2-乙内酰硫脲类和二氢苯并呋喃乙酸类手性药物衍生物及其中间体的色谱分离研究

发布时间：2018-05-02 02:20

本文选题：手性色谱拆分 + 2-乙内酰硫脲　；参考：《山东大学》2017年硕士论文

【摘要】：众所周知,手性药物的不同对映体可能具有不同的药理学、药动学和毒理学性质。在制药工业领域,制备光学纯度高的手性药物应用于临床,不仅能够避免无效(不良)对映异构体可能引起的毒副作用,还能够降低给药剂量、减少无效对映异构体在体内的代谢过程和风险。因此研究手性药物及其类药衍生物和关键中间体的手性光学纯度质控技术,已成为当前医药行业的一个热点研究领域。特别是我国当前正处于迈向创新药物研究的关键阶段,大量新型骨架结构的手性药物及其类药衍生物不断涌现,控制其手性光学纯度也已成为我国当前重大新药创制领域急需解决的关键问题。近年来,通过色谱技术对手性药物进行拆分并进行质量控制研究已成为国际制药领域最重要的研究手段。本论文也正是应用手性色谱分离技术,研究了两类手性药物的类药衍生物和关键中间体的拆分和质控方法。2-乙内酰硫脲类化合物作为一种五元杂环化合物,具有多种生物和化学活性,已广泛应用于生命科学领域、农学研究领域及合成化学领域。过去该类结构的化合物曾发现具有抗菌和抗肿瘤方面的治疗用途。近年来发现的2-乙内酰硫脲类手性药物Nec-1是近年新报道的创新型药物靶标RIP1激酶的抑制剂,该类结构也是首次被发现具有细胞坏死性调亡抑制作用的类药分子。由于该类化合物的结构中存在一个手性中心,且R异构体的生理活性明显高于S异构体。因此,建立2-乙内酰硫脲类手性类药衍生物的色谱拆分方法,对于探索该类手性化合物的新型制备方法和质控技术具有重要意义。GPR40是一种主要分布于胰腺β细胞,肠道K和L细胞的G蛋白偶联受体。该受体可被游离长链脂肪酸激活,使细胞内钙离子浓度升高,促进胰岛素的释放,因此被认为是治疗II型糖尿病的新型药物靶点。GPR 40激动剂的结构较多,其中活性较好且研究较多的是二氢苯并呋喃乙酸衍生物。二氢苯并呋喃类药物的分子结构中有一个手性中心,不同构型的化合物的活性不同。因此,建立快速拆分该类化合物的分析方法,控制其含量十分必要。本论文首次采用多糖衍生化的手性固定相Chiralpak IA柱和Chiralpak IC柱对8个乙内酰硫脲化合物和3个二氢苯并呋喃乙酸衍生物进行了手性色谱分离研究。在正相体系下系统考察上述手性药物或中间体的分离条件,研究了流动相中醇的种类,浓度及色谱柱温度对手性分离的影响,并通过计算热力学常数,初步探讨了上述手性药物的手性分离机制。部分手性化合物存在溶剂种类诱导的和温度诱导的流出顺序反转现象,其分离过程涉及熵驱动或焓驱动两种机制。另外,初步应用毛细管电泳方法,成功的完成了手性二氢苯并呋喃乙酸甲酯的拆分,为相关手性药物的中间体质量控制提供了新型简便的测试方法。
[Abstract]:It is well known that different enantiomers of chiral drugs may have different pharmacological, pharmacokinetic and toxicological properties. In the pharmaceutical industry, the preparation of chiral drugs with high optical purity for clinical use can not only avoid the side effects that may be caused by ineffective (adverse) enantiomers, but also reduce the amount of drugs given. Reduce the metabolic process and risk of ineffective enantiomers in vivo. Therefore, the study of chiral optical purity quality control of chiral drugs, their derivatives and key intermediates has become a hot research field in the pharmaceutical industry. Especially, our country is now in the key stage of the research of innovative drugs. A large number of new chiral drugs with skeleton structure and their derivatives are emerging. Controlling its chiral optical purity has also become a key problem in the field of major new drug creation in China. In recent years, the separation and quality control of chiral drugs by chromatography has become the most important research method in international pharmaceutical field. In this paper, the separation and quality control of derivatives and key intermediates of two kinds of chiral drugs by chiral chromatography were studied. The method of separation and quality control of 2-ethylethanolthioureas as a quaternary heterocyclic compound was studied. With a variety of biological and chemical activities, has been widely used in the field of life science, agronomy and synthetic chemistry. In the past, compounds with such structures have been found to have antimicrobial and anti-tumor therapeutic uses. Recently, 2-ethylthiourea (Nec-1) is a novel inhibitor of novel drug target RIP1 kinase, and it is also the first drug-like molecule to be found to have the inhibitory effect of cell necrotic apoptosis. Because of the existence of a chiral center in the structure of the compounds, the physiological activity of the R isomer is obviously higher than that of the S isomer. Therefore, it is of great significance to establish a chromatographic resolution method for 2-ethylthiourea chiral derivatives, which is of great significance for exploring new preparation methods and quality control techniques of these chiral compounds. GPR40 is mainly distributed in pancreatic 尾 cells. G protein coupled receptors in intestinal K and L cells. The receptor can be activated by free long chain fatty acids, increase intracellular calcium concentration and promote insulin release, so it is considered to be a new drug target for type 2 diabetes mellitus. GPR40 agonist has more structure. Among them, dihydrobenzofuranacetic acid derivatives are more active and studied. There is a chiral center in the molecular structure of dihydrobenzofurans. Therefore, it is necessary to establish an analytical method for the rapid resolution of these compounds and to control their content. In this paper, the chiral chromatographic separation of eight glycosylthiourea compounds and three dihydrobenzofuranacetic acid derivatives by Chiralpak IA column and Chiralpak IC column was studied for the first time. The separation conditions of the chiral drugs or intermediates mentioned above were systematically investigated in the normal phase system. The effects of the kinds of alcohols in the mobile phase, the concentration of alcohols and the column temperature on the chiral separation were studied, and the thermodynamic constants were calculated. The mechanism of chiral separation of these chiral drugs was preliminarily discussed. Some chiral compounds have the phenomena of solvent type induced and temperature induced outflow order reversal. The separation process involves two mechanisms: entropy driving and enthalpy driving. In addition, the chiral resolution of methyl dihydrobenzofuranacetate was successfully completed by capillary electrophoresis, which provided a new and simple method for the quality control of the intermediates of chiral drugs.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R917

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