RACEMIZATION OF DRUG ENANTIOMERS BY BENZYLIC PROTON ABSTRACTION AT PHYSIOLOGICAL PH

The enantiomers of the aromatase inhibitors 3-(4-aminophenyl)-pyrrolidine-2,5-dione (WSP-3, II), its N-pentyl derivative (III), and the antifungal econazole (IV), all possessing a benzylic proton at the chiral centre, are rapidly racemised in vitro in phosphate buffer (0.01 M) at pH 7.4 and 23-degrees-C with t1/2 values of 7, 6, and 5 h respectively. In vivo studies in rats show that (+)-econazole is racemised after intraperitoneal injection with t1/2 = 1.24h. The enantiomers of the antifungal 1-[(benzofuran-2-yl)-4-chlorophenylmethyl] imidazole (V) were stable at pH 7.4, attributable to steric hindrance to carbanion formation in the racemisation step. (C) 1994 Wiley-Liss, Inc.