發(fā)布時間：2018-05-10 07:49

  本文選題：噻吩并四氫吡啶 + 抗血小板�。� 參考：《天津醫(yī)科大學(xué)》2017年碩士論文

【摘要】：血栓栓塞性疾病是一種循環(huán)系統(tǒng)疾病,其發(fā)病率和死亡率特別高,嚴(yán)重威脅著中老年人的健康。目前,治療血栓疾病的手段有多種,其中噻吩并吡啶類抗血小板藥物是臨床上用于預(yù)防和治療血栓的一線用藥,如氯吡格雷和普拉格雷等。但是這些藥物存在著一些不足,如氯吡格雷起效慢,個體差異比較大;普拉格雷有嚴(yán)重的出血風(fēng)險等。因此開發(fā)和研制療效更好、安全性更高的藥物具有很重要的意義。鹽酸替比格雷是一種含氰基的噻吩并吡啶類衍生物,經(jīng)過臨床前系統(tǒng)地研究,發(fā)現(xiàn)其具有較好的抗血小板聚集活性,在穩(wěn)定性、藥代動力學(xué)特性及出血副作用等方面具有一定的優(yōu)勢,有很大的開發(fā)潛力和應(yīng)用前景。針對現(xiàn)有鹽酸替比格雷合成工藝存在的缺陷,本文作者首先查閱大量的文獻(xiàn),對其合成路線進(jìn)行了合理設(shè)計;然后,通過大量的實(shí)驗(yàn)研究,對每步反應(yīng)的工藝條件進(jìn)行了探索和優(yōu)化,最終確定了一條經(jīng)濟(jì)、環(huán)保、操作簡單的合成工藝。與原有工藝相比,新工藝的成本由每公斤5750元降低到3558元;合成步驟由6步減少到4步;收率也由16.3%提高到54.8%;革除了兩步柱層析分離純化,有利于工業(yè)化生產(chǎn)。為了研究和開發(fā)療效更好、安全性更高的新型的噻吩并四氫吡啶類藥物,本文通過對已上市以及文獻(xiàn)報道的化合物進(jìn)行分析研究,保留了噻吩并吡啶母核,利用合理藥物設(shè)計原理,設(shè)計合成了23個噻吩并四氫吡啶類化合物,其中17個為新化合物。這些化合物的結(jié)構(gòu)均經(jīng)1H-NMR和MS進(jìn)行確證,并對它們的生物活性進(jìn)行測試。生物活性測試結(jié)果顯示,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的活性優(yōu)于陽性藥物噻氯匹定,具有進(jìn)一步的研究價值。
[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.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914

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本文編號：1868472