摘 要：他汀类药物可以使得人体内的血脂浓度显著的降低，被广泛的用于降低人体内的胆固醇浓度。HMG-CoA还原酶抑制剂的结构主要是由亲脂部分、亲水部分及连接部分三部分构成，现阶段科研工作者对于他汀类药物的结构修饰主要集中在亲脂母环和连接部分上，而对于亲水侧链结构的改进工作却很少有人去做。因此本文在计算机辅助药物设计指导下，拟从匹伐他汀母核丙烯醛出发，在HMG-CoA还原酶抑制剂亲水侧链的4号位引入二氟亚甲基，对他汀类药物的亲水基团进行氟代修饰，合成出氟代他汀类衍生物；然后对所合成化合物进行生物活性测试；通过研究所合成的化合物的结构，探究氟原子的引入对其生物活性的影响，从而选择出具有较高生物活性的HMG-CoA还原酶抑制剂。71018

毕业论文关键词： 偕二氟；HMG-CoA还原酶；抑制剂；高血脂

Search of New HMG - CoA Reductase Inhibitors

Abstract: Statins can significantly reduce blood lipid levels in the human body and they are widely used to reduce the cholesterol levels in our body. HMG-CoA reductase inhibitor structure is mainly composed of lipophilic part, hydrophilic part and the connection part. Now scientific research workers for the structural modification of statins mainly concentrated in the lipophilic ring and the connection part, while the improvement of the hydrophilic side chain structure was rarely done. Therefore, under the guidance of computer-aided drug design, it is proposed to introduce difluoromethylene group at the 4th position of HMG-CoA reductase inhibitor hydrophilic side chain from three kinds of statin nucleoside, and the affinity of statins .And then the biological activity of the synthesized compounds will be tested. The effects of the introduction of fluorine atoms on the bioactivity of the compounds will be studied by studying the structure of the compounds. The effects of the introduction of fluorine atoms on the bioactivity of the fluorinated compounds will be studied. We will select HMG-CoA reductase inhibitors with higher biological activity.

Key words: High blood lipids; Difluoromethylene group; HMG - CoA; reductase inhibitors

目  录

1 绪论 1

1.1心血管疾病与HMG-COA还原酶抑制剂 1

1.1.1心血管疾病的现状 1

1.1.2降血脂药物的种类 1

1.2近年来他汀类药物市场研究 3

1.2.1近年来国内典型医院用药分析 3

1.2.2近年来他汀类药物销售额变化 4

1.2.3全球市场 5

1.2.4国内市场 5

1.2.5他汀类药物的市场期望 6

2文献综述 7

2.1 HMG-CoA还原酶抑制剂（他汀类药物）的研究进展 7

2.2几种主流的他汀类药物 7

2.2.1洛伐他汀 7

2.2.2匹伐他汀 7

2.2.3氟伐他汀 8

2.3氟原子的引入对药物活性的影响 8

2.3.1电子效应 8

2.3.2代谢阻碍效应 8

2.3.3亲脂效应 8

2.3.4立体效应 8

3技术路线 9

3.1新型氟代HMG-COA还原酶抑制剂的设计