【摘要】：免疫抑制劑是對機(jī)體的免疫反應(yīng)具有抑制作用的藥物，有能抑制與免疫反應(yīng)有關(guān)細(xì)胞的增殖和功能，降低抗體免疫反應(yīng)的作用。免疫抑制劑是一類結(jié)合免疫病理學(xué)、臨床免疫學(xué)等多種學(xué)科的理論基礎(chǔ)發(fā)展而來的新型藥物。因其獨(dú)特的影響免疫應(yīng)答反應(yīng)而抑制機(jī)體的免疫功能，可廣泛應(yīng)用于在器官移植中的抗排斥反應(yīng)和自身免疫病的治療。常用的免疫抑制劑主要有五類：（1）糖皮質(zhì)激素類，如可的松和強(qiáng)的松；（2）微生物代謝產(chǎn)物，如環(huán)孢菌素和藤霉素等；（3）抗代謝物，如硫唑嘌呤和6-巰基嘌呤等；（4）多克隆和單克隆抗淋巴細(xì)胞抗體，，如抗淋巴細(xì)胞球蛋白和OKT3等；（5）烷化劑類，如環(huán)磷酰胺等。另外還有中藥類的免疫抑制劑和新開發(fā)的小分子類型的免疫抑制劑。 芬戈莫德是日本三菱（Mitsubishi）制藥公司研制開發(fā)的。Fujita教授等從科蟲夏草培養(yǎng)液中提取得到的一種新型免疫抑制制劑，為抗生素ISP-1經(jīng)化學(xué)修飾合成�？山�(jīng)口服給藥用于治療復(fù)發(fā)－緩解型多發(fā)性硬化癥（multiplesclerosis,MS）。研究表明，其免疫抑制機(jī)制與其它藥物完全不同，可改變淋巴細(xì)胞的趨向，促使淋巴細(xì)胞滯留于淋巴組織內(nèi)，淋巴細(xì)胞離開淋巴組織的幾率被降低，達(dá)到免疫抑制的效果。 本文查閱大量有關(guān)芬戈莫德合成方法的文獻(xiàn)，列舉了國內(nèi)的兩條合成路線及國外文獻(xiàn)中的三條合成路線。本試驗(yàn)在合成工藝研究方面，結(jié)合了工業(yè)生產(chǎn)的需要，設(shè)計(jì)的合成路線以β-苯乙醇為原料，經(jīng)鹵化反應(yīng)、傅克�；磻�(yīng)，縮合，羰基還原，酯基還原，水解去乙�；�，最終成鹽得到目標(biāo)分子。總收率達(dá)到22.4%。與文獻(xiàn)中的合成路線相比，本試驗(yàn)所得到的合成路線工藝簡化，成本降低，反應(yīng)條件溫和，收率高，適合于工業(yè)化規(guī)模生產(chǎn)。關(guān)鍵中間體與最終的目標(biāo)產(chǎn)物的結(jié)構(gòu)經(jīng)紫外光譜、紅外光譜、核磁共振氫譜及碳譜等均得到確證。 本文建立了HPLC法測定鹽酸芬戈莫德原料藥的含量和有關(guān)物質(zhì)的方法。含量測定HPLC法試驗(yàn)結(jié)果表明：鹽酸芬戈莫德在0.055~0.165mg/mL范圍內(nèi)呈良好的線性關(guān)系，Y＝158490160X－51837.4，r2＝0.9998；精密度RSD為0.11%，表明儀器精密度良好；重復(fù)性RSD為0.09%，表明含量測定重復(fù)性良好；穩(wěn)定性RSD為0.13%，表明供試品溶液至少在12h內(nèi)穩(wěn)定；加樣回收率RSD為1.37%，表明此方法可行；樣品耐受性良好。有關(guān)物質(zhì)HPLC法試驗(yàn)結(jié)果表明：穩(wěn)定性RSD為0.022%，表明供試品溶液至少在12h內(nèi)穩(wěn)定；耐受性良好。由以上數(shù)據(jù)顯示測定結(jié)果準(zhǔn)確，可靠，表明所建立的HPLC法能有效的控制本品的質(zhì)量。
[Abstract]:Immunosuppressant is a kind of drug which can inhibit the immune response of the body. It can inhibit the proliferation and function of the cells related to the immune reaction and reduce the immune response of antibody. Immunosuppressant is a new kind of medicine which combines with immunopathology, clinical immunology and so on. Because of its unique effect on immune response, it can be widely used in the treatment of autoimmune diseases and anti-rejection in organ transplantation. There are five main types of immunosuppressants: (1) glucocorticoids, such as cortisone and prednisone; (2) microbial metabolites, such as cyclosporin and tenomenine; (3) antimetabolites, such as azathioprine and 6-mercaptopurine; (4) polyclonal and monoclonal anti-lymphocyte antibodies, such as antilymphocyte globulin and OKT3, (5) alkylates, such as cyclophosphamide, etc. There are also traditional Chinese medicine immunosuppressants and newly developed small molecule type immunosuppressants. Fengomod was developed by Mitsubishi (Mitsubishi) Pharmaceutical Company of Japan. Professor Fujita and others obtained a new immunosuppressive preparation from the culture medium of Herba Compositae. It is a chemically modified synthesis of antibiotic ISP-1. It can be used orally in the treatment of recurrent-remission multiple sclerosis (multiplesclerosis,MS). The results showed that the immunosuppressive mechanism was completely different from that of other drugs, which could change the tendency of lymphocytes, promote the retention of lymphocytes in lymphoid tissues, and reduce the probability of lymphocytes leaving lymphoid tissues, so as to achieve the effect of immunosuppression. In this paper, a large number of literatures on the synthesis of Fingomod are reviewed, and two synthetic routes at home and three synthetic routes in foreign literature are listed. In the aspect of synthesis technology, the synthetic route was designed with 尾 -phenylethanol as raw material through halogenation reaction, Fourier acylation reaction, condensation, carbonyl reduction, ester reduction, hydrolysis and deacetylation. The target molecule is eventually formed into salt. The total yield was 22. 4%. Compared with the synthetic route in the literature, the synthetic route obtained in this paper has the advantages of simple process, low cost, mild reaction conditions and high yield, which is suitable for industrial scale production. The structures of the key intermediates and the final target products were confirmed by UV, IR, NMR and C spectra. A HPLC method for the determination of the content and related substances of fengormod hydrochloride was established. The results of HPLC method showed that Fengomod hydrochloride had a good linear relationship in the range of 0.055~0.165mg/mL, YC158490160X-51837.4X ~ (2) 0.9998, and the precision RSD was 0.11, which indicated that the precision of the instrument was good. The reproducibility RSD was 0.09, which indicated that the content determination was reproducible, the stable RSD was 0.13, the sample solution was stable in at least 12 hours, the sample recovery RSD was 1.37, which indicated that the method was feasible and the sample tolerance was good. The results of HPLC test showed that the stability of RSD was 0.022, which indicated that the solution of the sample was stable in at least 12 hours and had good tolerance. The above data show that the determination results are accurate and reliable, which indicates that the established HPLC method can effectively control the quality of this product.
【學(xué)位授予單位】：吉林大學(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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