Reversible Ring-opening Reactions of Triazolobenzo- and Triazolothieno-diazepines in Acidic Media at around Body Temperature

Abstract

Hydrolytic reactions of triazolobenzo- and triazolothienodiazepines (estazolam and etizolam) as well as a thienodiazepine (clotiazepam) were studied spectrophotometrically. Cleavage reactions of the azomethine bonds of estazolam and etizolam were reversible and the open-ring compounds were in equilibrium with the closed-ring compounds (protonated forms of the parent drugs). However, little spectral change was observed in clotiazepam. The rate of ring-closure reaction was greater than that of ring-opening reaction in estazolam whereas the opposite was the case in etizolam. The activation energies of the forward and reverse reactions were obtained from Arrhenius-type plots. In addition, the pK_a value of etizolam was determined.