三唑并[4,5-d]嘧啶类化合物的合成及其抗血小板聚集活性研究  

Synthesis and in vitro antiplatelet activity of triazolo [4,5-d]pyrimidine derivatives

作　　者：刘斌[1,2] 左斌海 孙超 蔡泽江 鄢明[1] 

机构地区：[1]中山大学药学院,广东广州510006 [2]珠海联邦制药股份有限公司,广东珠海519040

出　　处：《中国药物化学杂志》2015年第1期1-7,共7页Chinese Journal of Medicinal Chemistry

摘　　要：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。Seventeen triazolo[4,5-d] pyrimidine derivatives were designed based on the structural simplifica- tion of ticagrelor. The target compounds were prepared via three steps starting from amino alcohols and 4,6- dichloro-2-propylsulfanyl-5-pyrimidinamine. Their chemical structures were confirmed by ^1H-NMR, ^13 C-NMR and MS. The in vitro antiplatelet activities were evaluated by Born＇s assay against rabbit platelet. The com- pounds containing vicinal diol substructure showed better activities than others. The results demonstrate that vicinal diol substructure is crucial for the antiplatelet activity of triazolo [4,5-d] pyrimidine derivatives. Among these compounds,compound 9i showed the best antiplatelet activity. The inhibition ratio of platelet aggregation achieved about 80% level of ticagrelor. Considering much simpler structure of 9i in comparison with ticagrelor,it holds the potential as a new leading compound for the development of efficient anti-thrombosis drugs.

关 键 词：替格瑞洛 结构修饰 抗血小板聚集 合成 

分 类 号：R914[医药卫生—药物化学]