噻吩并吡啶类ADP受体拮抗剂的研究

发布时间：2018-05-10 07:49

本文选题：噻吩并四氢吡啶 + 抗血小板　；参考：《天津医科大学》2017年硕士论文

【摘要】：血栓栓塞性疾病是一种循环系统疾病,其发病率和死亡率特别高,严重威胁着中老年人的健康。目前,治疗血栓疾病的手段有多种,其中噻吩并吡啶类抗血小板药物是临床上用于预防和治疗血栓的一线用药,如氯吡格雷和普拉格雷等。但是这些药物存在着一些不足,如氯吡格雷起效慢,个体差异比较大;普拉格雷有严重的出血风险等。因此开发和研制疗效更好、安全性更高的药物具有很重要的意义。盐酸替比格雷是一种含氰基的噻吩并吡啶类衍生物,经过临床前系统地研究,发现其具有较好的抗血小板聚集活性,在稳定性、药代动力学特性及出血副作用等方面具有一定的优势,有很大的开发潜力和应用前景。针对现有盐酸替比格雷合成工艺存在的缺陷,本文作者首先查阅大量的文献,对其合成路线进行了合理设计;然后,通过大量的实验研究,对每步反应的工艺条件进行了探索和优化,最终确定了一条经济、环保、操作简单的合成工艺。与原有工艺相比,新工艺的成本由每公斤5750元降低到3558元;合成步骤由6步减少到4步;收率也由16.3%提高到54.8%;革除了两步柱层析分离纯化,有利于工业化生产。为了研究和开发疗效更好、安全性更高的新型的噻吩并四氢吡啶类药物,本文通过对已上市以及文献报道的化合物进行分析研究,保留了噻吩并吡啶母核,利用合理药物设计原理,设计合成了23个噻吩并四氢吡啶类化合物,其中17个为新化合物。这些化合物的结构均经1H-NMR和MS进行确证,并对它们的生物活性进行测试。生物活性测试结果显示,所合成的化合物均有一定的抑制血小板聚集活性,其中化合物C4、C8、C9的活性优于阳性药物噻氯匹定,具有进一步的研究价值。
[Abstract]:Thromboembolic disease is a circulatory disease with high morbidity and mortality, which is a serious threat to the health of the elderly. At present, there are many ways to treat thrombotic diseases, among which thiophene pyridine antiplatelet drugs are the first-line drugs for the prevention and treatment of thrombus, such as clopidogrel and Pragray. However, there are some deficiencies in these drugs, such as clopidogrel is slow, individual differences; Pragray has a serious risk of bleeding, etc. Therefore, it is of great significance to develop and develop drugs with better efficacy and higher safety. Tibigray hydrochloride is a kind of thiophene pyridine derivatives containing cyano group. It is found that tibigray hydrochloride has a good antiplatelet aggregation activity and is stable after systematic study before clinical application. Pharmacokinetic characteristics and bleeding side effects have some advantages and have great development potential and application prospect. In view of the defects of the existing synthesis process of tibigray hydrochloride, the author first consulted a large number of literatures and designed the synthesis route reasonably, and then, through a lot of experimental research, The process conditions of each step reaction were explored and optimized, and an economical, environmentally friendly and simple synthetic process was finally determined. Compared with the original process, the cost of the new process was reduced from 5750 yuan per kilogram to 3558 yuan, the synthesis step was reduced from 6 steps to 4 steps, the yield was also increased from 16.3% to 54.8%, and the two-step column chromatography separation and purification was eliminated, which was conducive to industrial production. In order to study and develop new thiophene tetrahydropyridine drugs with better efficacy and higher safety, the mother nucleus of thiophene pyridine was retained by the analysis of the compounds listed and reported in the literature. Based on the principle of rational drug design, 23 thiophene tetrahydropyridine compounds were designed and synthesized, of which 17 were new compounds. The structures of these compounds were confirmed by 1H-NMR and MS, and their biological activities were tested. The results of bioactivity test showed that the synthesized compounds had a certain inhibitory activity on platelet aggregation, and the activity of compound C4C8C9 was better than that of the positive drug ticlopidine, which was valuable for further study.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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