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目的合成新的替格瑞洛衍生物并研究其抗血小板聚集活性。方法将化合物替格瑞洛复杂的手性环丙基胺片段用相对简单的苯基烷胺或杂环烷胺类取代,设计合成了一系列非环丙基取代的替格瑞洛衍生物。以Boc保护的(R)-丙氨酸为原料,根据文献经多步反应得到中间体1;该中间体与4,6-二氯-2-正丙巯基嘧啶-5-胺缩合,环化生成三氮唑,最后再与各类胺缩合生成目标化合物。测定所有目标化合物抗兔血小板聚集的活性。结果共制得19个化合物,其化学结构由1 H-NMR和MS确证,且均未见文献报道。目标化合物表现出不同程度的抑制血小板聚集的活性,其中4f(IC_(50)=49.7μmol·L~(-1))活性明显高于阳性对照药替格瑞洛(IC50=71.5μmol·L~(-1)),有进一步研究价值。结论替格瑞洛分子的手性环丙基侧链并非活性必需基团,可作为结构优化的对象深入研究。
Objective To synthesize a new ticagrelor derivative and study its anti-platelet aggregation activity. Methods A series of non-cyclopropyl-substituted ticagrelor derivatives were designed and synthesized by replacing the compound ticagrelor complex chiral cyclopropylamine with relatively simple phenylalkamines or heterocycloalkane amines. The Boc-protected (R) -alanine was used as a starting material to obtain intermediate 1 through several steps according to the literature; the intermediate was condensed with 4,6-dichloro-2-n-propyrcapto pyrimidin- Generate triazole, and finally with various types of amines condensation to generate the target compound. All target compounds were tested for anti-rabbit platelet aggregation activity. Results A total of 19 compounds were obtained. Their chemical structures were confirmed by1H-NMR and MS, and none were reported in the literature. The target compounds showed different degrees of inhibition of platelet aggregation activity, 4f (IC 50 = 49.7μmol·L -1) activity was significantly higher than the positive control drug ticagrelor (IC50 = 71.5μmol·L ~ (-1)), there is further research value. Conclusion The chiral cyclopropyl side chain of ticagrelor is not an active essential group and can be further studied as a structural optimization target.