抗肿瘤多肽药布舍瑞林的合成研究

发布时间：2018-04-28 18:15

本文选题：布舍瑞林 + 固液相　；参考：《苏州大学》2014年硕士论文

【摘要】：在欧美发达国家，前列腺癌的发病率高居男性恶性肿瘤第2位，在亚洲国家则相对较低，但呈上升趋势。研究资料显示，全球每年死于前列腺癌的患者人数达到25.8万。随着国民经济的发展和生活方式的改变，我国男性前列腺癌发病率已从1993年的1.71/10万上升至2010年的10/10万，形势不容乐观。与此同时，乳腺癌、子宫内膜异位症及子宫肌瘤等妇科疾病也影响着全球女性的健康。世卫组织官方网站资料显示，全球每年新增乳腺癌患者约138万，年死亡人数为45.8万。我国妇女的乳腺癌发病率约为21.6/10万，，子宫内膜异位症患者占到育龄妇女的10~15%，有20~30%的成年女性患有不同程度的子宫肌瘤。这些性激素依赖性疾病不仅给患者身体带来了严重病痛，也极大影响了他们的生活质量。 GnRH(促性腺激素释放激素)类似物自问世以来，由于具备活性高，用量少，不良反应小及疗效稳定等优势，在性激素依赖性疾病的治疗中发挥着重要作用。根据作用机制不同，GnRH类似物均为多肽，分为两类，一类是GnRH激动剂，如曲普瑞林，布舍瑞林，戈舍瑞林，亮丙瑞林等；另一类是GnRH拮抗剂，如西曲瑞克，加尼瑞克，阿巴瑞克等。这些专利多肽药带来良好疗效的同时，其昂贵的价格也给发展中国家的患者带来了沉重的经济负担。为此，开发价格低廉并具备同等质量和疗效的仿制药，具有重要的现实意义。布舍瑞林由法国赛诺菲-安万特公司研制生产，于1984年首次在德国上市，目前主要在欧洲，亚洲，部分拉丁美洲和非洲国家销售，在美国处于临床三期阶段。基于其良好的疗效和市场销售，并且专利保护即将到期，本论文在查阅相关文献和专利的基础上，采用固液相结合的技术，设计和优化了一种新的布舍瑞林合成路线。该路线操作简便，生产周期短，产品纯度和收率均较高，成本较低，易于放大生产,能在一定程度上带动布舍瑞林原料药的市场销售价格的下降，从而对其成品药价格的进一步降低起到积极促进作用，有利于减轻患者的经济负担。
[Abstract]:In the developed countries of Europe and America, the incidence of prostate cancer is the second highest in men with malignant tumor, but it is relatively low in Asian countries, but it is on the rise. According to the study, the number of people dying of prostate cancer every year in the world reached 258000. With the development of national economy and the change of life style, the incidence of prostate cancer in men in China has risen from 17.1 / 100 thousand in 1993 to 10 / 100 thousand in 2010. The situation is not optimistic. At the same time, gynecological diseases such as breast cancer, endometriosis and hysteromyoma affect women's health around the world. According to WHO's official website, there are about 1.38 million new cases of breast cancer worldwide each year, with 458000 deaths per year. The incidence of breast cancer in women in China is about 21.6 / 100 thousand. Endometriosis patients account for 10, 15 women of childbearing age, and 20% of adult women have different degrees of uterine leiomyoma. These sex hormone-dependent diseases not only bring serious pain to patients, but also greatly affect their quality of life. GnRH (gonadotropin releasing hormone) analogue has played an important role in the treatment of gonadotropin-dependent diseases because of its advantages of high activity, low dosage, small adverse reaction and stable curative effect. The GnRH analogues are polypeptides according to their mechanism of action, one is GnRH agonists, such as troplin, Buserelin, Goserelin, Leuprilline, and the other is GnRH antagonists, such as citrork, ganirk, and so on. Abalic, etc. While these patented polypeptide drugs have good efficacy, their high prices also impose a heavy economic burden on patients in developing countries. Therefore, it is of great practical significance to develop low-cost generic drugs with the same quality and efficacy. Buserelin, which was developed and manufactured by France's Sanofi-Aventis, was first listed in Germany in 1984. It is currently mainly sold in Europe, Asia, some Latin American and African countries, and is in the third phase of the clinical phase in the United States. Based on its good effect and marketing, and the expiration of patent protection, a new synthesis route of Buserelin is designed and optimized based on the review of relevant literatures and patents. This route is easy to operate, short production cycle, high product purity and yield, low cost, easy to enlarge production, and can lead to the decrease of market sales price of Buserelin API to a certain extent. Thus, the further reduction of the price of its finished medicine plays an active role in reducing the economic burden of patients.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.3

【参考文献】