本文選題：氯吡格雷　切入點：普拉格雷　出處：《河南大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：心腦血管疾病是威脅中老年人健康的常見病,其中發(fā)病率、致殘率和死亡率最高的是血栓性疾病。因此開發(fā)預(yù)防和治療血栓性疾病的藥物成為近年來醫(yī)藥領(lǐng)域關(guān)注和研究的熱點,噻吩并吡啶類ADP受體拮抗劑是臨床常用的抗血栓藥物,其中代表性藥物氯吡格雷和普拉格雷具有口服性好、穩(wěn)定性較好以及毒性低等優(yōu)點,這些藥物不僅長時間被歐美技術(shù)壟斷且價格昂貴；同時也存在很多缺陷；氯吡格雷存在血栓性血小板減少性紫癜(TTP)和溶血尿毒綜合癥(HUS)等副作用,更嚴(yán)重的是存在“氯吡格雷抵抗”現(xiàn)象,有三分之一的患者服用后無效；普拉格雷雖然克服了這些缺陷,卻存在嚴(yán)重的出血傾向。因此,開發(fā)活性更高、安全性更好的噻吩并吡啶類ADP受體拮抗劑迫在眉睫。 本課題通過對已上市的噻吩并吡啶類ADP受體拮抗劑分析研究,并參考相關(guān)文獻(xiàn),運(yùn)用藥物分子設(shè)計方法中的"Me-Too"藥物研發(fā)思路,利用拼合原理,在保留噻吩并吡啶母核的前提下,設(shè)計并合成了一系列結(jié)構(gòu)新穎的含取代哌嗪基的噻吩并吡啶酯類化合物,這類化合物以噻吩并吡啶酮鹽酸鹽為原料,先經(jīng)N-�；�,再經(jīng)N-烷基化,最后經(jīng)酯化反應(yīng)制得16個未見于文獻(xiàn)報道的結(jié)構(gòu)新穎的化合物(3a-3p),其結(jié)構(gòu)經(jīng)1H NMR、 ESI-HRMS進(jìn)行表征。 對所合成的16個新化合物進(jìn)行大鼠凝血時間的影響實驗,實驗結(jié)果表明：它們對大鼠血液凝固時間均有明顯延長作用。初步的構(gòu)效關(guān)系研究表明,當(dāng)哌嗪基上的取代基為苯環(huán)時,隨著苯環(huán)上取代基吸電子能力的增強(qiáng),其抗凝血活性也相應(yīng)增強(qiáng)；苯環(huán)上雙鹵取代活性低于單取代；化合物3n、3m和3k的活性明顯優(yōu)于陽性對照藥噻氯匹定,對大鼠凝血時間增長率分別為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�；〈倪哙貉苌�,具有一定的成藥前景。
[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.

【學(xué)位授予單位】：河南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5

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本文編號：1579084