新型苯并咪唑衍生物的合成及其抗凝血活性

以3-［(3-氨基-4-甲基氨基苯甲酰)吡啶-2-基氨基］丙酸乙酯为原料，与4-氰基-3-氟苯取代基乙酸经环化反应制得3-【【2-｛［(4-氰基-3-氟苯取代基）甲基］-1-甲基-1-H-苯并咪唑-5-基｝羰基】吡啶-2-基】氨基丙酸乙酯（3a, 3e）; 3经水解和酰胺化反应制得3-【【【2-｛［(4-氰基-3-氟苯基)取代基］甲基｝-1-甲基-1H-苯并咪唑-5-基】羰基】吡啶-2-基氨基】丙酰取代胺基（6a~6h）；6与乙酰氧肟酸经环合反应合成了8个新型的苯并咪唑衍生物（7a~7h），其结构经1H NMR和HR-ESI-MS表征。抗凝血活性结果表明： 7a和7c的抗凝血活性最好，其aPTT值分别为(83.1±4.2) s和(80.7±2.9) s，优于阳性对照药达比加群酯(75.3±2.1)s。

Synthesis and Anticoagulant Activities of Novel Benzimidazole Derivatives

Ethyl 3-｛2-［(4-cyano-3-fluorophenyl substituent)methyl］-1-methyl-N-(pyridin-2-yl)-1H-benzo［d］imidazole-5-carboxamido｝propanoate（3a，3e） were prepared by cyclization of ethyl-3-［3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido］propanoate with 2-(4-cyano-3-fluorophenyl substituent)acetic acid． 2-{3-［2-(4-Cyano-3-fluorophenyl substituent)methyl］-1-methyl-N-(pyridin-2-yl)-1H-benzo［d］imidazole-5-carboxamido｝propanamido substituent（6a~6h） were prepared by hydrolysis and amidation from 3． Eight novel benzoimidazole derivatives（7a~7h） were synthesized by cyclization reaction of 6 with acetomenadione． The structures were characterized by ¹H NMR and HR-ESI-MS. The anticoagulant activities of 7a~7h were investigated. The results showed that 7a and 7c exhibited anticoagulant activities. The aPTTs were （83.1±4.2）s and （80.7±2.9）s, respectively, which were better than dabigatran etexilate（75.3±2.1）s.