NOVEL POTASSIUM CHANNEL ACTIVATORS - SYNTHESIS AND STRUCTURE-ACTIVITYRELATIONSHIP STUDIES OF 3,4-DIHYDRO-2H-1,4-BENZOXAZINE DERIVATIVES

Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihy dro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as h alogenopyridine N-oxides (15a-c) and the borane adduct (15d) of 4-brom opyridine. Structure-activity relationship studies identified yl-6-nit ro-2H-1,4-benzoxazin-4-yl)pyridine-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertens ive effect than cromakalim in conscious spontaneously hypertensive rat s.