Design,Synthesis And Activity Of Thienopyridine Derivatives

Thrombus is caused by different etiology and pathogenesis that leads to abnormal blood coagulation,including myocardial infarction,ischemic stroke,cerebral embolism.The morbidity has gradually increased and harm to people’s health seriously.ADP was the first molecule found to promote platelet aggregation,binding to its receptor P2Y receptor lead to platelet activation,and platelet activation triggering aggregation between the blood clots easily with each other.ADP receptor antagonists mainly contain thienopyridine such as clopidogrel.Clopidogrel is a prodrug,being active metabolites with the cytochrome P450 metabolic enzymes and binding P2Y12 irreversible,thereby prevent platelet activation.But there are disadvantages can not be ignored,such as:slow onset,platelet individual differences in inhibition of large,irreversible effects on platelets,etc.,even appeared in the treatment of thrombocytopenic purpura(TTP)and hemolytic uremic syndrome(HUS).of a new generation of thienopyridine prasugrel,being approved for prevention of acute coronary syndrome patients undergoing percutaneous coronary intervention after atherosclerotic artery thrombosis by FDA in July 2009,has demonstrated good inhibitory activity of thrombosis,but there are fatal hemorrhagic risk,so develop a new generation thienopyridine antagonist is the urgent task of drug discovery.Atructure of thienopyridine mother nucleus was kept by the study of drugs in the market and reported thienopyridines.we refered to the principle of Me Too,as well as combination principles,prodrug,bioisostere and so on.Three novel thienopyridine derivatives,18 compounds synthesized.twenty derivatives,of which there were eighteen target compounds,were achieved from 2-Chlorobenzaldehyde or benzyl halides,and their structures were characterized by 1H NMR,IR and MS.The results showed that the activity of compound C1 was superior to ticlopidine in platelet aggregation inhibition tests in vivo and worthy of further investigation.Compound A4,B2,C4 and C7 possessed moderate platelet aggregation inhibitory activities.However,due to the limited compounds,the specific structure-activity relationship needs further study,witch will provide reference for designing novel thienopyridine derivatives and lay the foundations of new drugs.