Design,Synthesis And Study Of Novel Benzimidazole Derivatives As Anticoagulant Drug

Venous thromboembolism is the third largest cardiovascular disease after the acute coronary syndrome and stroke,and has become one of the serious diseases harming to human health.The prevention and treatment for thromboembolism have aroused wide attention in the world.It is imminent to find safe anticoagulant drugs with oral activity at present.Dabigatran etexilate is a non-peptidic thrombin inhibitor,having a broad therapeutic window,it can be taken orally and doesn't require routine monitoring.However,it also have some shortcomings,for instance low solubility,oral bioavailability difference(F=6.5%)and so on.So we need to find better anticoagulant drugs.In this paper,eleven new compounds were designed and synthesized based on the literature and the structure-activity relationship of benzimidazole-like drugs.The starting material 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate generate3-(phenyl substitut)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido)methyl propanoate(3a,3e,3i)which react with 2-(phenyl substitut)acetic acid by cyclization;2-{3-[2-(phenyl 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 3a,3e.Eleven novel benzoimidazole derivatives(7a-7h,8a,8e,8i)were synthesized by cyclization reaction of 6a-6h,3a,3e,3i with acetomenadione and the total yield was4.3-23.2%.In this paper,the advantages of the improved synthesis method are easy work-up,mild reaction conditions,little environmental pollution,and more convenient postprocessing.The target compounds were confirmed by IR,1H-NMR,all of them are new compounds.Eleven target compounds were evaluated for aPTT.The results showed that the aPTT of compound 7d(aPTT = 147.1 ± 3.5s)and the compound 7g(aPTT = 180.1 ± 2.9s)are higher than that of Dabigatran etexilate(aPTT =75.3 ± 2.1),but there is the risk of bleeding in clinical prone.7e(aPTT = 83.2 ± 2.3s),7f(aPTT =83.1 ± 4.2s)and 7h(aPTT = 81.5 ± 2.5s)can prolong the clotting time and do not have the risk of bleeding,so the activity is better;the anticoagulant activity of the remaining compounds is lower than that of dabigatran etexilate.