Kinetics and Mechanism of the Acid-Base Equilibrium of Mexazolam and Comparison with Those of Other Commercial Benzodiazepinooxazole Drugs(Pharmaceutical)

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The oxazolidine ring-opening and ring-closing reactions of mexazolam, cloxazolam, haloxazolam, and flutazolam were investigated by a pH-jump method, similarly to the case of oxazolam reported previously [Kurono et al, Chem. Pharm. Bull., 33, 1633 (1985)]. Mexazolam exists essentially as a single isomer, either cis or trans (referring to the 3-methyl group and 11b-(2'-chlorophenyl) group), differently from the case of oxazolam (cis isomer/trans isomer ratio for oxazolam≒1:1). Over the pH range of 1-13, the pH-rate profiles show two step reactions. For interpretation of these profiles, we propose a reaction mechanism including an intermediate, detected by the kinetic method, between the iminium structure (oxazolidine ring-opened form) and the ring-closed form. These kinetic properties of mexazolam differ from those of other benzodiazepinooxazoles, and the difference is caused by the presence of the 3-methyl group rather than the 2'-chlorine atom. The intrinsic rate constants of mexazolam, its 2'-chlorine deficient analog (3-methyl compound), cloxazolam, haloxazolam, and flutazolam were determined according to the appropriate reaction schemes.
公益社団法人日本薬学会の論文
1987-09-25