (15) was prepared from δ-valerolactam. Compounds 10, 10·H₃PO₄, 11, 11·H₃PO₄, 15, 21,...