17-α hydroxy-4-bromo-4-pregnene-3,20-dione | 96005-70-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 17-α hydroxy-4-bromo-4-pregnene-3,20-dione
• 英文别名: 4-bromo-17-hydroxy-pregn-4-ene-3,20-dione；4-Brom-17-hydroxy-pregn-4-en-3,20-dion；(8R,9S,10R,13S,14S,17R)-17-acetyl-4-bromo-17-hydroxy-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one
• CAS: 96005-70-8
• 化学式: C₂₁H₂₉BrO₃
• 分子量: 409.363
• InChiKey: HLHJCANZRQJZBB-FDLPIURMSA-N

物化性质

• 熔点：
  176 °C
• 沸点：
  517.0±50.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-羧基苯硼酸 、 17-α hydroxy-4-bromo-4-pregnene-3,20-dione 在 bis-triphenylphosphine-palladium(II) chloride potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 2.5h， 以79%的产率得到4-[(8R,9S,10R,13S,14S,17R)-17-acetyl-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-4-yl]benzoic acid
  参考文献：
  名称：

  Lukashev, Nikolay V.; Averin, Alexei D.; Latyshev, Gennadij V., Polish Journal of Chemistry, 2006, vol. 80, # 4, p. 559 - 572

  摘要：

  DOI：
• 作为产物：
  描述：

  醋羟孕酮 在 sodium hydroxide 、 氢溴酸 、 双氧水 作用下， 以 甲醇 为溶剂， 反应 36.5h， 生成 17-α hydroxy-4-bromo-4-pregnene-3,20-dione
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of 4-Halo Progesterone Derivatives as Antiandrogen.

  摘要：

  八种孕烷衍生物17-α乙酰氧基孕酮9、17-α乙酰氧基-4,5-环氧孕烷-3,20-二酮10、17-α乙酰氧基-4-氯-4-孕烯-3,20-二酮11、17-α乙酰氧基-4-溴-4-孕烯-3,20-二酮12、17-α羟基-4-溴-4-孕烯-3,20-二酮13、4-氯-17-α羟基-4-孕烯-3,20-二酮14、17-α苯甲酰氧基-4-溴-4-孕烯-3,20-二酮15和17-α苯甲酰氧基-4-氯-4-孕烯-3,20-二酮16的药理活性被研究。这些化合物被评估为去势仓鼠精囊的抗雄激素药。本研究的药理数据显示，具有C-17苯甲酰氧基的化合物15和16显示出最高的抗雄激素活性，以精囊重量的减少衡量，其次是类固醇11和12（17-α乙酰氧基）。自由醇13和14显示出较低的抗雄激素活性。显然，C-17处的酯部分是高抗雄激素活性存在的必要条件。显示上述类固醇对睾酮（T）转化为DHT的抑制作用，以产生的DHT 2量表示为pmoles DHT/g蛋白质/小时。类固醇11、12和16对睾酮（T）转化为二氢睾酮（DHT）的抑制活性远高于目前使用的非那雄胺3。

  DOI：

  10.1248/cpb.47.1232

文献信息

• New Progesterone Esters as 5.ALPHA.-Reductase Inhibitors.
  作者：Marisa CABEZA、Ivonne HEUZE、Eugene BRATOEFF、Eugenia MURILLO、Elena RAMIREZ、Alfonso LIRA

  DOI：10.1248/cpb.49.1081

  日期：——

  The pharmacological activity of four new progesterone derivatives: 4-bromo-17α-(p-fluorobenzoyloxy)-4-pregnene-3, 20-dione (7), 4-bromo-17α-(p-bromobenzoyloxy)-4-pregnene-3, 20-dione (8), 4-bromo-17α-(p-chlorobenzoyloxy)-pregnene-3, 20-dione (9) and 4-bromo-17α-(p-toluoyloxy)-4-pregnene-3, 20-dione (10) was determined. These compounds were evaluated as 5α-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 p-fluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5α-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.

  确定了四种新的孕酮衍生物的药理活性：4-溴-17α-(对氟苯甲酰氧基)-4-孕烯-3,20-二酮（7）、4-溴-17α-(对溴苯甲酰氧基)-4-孕烯-3,20-二酮（8）、4-溴-17α-(对氯苯甲酰氧基)-孕烯-3,20-二酮（9）和4-溴-17α-(对甲苯甲酰氧基)-4-孕烯-3,20-二酮（10）。这些化合物在去性腺仓鼠的精囊和侧腹器官中作为5α-还原酶抑制剂进行了评估。本研究的药理学数据表明，化合物7和9分别在C-17上具有对氟苯甲酰氧基和对氯苯甲酰氧基的功能，通过精囊重量减少的测量，显示出最高的抗雄激素作用。在侧腹器官模型中，相同的化合物7和9分别显示出较小的直径，分别为1.8和1.0毫米，比市售的非那雄胺3（2.3毫米）小，从而表明对5α-还原酶具有更高的抑制作用。类固醇7对T转化为DHT（图3）的抑制活性比目前使用的非那雄胺更高
• Kirk et al., Journal of the Chemical Society, 1956, p. 627
  作者：Kirk et al.

  DOI：——

  日期：——
• Molecular interactions of progesterone derivatives with 5α-reductase types 1 and 2 and androgen receptors
  作者：Eugene Bratoeff、Perla García、Yvonne Heuze、Juan Soriano、Adriana Mejía、Ana María Labastida、Norma Valencia、Marisa Cabeza

  DOI：10.1016/j.steroids.2010.03.006

  日期：2010.7

  The aim of this study was to ascertain the inhibitory effect of several progesterone derivatives for 5 alpha-reductase types 1 and 2 isozymes and to determine the binding to the androgen receptor.The 3,20-dioxopregna-4-ene-17 alpha-yl acetate 4 containing an acetoxy group in C-17 and steroid 17 alpha-hydroxypregn-4-ene-3,20-dione 5 having a hydroxyl group in the same position inhibited both isozymes. On the other hand, 17 alpha-hydroxy-4,5-epoxypregnan-3,20-dione 6 with an epoxy function at C-4, inhibited only the type 1 enzyme. Steroid 4-chloro-17 alpha-hydroxypregn-4-ene-3,20-dione 7a and 4-bromo-17 alpha-hydroxypregn-4-ene-3,20-dione 7b having the C-4 conjugated system and a chlorine or a bromine atom at C-4 respectively, inhibited both types of 5 alpha-reductase. These results indicate that an increase in the electronegativity of ring A produces a major inhibitory activity for 5 alpha-reductase type 1; however this increase was not observed for type 2 enzyme. When the free hydroxyl group of 7a or 7b was esterified, compounds 3,20-dioxo-4-chloropregn-4-ene-17 alpha yl-4-ethylbenzoate 8a and 3,20-dioxo-4-bromopregn-4-ene-17 alpha yl-4-ethylbenzoate 8b were obtained; these steroids inhibited only the 5 alpha-reductase type 2 enzyme.Finasteride and steroids 4. 5, 7b, 8a showed a comparable in vivo pharmacological activity, however the IC(50) values of these compounds were higher as compared to that of finasteride.These results indicated also that steroids 4, 5, 7a, and 7b bind to the androgen receptor whereas compounds 6, 8a and 8b failed to do so.The overall data from this study showed that steroids 5 and 7b bind to the AR and decreased of the growth of prostate and seminal vesicles. Moreover, 4 decreased also the growth of seminal vesicles. (C) 2010 Elsevier Inc. All rights reserved.