(1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-Dimethyl-7-oxo-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[i]phenanthridine-1-carboxylic acid tert-butylamide | 151519-75-4

• 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: (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-Dimethyl-7-oxo-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[i]phenanthridine-1-carboxylic acid tert-butylamide
• 英文别名: 17beta-N-t-butylcarbamoyl-6-azaandrost-4-en-3-one；(1S,3aS,3bS,9aR,9bS,11aS)-N-tert-butyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,8,9,9b,10,11-dodecahydrocyclopenta[i]phenanthridine-1-carboxamide
• CAS: 151519-75-4
• 化学式: C₂₃H₃₆N₂O₂
• 分子量: 372.551
• InChiKey: GGGHOARHZNQZFF-IKRAPHRESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-Dimethyl-7-oxo-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[i]phenanthridine-1-carboxylic acid tert-butylamide 、 碘甲烷 在 sodium hydride 作用下， 生成 17β-N,t-Butylcarbamoyl-6-methyl-6-azaandrost-4-en-3-one
  参考文献：
  名称：

  6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.alpha.-Reductase and Human Adrenal 3.beta.-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase

  摘要：

  6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar K-i's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

  DOI：

  10.1021/jm00041a014
• 作为产物：
  描述：

  17β-carboxy-6-(tert-butylcarboxy)-6-azaandrost-4-en-3-one 在 吡啶 、 氯化亚砜 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 4.0h， 生成 (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-Dimethyl-7-oxo-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[i]phenanthridine-1-carboxylic acid tert-butylamide
  参考文献：
  名称：

  6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.alpha.-Reductase and Human Adrenal 3.beta.-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase

  摘要：

  6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar K-i's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

  DOI：

  10.1021/jm00041a014

文献信息

• Heterocyclic inhibitors of 5-.alpha.-testosterone reductase
  申请人：Glaxo, Inc.

  公开号：US05302589A1

  公开（公告）日：1994-04-12

  The present invention relates to certain substituted 17 .beta.-substituted carbonyl-6-azaandrost-4-en-3-ones of formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are i) independently hydrogen or lower alkyl and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single or a double bond, or ii) taken together are a --CH.sub.2 -- group to form a cyclopropane ring, and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond; X is ##STR2## wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or lower alkyl, p and q are independently either 0 or 1; R.sup.3 is lower alkyl, lower alkenyl, lower cycloalkyl, lower alkoxy, thiopyridyl, adamantyl, --NR.sup.9 R.sup.10 or --Ar--NR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are i) independently, hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower alkoxy, adamantyl, aryl, benzyl, diphenylmethyl, norbornyl or ii) taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group, ##STR3## wherein; Y represents O, CH.sub.2, --N.dbd., NH or N(lower alkyl) optionally substituted with one or more lower alkyl groups; Ar is an aromatic group of 6 to 12 carbons; R.sup.4 is hydrogen or methyl; Z is --O--, --NH--, --N(lower alkyl), --S--, --SO--, --SO.sub.2, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, CO, CO.sub.2, O.sub.2 C, --N.dbd.N-- --CH.dbd.N-- or --N.dbd.CH--; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts thereof; their preparation, medical use and pharmaceutical formulations.

  本发明涉及一种具有以下结构式（I）的取代17 .beta.-取代羰基-6-azaandrost-4-en-3-酮： ##STR1## 其中R.sup.1和R.sup.2是i)独立的氢或低碳基，承载R.sup.1和R.sup.2的碳之间的键是单键或双键，或ii)共同形成一个--CH.sub.2--基团以形成环丙烷环，承载R.sup.1和R.sup.2的碳之间的键是单键；X是##STR2## 其中R.sup.5、R.sup.6、R.sup.7和R.sup.8是独立的氢或低碳基，p和q是独立的0或1；R.sup.3是低碳基，低烯基，低环烷基，低烷氧基，噻吡基，金刚烷基，--NR.sup.9 R.sup.10或--Ar--NR.sup.9 R.sup.10，其中R.sup.9和R.sup.10是i)独立的，氢或低碳基，低烯基，低炔基，低环烷基，低烷氧基，金刚烷基，芳基，苄基，二苯甲基，去甲环烷基或ii)与连接氮一起形成4到8原子的杂环基，##STR3## 其中；Y代表O，CH.sub.2，--N.dbd.，NH或N（低碳基），可选地取代一个或多个低碳基基团；Ar是6到12个碳的芳基；R.sup.4是氢或甲基；Z是--O--，--NH--，--N（低碳基），--S--，--SO--，--SO.sub.2，--CH.sub.2 CH.sub.2 --，--CH.dbd.CH--，CO，CO.sub.2，O.sub.2 C，--N.dbd.N--，--CH.dbd.N--或--N.dbd.CH--；n和m独立地为0、1或2；以及其制备、医药用途和制药配方的药学上可接受的盐。
• 6-Azasteroids: potent dual inhibitors of human type 1 and 2 steroid 5.alpha.-reductase
  作者：Stephen V. Frye、Curt D. Haffner、Patrick R. Maloney、Robert A. Mook、G. F. Dorsey、Roger N. Hiner、Kenneth W. Batchelor、H. Neal Bramson、J. Darren Stuart

  DOI：10.1021/jm00078a022

  日期：1993.12
• INHIBITORS OF 5-ALPHA-TESTOSTERONE REDUCTASE
  申请人：GLAXO WELLCOME INC.

  公开号：EP0641356B1

  公开（公告）日：1998-04-22
• US5302589A
  申请人：——

  公开号：US5302589A

  公开（公告）日：1994-04-12
• US5457098A
  申请人：——

  公开号：US5457098A

  公开（公告）日：1995-10-10