Study On ADP Receptor Antagonists Of Thienopyridine Derivatives

Thrombotic disease,which seriously threatens the health of the elderly,is a group of diseases of the circulatory system with high mobility and mortality.At present,there is a variety of treatments for thrombosis,in which the tetrahydro thienopyridines were the first-line drugs in the prevention and treatment of thrombosis,such as Clopidogrel and Prasugrel.However,these drugs have some disadvantages,for example,Clopidogrel has a slow onset and large individual differences;Prasugrel has severe risk of bleeding.Therefore,it has an important significance in the research and developme nt of new drugs with higher safety and efficacy.As a new class of thienopyridine derivatives with cyano,after a comprehens ive preclinical study,Tipidogrel hydrochloride shows a good anti-platelet aggregatio n activity and certain advantages in terms of stability,pharmacokinetic properties and bleeding side effects after a comprehensive preclinical study,which exhibits great development and application prospects.In order to avoid the defects of the present synthesis of Clopidogrel hydrochloride,the author reviewed lots of related literatures and designed the synthetic route reasonably.Then process conditions of each step were explored and optimized according to a plenty of experiments.Finally,a cost-effective,environmentally friendly and convenient synthetic route was established.Compared with the conventional process,the costs per kilogram of the product was reduced from 5750 yuan to 3558 yuan,the synthetic steps reduced from six to four,and the yield increased from 16.3% to 54.8%.Therefore,the new process is suitable for industr ia l preparation.Aiming at researching and developing new thienopyridine drugs with better safety and efficacy,using the rational drug design principles according to the analysis of the reported and listed thienopridines,twenty-three compounds were designed and synthesized based on terahydrothienopridine as mother nucleus,in which there were seventeen new compounds.The structures of these compounds were characterized by 1H-NMR and MS.The results of biological activity test showed that all the compounds have the anti-platelet aggregation activity,and the inhibition rates of C4,C8 and C9 were superior to the positive control ticlopidine,which suggested the value of further research.