苯并咪唑与苯并异噁唑桥连衍生物的合成及其生物活性
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摘要
以3-[(3-氨基-4-甲基氨基苯甲酰)吡啶-2-基氨基]丙酸乙酯为起始原料,经环合、水解、酰胺化等反应合成了5个新型的达比加群酯衍生物(5a～5e),其结构经~1H NMR、 IR和HR-MS(ESI)表征。并对5a～5e进行了凝血活酶抑制活性(IC_(50))及生物利用度(F)测试。结果表明:化合物5c的抗凝血活酶活性(IC_(50))和生物利用度(F)最好,分别为1.4±0.1(nM)和6.9%。
Five novel dabigatran etexilate derivatives were designed and synthesized from ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate by cyclization, hydrolysis and amidation reaction. The structures were characterized by ~1H NMR, IR and HR-MS(ESI). The clotting enzyme inhibitory activities(IC_(50)) and bioavailabilities(F) were investgated. The results showed that 5 c exhibited best anticoagulant activities with IC_(50) and F of 1.4±0.1(nM) and 6.9%, respectively.
Five novel dabigatran etexilate derivatives were designed and synthesized from ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate by cyclization, hydrolysis and amidation reaction. The structures were characterized by ~1H NMR, IR and HR-MS(ESI). The clotting enzyme inhibitory activities(IC_(50)) and bioavailabilities(F) were investgated. The results showed that 5 c exhibited best anticoagulant activities with IC_(50) and F of 1.4±0.1(nM) and 6.9%, respectively.
引文
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[8] 蔡志强,侯旭,侯玲,等.达比加群酯中间体3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯的合成[J].合成化学,2016,24(08):709-712.
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[10] GNAD F,DACH R,HEDDESHEIMER I,et al.Method for producing dabigatran etexilate:WO 2011061080[P].2011.
[11] 蔡志强,马维英,候旭,等.达比加群酯的合成工艺改进[J].精细化工,2015,32(3):308-311.
[12] 方干,郑永勇,张晓培,等.达比加群酯合成路线图解[J].中国医药工业杂志,2011,42(9):717-719.