Study On The Synthesis Of PAR-1Receptor Antagonist E5555Analogues

As a common clinical syndrome, thrombotic disease has drawn much concern.According to reliable statistics, the incidence of thrombotic disease is gradually thehighest among all the diseases, and moreover, it causes significant morbidity andmortality after onset of illness. In today’s society, thrombotic disease is becoming oneof the most heated topics of disease research.Anti-platelet drugs could be used in the treatment of thrombotic disease, whilePAR-1receptor antagonist is now the most attended and potential anti-platelet drugsCompared with traditional drugs, it could selectively inhibit thrombin-induced plateletactivation and thereby restrain the form of thrombus on the premise of not harmingnormal hemostatic function. So PAR-1receptor antagonist is a perfect drug for thetreatment of thrombotic disease.E5555studied by Japanese Eisai Corporation is a new protease activated receptorPAR-1antagonist. It is mainly used in the treatment of arterial thrombosis diseasessuch as acute artery syndrome (ACS). The phase II performance of E5555is prettygood and so the drug has tremendous potential.In this paper, we transformed the molecular structure of E5555and successfullysynthesized the analogues of PAR-1receptor antagonist E55558a-8c. Then we testedtheir anti-platelet activities and made a solid foundation for the further study of E5555.During the course of the experiment, we examined the effects of different conditionson the reaction and got the optimal reaction condition of each step. The structures ofall the synthetic compounds were characterized by1H NMR. The final compoundswere characterized by IR,1H NMR,13C NMR, and HRMS.And then, we successfully synthesized compound α-bromo-4-propoxy-5-(pyrrolidin-1-yl)-3-tert-butylphenylethanone(9) which is substituted by pyrrolidine andα-bromo-5-(N-methylpiperazine-1-yl)-4-propoxy-3-tert-butylphenyle-thanone (13)which is substiuted by N-methyl piperazine. The structures of all the synthetic compounds were characterized by1H NMR. In addition, we attempted to synthesize5,6-diethoxybenzo[d]isoxazol-3(2H)-imine(21). We designed the synthetic route andsuccessfully got4,5-diethoxy-2-hydroxybenzonitrile(20), but when we synthesisedcompound(21) in the last step we encountered a great difficult. Until now, we have notgot designed compound21and need further research and analysis. The structures of allthe synthetic compounds were characterized by1H NMR. Some compounds whichcontained characteristic groups were confirmed by IR. All of this laid the groundworkfor the further study.