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目的合成新的三唑并[4,5-d]嘧啶类化合物,并对其体外抗血小板聚集活性进行评价。方法以抗血栓新药替格瑞洛为先导化合物,对其进行结构简化,将难以合成的环戊醇结构用简单的链状醇结构代替,设计合成了一系列三唑并[4,5-d]嘧啶类化合物。以氨基醇为原料,首先与4,6-二氯-2-正丙巯基嘧啶-5-胺进行缩合,然后环化成三唑环,再与各种取代胺发生第二次缩合,最终合成目标化合物。采用Born氏法对化合物抗兔血小板聚集活性进行了评价。结果与结论共合成了17个新的三唑并[4,5-d]嘧啶类化合物,其结构均经1H-NMR、13C-NMR和MS谱确证。体外抗血小板聚集活性结果显示,具有邻二羟基结构的化合物的活性明显高于其他化合物,表明邻二羟基是该类化合物的关键活性基团。化合物9i对血小板聚集的抑制率为75.2%,约为阳性对照药替格瑞洛的80%,但其结构远比替格瑞洛简单,更易于合成,可作为先导化合物继续进行结构优化,以期发现更高效的抗血栓新药。
OBJECTIVE: To synthesize new triazolo [4,5-d] pyrimidine compounds and evaluate their in vitro anti-platelet aggregation activity. Methods The antithrombotic ticagrelor was taken as the lead compound and its structure was simplified. The structure of cyclopentanol, which was difficult to synthesize, was replaced by a simple chain alcohol structure. A series of triazolo [4,5-d ] Pyrimidine compounds. The amino alcohol as the raw material, first with 4,6-dichloro-2-n-propyl mercaptopyrimidin-5-amine condensation, and then cyclized to triazole ring, and then with a variety of substituted amine second condensation, the final target of synthesis Compound. The anti-rabbit platelet aggregation activity of the compounds was evaluated by Born’s method. RESULTS AND CONCLUSIONS A total of 17 novel triazolo [4,5-d] pyrimidines were synthesized and their structures were confirmed by 1H-NMR, 13C-NMR and MS spectra. In vitro anti-platelet aggregation activity results show that compounds with ortho-dihydroxy structure activity was significantly higher than other compounds, indicating that o-dihydroxy group is the key active group of such compounds. The inhibitory rate of compound 9i on platelet aggregation was 75.2%, which was about 80% of that of ticagrelor, a positive control drug. However, the structure of compound 9i was far simpler and easier to synthesize than that of ticagrelor and could be used as the lead compound to continue the structural optimization. Find more effective anti-thrombotic drugs.