- Process development of potassium channel opener, TCV-295, based on convenient ring formation of 2H-1,3-benzoxazine and selective N-oxidation of the pyridyl moiety
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An efficient process for potassium channel opener, TCV-295, based on a novel and convenient 4-(2-pyridyl)-2H-1,3-benzoxazine ring formation from o-hydroxybenzoylpyridine by the NH4I/piperidine/2,2-dimethoxypropane system and the following selective pyridine-N-oxidation using dimethyldioxirane, has been developed. Additionally, the combination reagent of ammonium halide and sec- or tert- amine conveniently converted o-hydroxyphenyl arylketones with several ketones (or benzaldehyde) to various novel 4-aryl-2H-1,3-benzoxazines.
- Mizufune, Hideya,Irie, Hiroyuki,Katsube, Susumu,Okada, Tadataka,Mizuno, Yukio,Arita, Miichiro
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- 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 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).
- Yamamoto, Satoshi,Hashiguchi, Shohei,Miki, Shokyo,Igata, Yumiko,Watanabe, Toshifumi,Shiraishi, Mitsuru
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p. 734 - 745
(2007/10/03)
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- 1,3-benzoxazine derivatives, their production and use
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A new compound of the formula: STR1 wherein STR2 is an optionally substituted benzene ring; R1 is a carbocyclic or heterocyclic group which is linked to the 4-position of the 1,3-benzoxazine ring through a carbon-carbon bond, a hydrocarbon resi
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