Study On ADP Receptor Antagonists Of Tetrahydrothieno [3,2-c] Pyridine Derivatives

Thrombosis may lead to cardiac, cerebral and pulmonary circulation disorders such asacute myocardial infarction, apoplexy and pulmonary embolism etc., which threatenspeople’s health and lives, and is also a common complication of surgical operationsand a factor of reocclusion after interventional angioplasty. Therefore, developing anew medicament for preventing and treating cardiac and cerebral vascular diseasesbecomes a focus of attention and study in recent years. Clopidogrel and Prasugrel areclinical commonly-used antiplatelet agent of ADP receptor antagonists at present, buton the other side, Clopidogrel had been found a lot of ADR such as TTP&HUS,especially Clopidogrel resistance. Prasugrel has exhibits severe bleeding tendency.Therefore the new antiplatelet drugs are longed for to be developed.A new synthetic rute for Prasugrel has been established based on the reportedmethods.2-bromo-1-cyclopropyl-2-(2-fluorophenyl) ethanone, the intermediate Ⅱ,was synthesized from1-cyclopropyl-2-(2-fluorophenyl) ethanone by Wohl-Zieglerreaction in a yield of80.5%. Compound Ⅲ,5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydro thieno [3,2-c]pyridin-2(4H)-one was synthesizedfrom intermediate Ⅱ and5,6,7,7a-tetrahydrothieno[3,2-c] pyridine-2(4H)-onehydrochloride via SN2reaction. Target compound Prasugrel was obtained byacetylation reaction using acetic anhydride in a yield of81.2%. The overall yield is40.3%of theory (calculated for1-cyclopropyl-2-(2-fluorophenyl) ethanone).The established synthetic route has advantages of cheaper starting materials，avoiding of bromine and sodium hydride, cheaper and safer solvents and muchhigher yields. It is suitable for large-scale application.A series of novel thienopyridine derivatives containing piperazine ring weredesigned and synthesized using4,5,6,7-tetrahydrothieno [3,2-c] pyridine as thestarting material. Their structures were characterized by1H NMR,13C NMR, IR andESI-HRMS. Their in vivo anti-platelet aggregation activities were evaluated and theresults indicated that some compounds exhibited certain anti-platelet aggregationactivity. These new compounds have the prospect to be new drugs.