烟酸衍生物的合成及抗血小板聚集活性

Synthesis and anti-platelet aggregation activities of nicotinic acid derivatives

目的研究烟酸衍生物的合成及其抗血小板聚集活性,为寻找新型抗血小板聚集剂提供参考。方法以烟酸为先导物,利用拼合原理,以不同的连接桥分别与乙酰水杨酸、烟酸偶联,制得目标化合物。通过体外抗血小板聚集试验对目标化合物进行抗血小板聚集活性评价。结果与结论设计合成了10个未见文献报道的烟酸衍生物,目标物的结构经ESI-MS、IR及1H-NMR谱确证。体外活性结果表明,10个目标化合物在体外均具有一定的抗血小板聚集活性,且化合物3a、3b的活性强于阳性对照药阿司匹林,值得进一步研究。

Nicotinic acid,occurs naturally in food,could ameliorate levels of blood fats such as cholesterol and triglycerides.It was also reported that nicotinic acid could inhibit the aggregating activity of platelets in vitro.Aspirin is the most commonly used agents for the treatment of pain and inflammation.It also displays antithrombotic effects and protects against ischemic vascular disorders,including myocardial and cerebral infarction.With the consideration of the pharmacology action of nicotinic acid and aspirin,a group of derivatives of nicotinic acid,which act as a new class of novel antithrombus agents were synthesized based on combination principles.Intermediates 2a-2e and target compounds 3a-3e were designed and synthesized by reaction of nicotinic acid（1） with dibromoalkanes bearing two to six carbons in the presence of K2CO3.Then 2a-2e was reacted with aspirin to give 4a-4e,which was treated with HCl aq to afford target compounds 5a-5e.Ten new compounds were synthesized and their structures were confirmed by IR,MS and 1H-NMR spectra.Anti-platelet aggregation activities of target compounds were assayed in vitro.The results demonstrated that all target compounds exhibited expectedly much stronger anti-platelet aggregation activities than that of parent compound nicotinic acid in vitro.Compounds 3a,3b and 5c-5e,with AIR values of 41.13%,40.73%,28.23%,28.02%,26.21%,respectively,showed significant anti-platelet aggregation activities comparable to or stronger than that of control aspirin and were worth further development.The concept of designing nicotinic acid derivatives that possess potent anti-platelet aggregation activity warrants further investigation.