title: Synthesis and biological activity of novel 1,3-benzoxazine derivatives as K+ channel openers.
abstract: 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 halogeno 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 microM) against TEA and BaCl2-induced contraction and longer-lasting hypotensive effects than cromakalim (1).
authors.affiliation: Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.forename: S
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: S
authors.initials: S
authors.lastname: Miki
authors.forename: Y
authors.initials: Y
authors.lastname: Igata
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Shiraishi
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D000959:Antihypertensive Agents; D010078:Oxazines; D015221:Potassium Channels