17β-carbo-(2-adamantyl)-oxy-6-azaandrost-4-en-3-one

• 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: 17β-carbo-(2-adamantyl)-oxy-6-azaandrost-4-en-3-one
• 英文别名: (1S,9aR,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 adamantan-2-yl ester；2-adamantyl (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,8,9,9b,10,11-dodecahydrocyclopenta[i]phenanthridine-1-carboxylate
• 化学式: C₂₉H₄₁NO₃
• 分子量: 451.649
• InChiKey: CECSFCKUXJBSMW-WASAPHRGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-金刚烷醇 在 三氟乙酸 作用下， 生成 17β-carbo-(2-adamantyl)-oxy-6-azaandrost-4-en-3-one
  参考文献：
  名称：

  6-氮杂类固醇：人1型和2型类固醇5α-还原酶的有效双重抑制剂。

  摘要：

  DOI：

  10.1021/jm00078a022

文献信息

• 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
• US5543406A
  申请人：——

  公开号：US5543406A

  公开（公告）日：1996-08-06
• [EN] INHIBITORS OF 5-ALPHA-TESTOSTERONE REDUCTASE
  申请人：GLAXO INC.

  公开号：WO1993013124A1

  公开（公告）日：1993-07-08

  (EN) The present invention relates to certain substituted 17$g(b)-substituted carbonyl-6-azaandrost-4-en-3-ones of formula (I), especially those of formula (IG) wherein R1 and R1 are: i) independently hydrogen or lower alkyl and the bond between the carbons bearing R1 and R2 is a single or a double bond, or ii) taken together are a -CH2- group to form a cyclopropane ring, and the bond between the carbons bearing R1 and R2 is a single bond; R3c is hydrogen; R4c is hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, alkanoyl of 2-6 carbons, -(CH2)mCO2R16, -(CH2)mAra, -(CH2)n'CONR17R18, -(CH2)n'NR17R18 or -(CH2)n'OR16, wherein R16 is hydrogen, lower alkyl or lower alkenyl; R17 and R18 are independly hydrogen, lower alkyl lower cycloalkyl or lower alkenyl; Ara is an aromatic group of 6 to 12 carbons; n' is 0 or an integer from 1 to 5; m is an integer from 1 to 5; R19 and R20 are independently hydrogen or lower alkyl, or taken together R19 and R20 form a carbonyl group(=O); R5c is lower alkyl, lower alkenyl, lower cycloalkyl, lower alkoxy, or NR21R22, wherein R21 and R22 are independently hydrogen, lower alkyl or lower alkenyl; and pharmaceutically acceptable salts thereof, their preparation, medical use and pharmaceutical formulations.(FR) L'invention concerne certaines carbonyl-6-azaandrost-4-en-3-ones substituées à substitution en position 17$g(b) représentées par la formule (I), et notamment celles représentées par la formule (IG) où R1 et R2 représentent: i) hydrogène ou alkyle inférieur et/ou la liaison entre les carbones portant R1 et R2 est une liaison simple ou double, ou ii) représentent ensemble un groupe -CH2- pour former un cycle cyclopropane, et/ou la liaison entre les carbones portant R1 et R2 est une liaison simple; R3c est hydrogène; R4c est hydrogène, alkyle inférieur, cycloalkyle inférieur, alcényle inférieur, alcanoyle de 2-6 carbones, -(CH2)mCO2R16, -(CH2)mAra, -(CH2)n'CONR17R18, -(CH2)n'NR17R18 ou -(CH2)n'OR16, où R16 est hydrogène, alkyle inférieur ou alcényle inférieur; R17 et R18 représentent indépendamment hydrogène, alkyle inférieur, cycloalkyle inférieur ou alcényle inférieur; Ara est un groupe aromatique de 2 à 16 carbones; n' représente 0 ou un nombre entier compris entre 1 et 5; m est un entier compris entre 1 et 5; R19 et R20 représentent indépendamment hydrogène ou alkyle inférieur, ou pris ensemble, R19 et R20 forment un groupe carbonyle (=O); R5c est alkyle inférieur, alcényle inférieur, cycloalkyle inférieur, alcoxy inférieur ou NR21R22, où R21 et R22 représentent indépendamment hydrogène, alkyle inférieur ou alcényle inférieur; et des sels pharmaceutiquement acceptables, leur préparation, leur emploi en médecine et des formulations pharmaceutiques.
• 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
  作者：Stephen V. Frye、Curt D. Haffner、Patrick R. Maloney、Robert A. Mook、George F. Dorsey、Roger N. Hiner、Cindy M. Cribbs、Thomas N. Wheeler、John A. Ray

  DOI：10.1021/jm00041a014

  日期：1994.7

  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.