Synthesis and Biological Activity of Novel 1,3-Benzoxazine Derivatives as K^+ Channel Openers

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A new series of 1,3-benzoxazine derivatives with a 2-pyridine 1-oxide group at C4 was designed to explore novel K^+ channel openers. Synthesis swas carried out by using a palladium(0)-catalyzed carbon-carbon bond formation reaction of imino-triflates with organozinc reagents and via a new one-pot 1,3-benzoxazine skeleton formation reaction of benzoylpyridines. The compounds were tested for vasorelaxant activity in tetrathylammonium choloride (TEA) and BaCl_2-induced and high KCl-induced contraction of rat aorta to identify potential K^+ channel openers, and also for oral hypotensive effects in spontaneously htypertensive rats. An electron-withdrawing group with the proper shape at C6 and a methyl or halogeno group at C7 of the 1,3-benzoxazine nucleus were required for the development of opticmal vasorelaxant and hypotensive activity. In particular, 2-(6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine 1-oxide (71) showed more potent vasorelatzant activity (EC_<50>=0.14 μM) against TEA and BaCl_2-induced contraction and longer-lasting hypotensive effects than cromakalim (1).
社団法人日本薬学会の論文
1996-04-15