Maekawa T, Yamamoto S, Igata Y, Ikeda S, Watanabe T, Shiraishi M
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1997 Dec;45(12):1994-2004. doi: 10.1248/cpb.45.1994.
The search for novel K+ channel openers with a non-benzopyran skeleton, unlike cromakalim, led to the discovery of a new series of (Z)-2-(alpha-alkoxyimino)benzylpryridine derivatives. Synthesis was achieved by using a (Z)-dominant condensation reaction of benzoylpyridines with O-alkylhydroxylamines, followed by m-chloroperbenzoic acid (m-CPBA) oxidation. The compounds were tested for their vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl2- and high KCl-induced contraction of rat aorta to identify potential K+ channel openers, and also for their effects on the coronary blood flow (CBF) after intracoronary injection in anesthetized dogs. A large number of the 2-(alpha-alkoxyimino)benzylpyridines strongly inhibited TEA and BaCl2-induced contraction, had no effect on 80 nM KCl-induced contraction, and increased the CBF to more than 200% of the basal flow 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 vasorelaxant activity (EC50 = 0.28 microM) comparable to that of levcromakalim (EC50 = 0.17 microM), and gave a significantly longer-lasting increase (T1/2 = 30 min) in the CBF compared to levcromakalim, nicorandil, nitroglycerin, or diltiazem (T1/2 = 5.2, 0.9, 0.4, and 2.2 min, respectively). It also exhibited a stable and long-lasting hypotensive effect (over 7 h) upon oral administration of 1 mg/kg in spontaneously hypertensive rats (SHRs).
对具有非苯并吡喃骨架的新型钾通道开放剂的研究，与克罗卡林不同，导致发现了一系列新的(Z)-2-(α-烷氧基亚氨基)苄基吡啶衍生物。通过苯甲酰吡啶与O-烷基羟胺的(Z)-主导缩合反应，然后用间氯过苯甲酸(m-CPBA)氧化来实现合成。测试这些化合物在四乙铵氯化物(TEA)和BaCl2以及高KCl诱导的大鼠主动脉收缩中的血管舒张活性，以鉴定潜在的钾通道开放剂，还测试它们在麻醉犬冠状动脉内注射后对冠状动脉血流量(CBF)的影响。大量的2-(α-烷氧基亚氨基)苄基吡啶强烈抑制TEA和BaCl2诱导的收缩，对80 nM KCl诱导的收缩无影响，并在10 - 30微克/犬时使CBF增加至基础流量的200%以上。特别是，(Z)-2-[5-溴-α-(叔丁氧基亚氨基)-4-氟-2-羟基苄基]-3-羟基吡啶1-氧化物(7d)显示出与左克罗卡林(EC50 = 0.17 microM)相当的高效血管舒张活性(EC50 = 0.28 microM)，并且与左克罗卡林、尼可地尔、硝酸甘油或地尔硫卓相比，CBF增加的持续时间明显更长(T1/2 = 30分钟)(分别为T1/2 = 5.2、0.9、0.4和2.2分钟)。在自发性高血压大鼠(SHRs)中口服1 mg/kg时，它还表现出稳定且持久的降压作用(超过7小时)。
