Novel potassium channel activators. III. Synthesis and pharmacological evaluation of 3,4-dihydro-2H-1,4-benzoxazine derivatives: Modification at the 2 position

A new series of 3,4-dihydro-2H-1,4-benzoxazine derivatives, where various s ubstituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activit y was evaluated. Introduction of a hydroxyl group, as in compound 5. result ed in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrate group, as in compound 8, p roduced typical nitrate activity such as exhibited by nitroglycerine in add ition to potassium channel-activating activity. X-ray structural analysis o f compound 5 showed that the sum of the bond angles around the N atom at th e 4 position was 357.8 degrees, suggesting that the N atom had an approxima tely sp(2)-like planar bond configuration.