Matsumoto Y, Tsuzuki R, Matsuhisa A, Takayama K, Yoden T, Uchida W, Asano M, Fujita S, Yanagisawa I, Fujikura T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1996 Jan;44(1):103-14. doi: 10.1248/cpb.44.103.
Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihydro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a--c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.
在一系列新型4-取代的3,4-二氢-2H-1,4-苯并恶嗪衍生物中发现了强大的钾通道激活作用。制备的关键步骤是3,4-二氢-2H-1,4-苯并恶嗪（3）与活性卤代吡啶进行亲核取代反应，如卤代吡啶N-氧化物（15a - c）和4-溴吡啶的硼烷加合物（15d）。构效关系研究确定2-(3,4-二氢-2,2-二甲基-6-硝基-2H-1,4-苯并恶嗪-4-基)吡啶-1-氧化物（16a：YM934）为最佳化合物。该化合物（16a）在清醒的自发性高血压大鼠中显示出比克罗卡林更强的口服降压作用。
