Synthesis and biological activity of novel 2-(alpha-alkoxyimino)benzylpyridine derivatives as K+ channel openers.

摘要: The search for novel K+ channel openers with a non-benzopyran skeleton, unlike cromakalim, led to the discovery of new series (Z)-2-(alpha-alkoxyimino)benzylpryridine derivatives. Synthesis was achieved by using (Z)-dominant condensation reaction benzoylpyridines O-alkylhydroxylamines, followed m-chloroperbenzoic acid (m-CPBA) oxidation. compounds were tested their vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl2- high KCl-induced contraction rat aorta identify potential openers, also effects on coronary blood flow (CBF) after intracoronary injection anesthetized dogs. A large number 2-(alpha-alkoxyimino)benzylpyridines strongly inhibited TEA BaCl2-induced contraction, had no effect 80 nM increased CBF more than 200% basal at 10-30 micrograms/dog. In particular, (Z)-2-[5-bromo-alpha-(tert-butoxyimino)-4-fluoro-2-hydroxybenzyl]- 3- hydroxypyridine 1-oxide (7d) showed highly potent (EC50 = 0.28 microM) comparable that levcromakalim 0.17 microM), gave significantly longer-lasting increase (T1/2 30 min) compared levcromakalim, nicorandil, nitroglycerin, or diltiazem 5.2, 0.9, 0.4, 2.2 min, respectively). It exhibited stable long-lasting hypotensive (over 7 h) upon oral administration 1 mg/kg spontaneously hypertensive rats (SHRs).