| Cardiovascular diseases(CVD) are general terms for cardiovascular and cerebrovascular diseases. In recent years, the incidence of coronary heart disease and cerebral thrombosis of cardiovascular thromboembolic disease increase year by year, showing the trend of younger obviously, and thrombosis is the key factor that leads to this disease. Therefore, the development of drugs in prevention and treatment of thromboembolic disease becomes the focus attention and research in medical field. The ADP receptors on the platelet which play an important role in the process of thrombogenesis can increase or enlarge the action of the other platelet agonists. Thus, the ADP receptor antagonist has always been the hot spot of the research and development.At present, Clopidogrel, Prasugrel and Ticagrelor, and so on, have been listed, and they are the most commonly-used clinical antithrombotic drugs of ADP receptor antagonists. But Clopidogrel and Prasugrel are irreversible combined with ADP receptor, delaying function recovery of platelet after the drug withdrawal and emerging “Clopidogrel resistance” on some patients. Ticagrelor is the first reversible, direct acting and oral ADP receptor antagonist. In July 2011, the USFood and Drug Administration(FDA) approved Ticagrlor for the treatment of acute coronary syndrome(ACS). Compared with Clopidogrels, Ticagrelor has great advatange for its reversible combination with ADP receptor, but there is the risk of bleeding and breathing difficulties. Therefore, it is necessary to find a more effective and safer antiplatelet drug.Firstly, after the optimization of the synthetic route on the basis of extensive literature, exploration and optimized to determine a simple, economical, environment-tally friendly, high yield synthetic route. Ticagrelor was synthesized from 4,6-dichloro-2-(propylthio)pyrimidin-5-amine and 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol tartrate via nucleophilic subsititution, diazotization, nucleophilic subsititution, and acetal hydrolysis in 4 steps, and the reaction conditions of the nucleophilic substitution and recrystallization conditions for Ticagrelor were explored and optimized,after optimization, the overall yield is 54.5%(based on4,6-dichloro-2-(propylthio)pyrimidin-5-amine). Because there are some flaws for ticagrelor, access to large amounts of ticagrelor structure modified literature, avoiding compound patent,based on Ticagrelor and its active metabolites AR-C124910 XX respectively, the triazole[4,5-d]pyrimidine was retained for new drug design. The chlorine in the pyrimidine was substituted by simple, easy and relatively low cost amines according to the principal of rational drug design and modified drug design. Two series of 26 novel compounds without reported were designed and synthesized. The design synthetic compounds structure by confirmed 1H-NMR and ESI-MS, and determine the melting point and other related physical and chemical constants.Based on the Ticagrelor for positive drug, we tested the antiplatelet aggregation activityby the SD rat model. The maximum aggregation percentage was measured and the inhibition rate of platelet aggregation was calculated.The results show thatthe synthesized compounds have certain antiplatelet aggregation activity, but there is a certain gap compared with ticagrelor,on the whole, the active compound is better than A series B series compounds, the antiplatelet aggregation of A4, A9, A12 and B9 were relatively good, the percent inhibition were 61.9%, 69.3%, 71.2% and 45.5% respectively, deserving further research and development, and providing a reference for the design and synthesis of new ADP receptor antagonists. |
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