第十章 激素类药物

1、ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OABCD1234567891011121317161514ONH3COO

2、HCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O1819ONH3COOHCH3H3PO41 1/2H2O雌甾烷雌甾烷13-CH3雄甾雄甾烷烷10-CH313-CH3孕甾烷孕甾烷10-CH313-CH317-C2H5ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O用用-表示取代基处于环平面的上方，用实线连接；表示取代基处于环平面的上方，用实线连接； 用用-表示取代基处于环下方，用虚线连接。表示取代基处于环下方，用虚线连接。用用“去甲基去甲基”或或“降降”表示比原母核失去一个甲基表示比原母核失去一个甲基或环缩小一个碳

3、原子；用或环缩小一个碳原子；用“高高”表示环扩大一个碳原子。表示环扩大一个碳原子。双键的位次可用阿拉伯数字表示，亦可用双键的位次可用阿拉伯数字表示，亦可用“”来表示。来表示。123456789101112131415161712345678910111213141516171，41，5（10）ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHHOHOOOHHOOHHOOHO雌二醇脱氢酶雌二醇脱氢酶16-羟化酶16-羟化酶雌二醇雌酮雌三醇ONH3CO

4、OHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O结构特点：结构特点： 以雌甾烷为母核以雌甾烷为母核 A环芳构化环芳构化 3，17-二醇二醇HOHHHHCOHH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 雌二醇肌肉注射给药起效迅速，但作雌二醇肌肉注射给药起效迅速，但作用时间短；在胃肠道及肝脏中迅速失活，用时间短；在胃肠道及肝脏中迅速失活，因此口服无效。因此口服无效。 对雌激素的改造，不以增强药效为目对雌激素的改造，不以增强药效为目的。而是：的。而是：延效和口服延效和口服ONH3COOHCH3H3PO41

5、1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOOHOO苯甲酸雌二醇戊酸雌二醇CH3OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O炔雌醚炔雌醚ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 雌激素在动物体内含量较少，天然来雌激素在动物体内含量较少，天然来源非常有限，从源非常有限，从4-3-酮型甾体转化为芳酮型甾体转化为芳香化香化A环的合成非常复杂，所以雌激素来环的合成非常复杂，所以

6、雌激素来源困难。源困难。 因此研究雌激素类药物的另一个方向就是：因此研究雌激素类药物的另一个方向就是：寻找结构简单、制备方便的代用品寻找结构简单、制备方便的代用品ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O一些非甾体雌激素结构类型：一些非甾体雌激素结构类型：ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OSchueler（1946年）提出年）提出刚性甾体母核两端的富电子基团（刚性甾体母核两端的富电子基团（OH、=O、NH等）之间的距离应在等）之间的距离应在1.45nm，分子宽度应为分子宽度应为0

7、.388nm。0.72nm1.45nmONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CCH3HOOH己烯雌酚己烯雌酚结构：结构：1.反式有效，平面结构，双键氢化无效反式有效，平面结构，双键氢化无效 2.酚羟基酸性酚羟基酸性ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OClONCH3CH3ONCH3CH3H3C氯米芬他莫昔芬ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3P

8、O41 1/2H2OHOHHHHCOHH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OCH3H3CHOOHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3CCH3CH3，OHOOHHOOOHOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3CO

9、OHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OHOOOO雄素酮睾酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 睾酮作用时间短；易在消化道被破坏，睾酮作用时间短；易在消化道被破坏，因此口服无效；雄性激素作用强，蛋白通因此口服无效；雄性激素作用强，蛋白通化作用弱，不良反应较大。化作用弱，不良反应较大。 针对这些缺点，对睾酮进行一系列的针对这些缺点，对睾酮进行一系列的改造。改造。ONH3COOHCH3H3PO41

10、 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOOOOCH3O丙酸睾酮苯乙酸睾酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOH3CHH3COHHHCH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHHH3COHHHOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHCH3HOCH3NNH羟甲烯龙司坦唑醇ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOH3CHH3CO

11、HHHCH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHHH3COHHHOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41

12、1/2H2OOOHOOHCCHCCH炔孕酮炔诺酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 黄体酮口服易代谢失活，仅能注射给黄体酮口服易代谢失活，仅能注射给药，因此，获得可口服的长效孕激素，就药，因此，获得可口服的长效孕激素，就成了结构改造的主要目的。成了结构改造的主要目的。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOCH3OOOCH3CH3OCH3OOOCH3CH3OCH3OOOCH3Cl醋酸甲羟孕酮醋酸甲地孕酮醋酸氯地孕酮ONH3COOHCH3H3PO41 1/2H2OONH3COO

13、HCH3H3PO41 1/2H2OH3COH3CCH3OHHHHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHCCHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHNCCCH3ONH3COOHCH3H3

14、PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHOOOOHOHHOOOOHHOOOHCOOHHOO可的松氢化可的松皮质酮醛固酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHCH3OHCH3O氢化可的松的空间位阻ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOO

15、OOHOHOHOOOH泼尼松泼尼松龙ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOHOOOHOHFOOHOOOHOFCH3CH3曲安西龙曲安奈德ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOHOOOHCH3FOHOHOOOHCH3F地塞米松倍他米松ONH3COOHCH3H3PO41 1/2H2O

16、ONH3COOHCH3H3PO41 1/2H2OH3CH3COHOHOOHHHHOCH3OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CH3COHOHOOFHHHOCH3OHCH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3P

17、O41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OON

18、H3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O1. 磺脲类磺脲类甲磺丁脲甲磺丁脲 D860D860，为第一代磺脲类口，为第一代磺脲类口 服降糖药。服降糖药。格列苯脲格列苯脲 优降糖，优降糖，第二代脲类口服降第二代脲类口服降糖药，糖药，作用强、持久。作用强、持久。格列齐特格列齐特 达美康，达美康，第二代脲类口服降第二代脲类口服降糖药糖药 。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3

19、H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CSNHNHCH3OOOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OSNHOClH3CONHNHOOOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O2. 双胍类口服降糖药双胍类口服降糖药苯乙双胍苯乙双胍 降糖灵，价格便宜。降糖灵

20、，价格便宜。 二甲双胍二甲双胍 降糖片。降糖片。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2ONHH2NHNNHNCH3CH3，HClONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O新型口服降血糖药物，新型口服降血糖药物，通过在肠道内竞争性抑制葡萄糖苷通过在肠道内竞争性抑制葡萄糖苷酶，降低糖类的吸收，具有降低饭酶，降低糖类的吸收，具有降低饭后高血糖和血浆胰