Novel Potassium Channel Activators. III. Synthesis and Pharmacological Evaluation of 3, 4-Dihydro-2H-1, 4-benzoxazine Derivatives : Modification at the 2 Position

Abstract

A new series of 3, 4-dihydro-2H-1, 4-benzoxazine derivatives, where various substituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activity was evaluated. Introduction of a hydroxyl group, as in compound 5, resulted in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrato group, as in compound 8, produced typical nitrate activity such as exhibited by nitroglycerine in addition to potassium channel-activating activity. X-ray structural analysis of compound 5 showed that the sum of the bond angles around the N atom at the 4 position was 357.8°, suggesting that the N atom had an approximately sp²-like planar bond configuration.