双取代酯类吡咯烷酮衍生物的合成方法及研究.pdf

广东药学院硕士学位论文双取代酯类吡咯烷酮衍生物的合成方法研究姓名:郑澄申请学位级别:硕士专业:药物化学指导教师:林汉森;沈琼20090501广东药学院硕士研究生学位论文I 中文摘要黄皮酰胺是芸香科黄皮属植物黄皮叶水浸膏中分离得到的有效成分之一,它是一种吡咯烷酮类化合物。药理学研究表明黄皮酰胺具有明显的保肝和促智作用,它能够诱导小鼠肝细胞色素P450,并且对黄曲霉素B1引起的大鼠肝细胞损伤具有明显的保护作用,还能有效降低四氯化碳引起的小鼠高谷丙转氨酶。同时它还能改善中枢胆碱能系统,具有良好的促智、抗氧化、抗Aβ神经毒性以及抑制tau蛋白过度磷酸化的作用。由于黄皮酰胺的脂水分配系数lgP较小,为了增加其溶解性,改善其药代动力学性质。本课题以消旋黄皮酰胺为先导物,遵循先导物结构优化的基本原则即分子的的多样性、相似性、互补性,对先导物黄皮酰胺的3位及7位羟基进行酯化修饰,设计了12个酯类化合物,其中包括3位单取代酯类黄皮酰胺衍生物6个、3,7位双取代酯类黄皮酰胺类似物6个。论文对不同取代基所涉及的最佳酯化条件进行了详细的考察,根据先导物的结构特征以及各种酰化剂的酰化能力,从实验条件、反应物配比、反应时间、反应温度、反应后处理等方面分别考察了每种酰化剂的最佳酰化条件。所合成的酯类化合物均经过元素分析、MS、1H-NMR、IR分析确证结构。关键词:吡咯烷酮吡咯烷类衍生物酯化反应广东药学院硕士研究生学位论文i Methodolgy for the synthesis of the Derivates of Double Substituted Pyrrolidone Esters Zheng Cheng(Medicinal Chemistry) Supervisor: Lin Hansen Professor, Shen Qiong Lecturer [Abstract] Clausenamide, a kind of pounds, is isolated from aqueous extract of leaves of Clausena lansium. Bade on the pharmacological study, clausenamide could be used as liver protectant or nootropics. It can induce mouse liver cytochrome P450, have effects on aflatoxin B1-induced injury and the ability to reduce GPT level. Meanwhile it can improve the central cholinergic system, has a good nootropic, anti-oxidation, anti-Aβneurotoxicity, and inhibiting tau protein hyperphosphorylation effects. To improve ic properties and the dissolubility of clausenamide, some 3-subustitude and 3,7-disubstitude ester derivatives were synthesized, base on the principle of the optimization of the pound, such as molecular diversity, molecular similarity and plementarity. Methodolgy for the modify of clausenamide has been studied thoroughly. Considered the structure features of the pound and the acylation ability of all kinds of acylating agents, as well as other factors, a suitable path to synthesis the pounds is selected. Factors that effect the reaction conditions are also been discussed. All of the pounds were characterized by means of elemental analysis, IR, 1H-NMR, MS. Keywords: Pyrrolidone