F. Kajfež

STEREOSELECTIVE IN VITRO AROMATIC OXYGENATION OF CHIRAL 1,4-BENZODIAZEPIN-2-ONES

Publisher Summary This chapter focuses on stereoselective in vitro aromatic oxygenation of chiral 1,4-benzodiazepin-2-ones. Biotransformation pathways and pharmacology of drugs belonging to the group of l,4-benzodiazepin-2-ones are being extensively investigated. In these investigations, structure-activity relationships are of special interest. The most frequent in vivo biotransformations of 1,4-benzodiazepine derivatives are N(l)-dealkylation, hydroxylation of the heterocyclic and aromatic rings, hydrolysis of the lactam and azomethyne bonds, and N(4)-oxidation and formation of O-glucuronides. Actual metabolism depends on the substituents. Stereoselectivity in oxidative metabolism, presumably residing in cytochrome P-450, has been repeatedly reported for various drugs. The chapter describes a study in which stereoselectivity in biotransformation of enantiomeric 7-chloro-l,3-dihydro-3methyl-5-phenyl-2H-l,4-benzodiazepin-2-ones and their N(1)-methyl derivatives was analyzed. These experiments were carried out in vitro, using postmitochondrial and microsomal fractions of rat liver as enzyme sources. Results suggested that oxygenases involved in aromatic oxygenation of chiral 1,4-benzodiazepin-2-ones in vitro act stereoselectively on the S-form. Hydroxylation in position C(3), however, was found to be nonstereoselective. Hydroxylation in position C(3) and hydroxylation of aromatic rings should be catalyzed by different species of cytochrome P-450.

SYNTHESIS AND DESULFURATION OF THIANAPHTHEN-3-CARBOXYLIC ACID DERIVATIVES

Abstract Recently, we have been interested in the synthesis of some heterocyclic compounds as potential antiinflammatoric agents1. Derivatives of thianaphthen-3-carboxylic acid might also show such activity. Therefore, a rational synthetic pathway for these compounds was developed: