Chemical and Pharmaceutical Bulletin p. 734 - 745 (1996)
Update date:2022-09-26
Topics:
Yamamoto, Satoshi
Hashiguchi, Shohei
Miki, Shokyo
Igata, Yumiko
Watanabe, Toshifumi
Shiraishi, Mitsuru
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 was 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 tetraethylammonium chloride (TEA) and BaCl2-induced and high KCl-induced contraction of rat aorta to identify potential K+ channel openers, and also for oral hypotensive effects in spontaneously hypertensive rats. An electron- withdrawing group with the proper shape at C6 and a methyl or halogens group at C7 of the 1,3-benzoxazine nucleus were required for the development of optimal 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 vasorelaxant activity (EC50=0.14 μM) against TEA and BaCL2- induced contraction and longer-lasting hypotensive effects than cromakalim (1).
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