【作者】 张平平；

【导师】 侯长军；

【作者基本信息】 重庆大学 ， 药物化学， 2007， 硕士

【摘要】 本文以在心血管疾病方面有较好疗效的天然药物葛根素为研究对象,根据磺酸钠的合成方法对葛根素进行结构修饰,改善其溶解性能等理化性质,从根本上解决葛根素因溶解性能差而导致的生物利用度低的问题,并对其晶型进行了初步的研究,为筛选出药效较好的晶型提供参考。同时,通过开展本课题研究,可以将重庆的葛根资源优势转化为经济优势,促进重庆市的社会经济发展。针对葛根素溶解性能差,口服生物利用度小,临床应用受到限制的缺点,利用磺酸钠合成方法的理论基础,分两步进行了磺化和成盐反应,完成了对葛根素的结构修饰;采用TLC、硅胶柱层析等技术,完成产物的分离纯化;所得衍生物经U.V.、I.R.、1HNMR、13CNMR、元素分析等波谱学方法综合结构解析,确认衍生物为未见文献报导的新化合物。以产物收率为考察目标,对磺化反应采用正交设计和温度的单因素试验设计得到最佳合成工艺为:反应温度为40℃,持续反应1h,原料葛根素与与浓硫酸的摩尔比为1:50。反应后对所得产物,采用硅胶柱层析和TLC完成分离纯化,并对分离纯化条件进行了考察。衍生物的理化性质研究结果显示:由于在分子结构中4’位的两个邻位各引入了一个磺酸钠,衍生物的熔点为183.2±1.5℃,较葛根素有所降低;衍生物的醇溶性较葛根素降低较多(在甲醇、无水乙醇、正丁醇中较葛根素分别降低了85.4%、97.8%和99.6%,但在乙酸乙脂中提高2.9倍),而水溶性较葛根素增大很多(为葛根素的159.2倍);衍生物pKa值7.72呈弱碱性,符合药物化合物的基本性质;衍生物的油/水分配系数(P值)较小,说明其水溶性优于醇溶性,根据P值变化趋势可知,通过调节pH可以适当改变药物的分配行为;衍生物在实验条件下稳定性较葛根素差,主要原因是衍生物易吸收空气中的水分而潮解,建议密封保存;葛根素与衍生物的旋光度很相近,均为右旋,分别为0.190和0.182,说明衍生物中还存在葡萄糖基,因为5个手性碳全部在葡萄糖基上。对衍生物晶型进行了初步的研究,在不同的环境下结晶,得到了三种晶型,即不定型、针型和有对角线的不规则六面体型,为筛选出药效较好的晶型提供参考。本文制备的衍生物水溶性较葛根素有很大改善。因此,通过磺化反应的结构修饰可以改善葛根素类药物的水溶性等理化性质,有利于提高生物利用度,便于后续药物制剂开发工作。更多还原

【Abstract】 The natural medicine—Puerarin which have extensive curative effect in cardiovascular disease were choosed in this dissertation as the research object and the synthesizing approach of Sulfonic Acid Sodium is adopted to modify its structure to improve it’s physical and chemical performance such as solubility,and fundamentally solve the problem of low bioavailability caused by poor water. Crystalline forms with better drug eddect will screened through the preliminary study of its crystalline forms. Meanwhile, through promoting this research,the advantage of Puerarin resource in Chongqing can turn into the economic advantage with bring about an advance in social economy of Chongqing.To improve the poor solubility, low oral bioavailability and restriction in the clinical application of Puerarin, utilizing the theoretical ground of the synthesizing approach of Sulfonic Acid Sodium, two process of Sulfonation reaction and salt-forming reaction were adopted to modify its structure. The derivative of Puerarin was separated and purified with TLC and silica gel column chromatography. Through synthesized structure analysis of spectroscopy methods such as U.V.、I.R.、1HNMR、13CNMR、element-analysis,the derivative was confirmed as a innovative compound that not been reported before.Aiming at product receiving ratio, through orthogonal tests and single-factor experiment design, we got the best conditions of synthesize: reaction temperature was 40℃, reaction time was 1h, the mol ratio of Puerarin and oil of vitriol was 1:1.4. The derivative of Puerarin from the reacting was separated and purified with silica gel column chromatography and TLC and the condition of separating and purifying was investigated.By investgating physical and chemical performance of the derivative, the following results were obtained: compared to Puerarin, the melting point of the derivative was decreased to 183.2±1.5℃result from the introduction of Sulfonic Acid Sodium at the ortho positions of 4’location;alcohol solubility of the derivative is much lower than Puerarin( a decrease of 85.4%、97.8% and 99.6% for methanol, ethanol and normal butyl alcohol respectively, compared to Puerarin,but increased as much as 2.9 times in Banana Liquid),and water solubility is much higher than Puerarin( as much as 159.2 times than Puerarin); pKa value of the derivative is 7.72,exbiting alkalescence and comply with fundamentality of drug compounds;oil/water distribution coefficient of the derivative (P)is smaller, showing that its water solubility is better than alcohol solubility; from the value transformation trend of P, it can be concluded that the distribution behavior of the drug can be changed by adjusting its pH; under the experimental condition, the stability of the derivative is poorer than Puerarin, resulting from the deliquescence of the derivative which is caused by water adsorption in air, so airproof keeping is needed; rotary power of both Puerarin and its derivative are similar, and both are dextrorotation with 0.190 and 0.182 respectively, predicting Glicosyl group existing in the derivative, because all the five chiral carbon atoms are all in the Glicosyl group.Primary study for crystal structure is presented, and we obtained three types crystal structure: amorphous, acicula and irregular hexahedron with diagonal, providing a reference for the sceening of more efficient drug.The derivative prepared in this paper has better water solubility compared to Puerarin. Therefor, by the structure modifying from sulfonation reaction,we can improve the physical and chemical performance of the Puerarin such as water solubility, which is propitious to enhancing its bioavailability and convenient for continuous drug development.更多还原