本文選題：手性色譜拆分 + 2-乙內(nèi)酰硫脲��； 參考：《山東大學(xué)》2017年碩士論文

【摘要】：眾所周知,手性藥物的不同對(duì)映體可能具有不同的藥理學(xué)、藥動(dòng)學(xué)和毒理學(xué)性質(zhì)。在制藥工業(yè)領(lǐng)域,制備光學(xué)純度高的手性藥物應(yīng)用于臨床,不僅能夠避免無(wú)效(不良)對(duì)映異構(gòu)體可能引起的毒副作用,還能夠降低給藥劑量、減少無(wú)效對(duì)映異構(gòu)體在體內(nèi)的代謝過(guò)程和風(fēng)險(xiǎn)。因此研究手性藥物及其類藥衍生物和關(guān)鍵中間體的手性光學(xué)純度質(zhì)控技術(shù),已成為當(dāng)前醫(yī)藥行業(yè)的一個(gè)熱點(diǎn)研究領(lǐng)域。特別是我國(guó)當(dāng)前正處于邁向創(chuàng)新藥物研究的關(guān)鍵階段,大量新型骨架結(jié)構(gòu)的手性藥物及其類藥衍生物不斷涌現(xiàn),控制其手性光學(xué)純度也已成為我國(guó)當(dāng)前重大新藥創(chuàng)制領(lǐng)域急需解決的關(guān)鍵問(wèn)題。近年來(lái),通過(guò)色譜技術(shù)對(duì)手性藥物進(jìn)行拆分并進(jìn)行質(zhì)量控制研究已成為國(guó)際制藥領(lǐng)域最重要的研究手段。本論文也正是應(yīng)用手性色譜分離技術(shù),研究了兩類手性藥物的類藥衍生物和關(guān)鍵中間體的拆分和質(zhì)控方法。2-乙內(nèi)酰硫脲類化合物作為一種五元雜環(huán)化合物,具有多種生物和化學(xué)活性,已廣泛應(yīng)用于生命科學(xué)領(lǐng)域、農(nóng)學(xué)研究領(lǐng)域及合成化學(xué)領(lǐng)域。過(guò)去該類結(jié)構(gòu)的化合物曾發(fā)現(xiàn)具有抗菌和抗腫瘤方面的治療用途。近年來(lái)發(fā)現(xiàn)的2-乙內(nèi)酰硫脲類手性藥物Nec-1是近年新報(bào)道的創(chuàng)新型藥物靶標(biāo)RIP1激酶的抑制劑,該類結(jié)構(gòu)也是首次被發(fā)現(xiàn)具有細(xì)胞壞死性調(diào)亡抑制作用的類藥分子。由于該類化合物的結(jié)構(gòu)中存在一個(gè)手性中心,且R異構(gòu)體的生理活性明顯高于S異構(gòu)體。因此,建立2-乙內(nèi)酰硫脲類手性類藥衍生物的色譜拆分方法,對(duì)于探索該類手性化合物的新型制備方法和質(zhì)控技術(shù)具有重要意義。GPR40是一種主要分布于胰腺β細(xì)胞,腸道K和L細(xì)胞的G蛋白偶聯(lián)受體。該受體可被游離長(zhǎng)鏈脂肪酸激活,使細(xì)胞內(nèi)鈣離子濃度升高,促進(jìn)胰島素的釋放,因此被認(rèn)為是治療II型糖尿病的新型藥物靶點(diǎn)。GPR 40激動(dòng)劑的結(jié)構(gòu)較多,其中活性較好且研究較多的是二氫苯并呋喃乙酸衍生物。二氫苯并呋喃類藥物的分子結(jié)構(gòu)中有一個(gè)手性中心,不同構(gòu)型的化合物的活性不同。因此,建立快速拆分該類化合物的分析方法,控制其含量十分必要。本論文首次采用多糖衍生化的手性固定相Chiralpak IA柱和Chiralpak IC柱對(duì)8個(gè)乙內(nèi)酰硫脲化合物和3個(gè)二氫苯并呋喃乙酸衍生物進(jìn)行了手性色譜分離研究。在正相體系下系統(tǒng)考察上述手性藥物或中間體的分離條件,研究了流動(dòng)相中醇的種類,濃度及色譜柱溫度對(duì)手性分離的影響,并通過(guò)計(jì)算熱力學(xué)常數(shù),初步探討了上述手性藥物的手性分離機(jī)制。部分手性化合物存在溶劑種類誘導(dǎo)的和溫度誘導(dǎo)的流出順序反轉(zhuǎn)現(xiàn)象,其分離過(guò)程涉及熵驅(qū)動(dòng)或焓驅(qū)動(dòng)兩種機(jī)制。另外,初步應(yīng)用毛細(xì)管電泳方法,成功的完成了手性二氫苯并呋喃乙酸甲酯的拆分,為相關(guān)手性藥物的中間體質(zhì)量控制提供了新型簡(jiǎn)便的測(cè)試方法。
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R917

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本文編號(hào)：1831982