含取代哌嗪基的噻吩并吡啶酯类化合物的合成与抗凝血活性研究

发布时间：2018-03-07 11:23

本文选题：氯吡格雷　切入点：普拉格雷　出处：《河南大学》2014年硕士论文　论文类型：学位论文

【摘要】：心脑血管疾病是威胁中老年人健康的常见病,其中发病率、致残率和死亡率最高的是血栓性疾病。因此开发预防和治疗血栓性疾病的药物成为近年来医药领域关注和研究的热点,噻吩并吡啶类ADP受体拮抗剂是临床常用的抗血栓药物,其中代表性药物氯吡格雷和普拉格雷具有口服性好、稳定性较好以及毒性低等优点,这些药物不仅长时间被欧美技术垄断且价格昂贵；同时也存在很多缺陷；氯吡格雷存在血栓性血小板减少性紫癜(TTP)和溶血尿毒综合症(HUS)等副作用,更严重的是存在“氯吡格雷抵抗”现象,有三分之一的患者服用后无效；普拉格雷虽然克服了这些缺陷,却存在严重的出血倾向。因此,开发活性更高、安全性更好的噻吩并吡啶类ADP受体拮抗剂迫在眉睫。本课题通过对已上市的噻吩并吡啶类ADP受体拮抗剂分析研究,并参考相关文献,运用药物分子设计方法中的"Me-Too"药物研发思路,利用拼合原理,在保留噻吩并吡啶母核的前提下,设计并合成了一系列结构新颖的含取代哌嗪基的噻吩并吡啶酯类化合物,这类化合物以噻吩并吡啶酮盐酸盐为原料,先经N-酰基化,再经N-烷基化,最后经酯化反应制得16个未见于文献报道的结构新颖的化合物(3a-3p),其结构经1H NMR、 ESI-HRMS进行表征。对所合成的16个新化合物进行大鼠凝血时间的影响实验,实验结果表明：它们对大鼠血液凝固时间均有明显延长作用。初步的构效关系研究表明,当哌嗪基上的取代基为苯环时,随着苯环上取代基吸电子能力的增强,其抗凝血活性也相应增强；苯环上双卤取代活性低于单取代；化合物3n、3m和3k的活性明显优于阳性对照药噻氯匹定,对大鼠凝血时间增长率分别为71.8%、58.0%和43.5%。其中3k是嘧啶基取代的哌嗪衍生物；3m和3n是苯磺酰基取代的哌嗪衍生物,具有一定的成药前景。
[Abstract]:Cardiovascular disease is a common disease that threatens the health of the elderly, the incidence, morbidity and mortality is the highest in thrombotic diseases. So the development of drugs for prevention and treatment of thrombotic diseases has become the focus of attention in the field of medicine and research in recent years, thienopyridine ADP receptor antagonist is clinical antithrombotic drugs commonly used, including representative drug clopidogrel and prasugrel with oral sex good, good stability and low toxicity of these drugs, not only for a long time by European and American technology monopoly and the price is expensive; there are also many defects; clopidogrel exists thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) and other side effects, there is more serious "clopidogrel resistance" phenomenon, taking 1/3 of the patients after the invalid; although prasugrel overcomes these shortcomings, but in serious Therefore, the development of more active and safer thiophene and pyridine ADP receptor antagonists is imminent.
This paper through the analysis and research of thiophene and pyridine have been listed on the ADP receptor antagonist, and reference to the relevant literature, the use of molecular drug design methods in the "Me-Too" drug development ideas, using the composition principle, while retaining the thienopyridine mother nucleus, and the design of thienopyridine ester compounds containing substituted piperazine based novel a series of structural synthesis of these compounds with thienopyridone hydrochloride as raw materials, first by N- N- by acylation, alkylation, compound structure finally prepared by esterification of 16 has not been reported in the literature of the novel (3a-3p), characterized by 1H NMR and ESI-HRMS were characterized.
The influence of the coagulation time of rats of 16 new compounds, the experimental results show that they are on rat blood coagulation time were significantly prolonged. The preliminary structure-activity relationship studies showed that when piperazine substituent on the benzene ring, with the enhancement of electron withdrawing ability of the substituent on the benzene ring, the anticoagulant activity increases; double benzene ring substituted by halogen was lower than that of mono substituted compounds; 3N, 3M and 3K was significantly better than the positive control drug ticlopidine on coagulation time of rats growth rates were 71.8%, 58% and 43.5%. 3K which is the ethyl pyridyl substituted piperazine derivatives; 3M and 3N benzene sulfonyl substituted piperazine derivatives, medicine has certain prospects.

【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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