10第十章 激素類藥物

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-表示取代基處于環(huán)平面的上方，用實(shí)線連接；表示取代基處于環(huán)平面的上方，用實(shí)線連接； 用用-表示取代基處于環(huán)下方，用虛線連接。表示取代基處于環(huán)下方，用虛線連接。用用“去甲基去甲基”或或“降降”表示比原母核失去一個(gè)甲基表示比原母核失去一個(gè)甲基或環(huán)縮小一個(gè)碳

3、原子；用或環(huán)縮小一個(gè)碳原子；用“高高”表示環(huán)擴(kuò)大一個(gè)碳原子。表示環(huán)擴(kuò)大一個(gè)碳原子。雙鍵的位次可用阿拉伯?dāng)?shù)字表示，亦可用雙鍵的位次可用阿拉伯?dāng)?shù)字表示，亦可用“”來表來表示。示。123456789101112131415161712345678910111213141516171，41，5（10）ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHHOHOOOHHOOHHOOHO雌二醇脫氫酶雌二醇脫氫酶16-羥化酶16-羥化酶雌二醇雌酮雌三醇ONH3CO

4、OHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O結(jié)構(gòu)特點(diǎn)：結(jié)構(gòu)特點(diǎn)： 以雌甾烷為母核以雌甾烷為母核 A環(huán)芳構(gòu)化環(huán)芳構(gòu)化 3，17-二醇二醇HOHHHHCOHH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 雌二醇肌肉注射給藥起效迅速，但作雌二醇肌肉注射給藥起效迅速，但作用時(shí)間短；在胃腸道及肝臟中迅速失活，用時(shí)間短；在胃腸道及肝臟中迅速失活，因此口服無效。因此口服無效。 對(duì)雌激素的改造，不以增強(qiáng)藥效為目對(duì)雌激素的改造，不以增強(qiáng)藥效為目的。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 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 雌激素在動(dòng)物體內(nèi)含量較少，天然來雌激素在動(dòng)物體內(nèi)含量較少，天然來源非常有限，從源非常有限，從4-3-酮型甾體轉(zhuǎn)化為芳酮型甾體轉(zhuǎn)化為芳香化香化A環(huán)的合成非常復(fù)雜，所以雌激素來環(huán)的合成非常復(fù)雜，所以雌激素來源困

6、難。源困難。 因此研究雌激素類藥物的另一個(gè)方向就是：因此研究雌激素類藥物的另一個(gè)方向就是：尋找結(jié)構(gòu)簡(jiǎn)單、制備方便的代用品尋找結(jié)構(gòu)簡(jiǎn)單、制備方便的代用品ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O一些非甾體雌激素結(jié)構(gòu)類型：一些非甾體雌激素結(jié)構(gòu)類型：ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OSchueler（1946年）提出年）提出剛性甾體母核兩端的富電子基團(tuán)（剛性甾體母核兩端的富電子基團(tuán)（OH、=O、NH等）之間的距離應(yīng)在等）之間的距離應(yīng)在1.45nm，分子寬度應(yīng)為分子寬度應(yīng)為0.388nm

7、。0.72nm1.45nmONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CCH3HOOH己烯雌酚己烯雌酚結(jié)構(gòu)：結(jié)構(gòu)：1.反式有效，平面結(jié)構(gòu)，雙鍵氫化無效反式有效，平面結(jié)構(gòu)，雙鍵氫化無效 2.酚羥基酸性酚羥基酸性O(shè)NH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OClONCH3CH3ONCH3CH3H3C氯米芬他莫昔芬ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/

8、2H2OHOHHHHCOHH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OCH3H3CHOOHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3CCH3CH3，OHOOHHOOOHOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H

9、3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OHOOOO雄素酮睪酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 睪酮作用時(shí)間短；易在消化道被破壞，睪酮作用時(shí)間短；易在消化道被破壞，因此口服無效；雄性激素作用強(qiáng)，蛋白通因此口服無效；雄性激素作用強(qiáng)，蛋白通化作用弱，不良反應(yīng)較大?；饔萌?，不良反應(yīng)較大。 針對(duì)這些缺點(diǎn)，對(duì)睪酮進(jìn)行一系列的針對(duì)這些缺點(diǎn)，對(duì)睪酮進(jìn)行一系列的改造。改造。ONH3COOHCH3H3PO41 1/2H2

10、OONH3COOHCH3H3PO41 1/2H2OOOOOOCH3O丙酸睪酮苯乙酸睪酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOH3CHH3COHHHCH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHHH3COHHHOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHCH3HOCH3NNH羥甲烯龍司坦唑醇ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOH3CHH3COHHHCH3

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

12、OOHOOHCCHCCH炔孕酮炔諾酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O 黃體酮口服易代謝失活，僅能注射給黃體酮口服易代謝失活，僅能注射給藥，因此，獲得可口服的長(zhǎng)效孕激素，就藥，因此，獲得可口服的長(zhǎng)效孕激素，就成了結(jié)構(gòu)改造的主要目的。成了結(jié)構(gòu)改造的主要目的。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOCH3OOOCH3CH3OCH3OOOCH3CH3OCH3OOOCH3Cl醋酸甲羥孕酮醋酸甲地孕酮醋酸氯地孕酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3

13、PO41 1/2H2OH3COH3CCH3OHHHHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHCCHONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHNCCCH3ONH3COOHCH3H3PO41 1

14、/2H2OONH3COOHCH3H3PO41 1/2H2O ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHOOOOHOHHOOOOHHOOOHCOOHHOO可的松氫化可的松皮質(zhì)酮醛固酮ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOOHOHCH3OHCH3O氫化可的松的空間位阻ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOOOOHOHO

15、HOOOH潑尼松潑尼松龍ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOHOOOHOHFOOHOOOHOFCH3CH3曲安西龍曲安奈德ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OOHOHOOOHCH3FOHOHOOOHCH3F地塞米松倍他米松ONH3COOHCH3H3PO41 1/2H2OONH3CO

16、OHCH3H3PO41 1/2H2OH3CH3COHOHOOHHHHOCH3OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CH3COHOHOOFHHHOCH3OHCH3ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/

17、2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOH

18、CH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O1. 磺脲類磺脲類甲磺丁脲甲磺丁脲 D860D860，為第一代磺脲類口為第一代磺脲類口 服降糖藥。服降糖藥。格列苯脲格列苯脲 優(yōu)降糖，優(yōu)降糖，第二代脲類口服降第二代脲類口服降糖藥，糖藥，作用強(qiáng)、持久。作用強(qiáng)、持久。格列齊特格列齊特 達(dá)美康，達(dá)美康，第二代脲類口服降第二代脲類口服降糖藥糖藥 。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41

19、1/2H2OONH3COOHCH3H3PO41 1/2H2OH3CSNHNHCH3OOOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OSNHOClH3CONHNHOOOONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O2. 雙胍類口服降糖藥雙胍類口服降糖藥苯乙雙胍苯乙雙胍 降糖靈，價(jià)格便宜。降糖靈，價(jià)格便宜。

20、二甲雙胍二甲雙胍 降糖片。降糖片。ONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2ONHH2NHNNHNCH3CH3，HClONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2OONH3COOHCH3H3PO41 1/2H2O新型口服降血糖藥物，新型口服降血糖藥物，通過在腸道內(nèi)競(jìng)爭(zhēng)性抑制葡萄糖苷通過在腸道內(nèi)競(jìng)爭(zhēng)性抑制葡萄糖苷酶，降低糖類的吸收，具有降低飯酶，降低糖類的吸收，具有降低飯后高血糖和血漿胰島