17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one | 151520-59-1

• 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-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one
• 英文别名: 17beta-Carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one；5-O-tert-butyl 1-O-methyl (1S,3aS,3bS,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-2,3,3a,3b,4,8,9,9b,10,11-decahydro-1H-cyclopenta[i]phenanthridine-1,5-dicarboxylate
• CAS: 151520-59-1
• 化学式: C₂₅H₃₇NO₅
• 分子量: 431.572
• InChiKey: LVQDAHBABSYKEG-QPLKWUTOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one 在 吡啶 、 氯化亚砜 、 N,N-二甲基甲酰胺 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 35.0h， 生成 (1S,3aS,3bS,9aR,9bS,11aS)-1-Benzylcarbamoyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,7,8,9,9a,9b,10,11,11a-tetradecahydro-cyclopenta[i]phenanthridine-5-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities

  摘要：

  One-third of the world's population carries Mycobacterium tuberculosis (Mtb), the infectious agent that causes tuberculosis (TB), and every 17 s someone dies of TB. After infection, Mtb can live dormant for decades in a granuloma structure arising from the host immune response, and cholesterol is important for this persistence of Mtb. Current treatments require long-duration drug regimens with many associated toxicities, which are compounded by the high doses required. We phenotypically screened 35 6-azasteroid analogues against Mtb and found that, at low micromolar concentrations, a subset of the analogues sensitized Mtb to multiple TB drugs. Two analogues were selected for further study to characterize the bactericidal activity of bedaquiline and isoniazid under normoxic and low-oxygen conditions. These two 6-azasteroids showed strong synergy with bedaquiline (fractional inhibitory concentration index = 0.21, bedaquiline minimal inhibitory concentration = 16 nM at 1 mu M 6-azasteroid). The rate at which spontaneous resistance to one of the 6-azasteroids arose in the presence of bedaquiline was approximately 10-9, and the 6-azasteroid-resistant mutants retained their isoniazid and bedaquiline sensitivity. Genes in the cholesterol-regulated Mce3R regulon were required for 6-azasteroid activity, whereas genes in the cholesterol catabolism pathway were not. Expression of a subset of Mce3R genes was down-regulated upon 6-azasteroid treatment. The Mce3R regulon is implicated in stress resistance and is absent in saprophytic mycobacteria. This regulon encodes a cholesterol-regulated stress-resistance pathway that we conclude is important for pathogenesis and contributes to drug tolerance, and this pathway is vulnerable to small-molecule targeting in live mycobacteria.

  DOI：

  10.1021/acsinfecdis.9b00099
• 作为产物：
  描述：

  孕烯醇酮 在 吡啶 、 咪唑 、 重铬酸吡啶 、 sodium azide 、 草酰氯 、 四丁基氟化铵 、 碘 、 臭氧 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 、 正戊烷 为溶剂， 反应 133.33h， 生成 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one
  参考文献：
  名称：

  [EN] AZASTEROIDS FOR TREATMENT OF TUBERCULOSIS
  [FR] COMPOSITION POUR LE TRAITEMENT DE LA TUBERCULOSE

  摘要：

  本发明提供了一种具有结构：式（I）的化合物，用于与抗结核药物结合，用于治疗感染结核分枝杆菌的受试者。

  公开号：

  WO2017190034A1

文献信息

• Substituted 6-azaandrostenones
  申请人：Glaxo Wellcome Inc.

  公开号：US05708001A1

  公开（公告）日：1998-01-13

  The present invention relates to certain substituted 17.beta.-substituted carbonyl-6-azaandrost-4-en-3-ones of formula (I), wherein R.sup.1 and R.sup.2 i) are 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 forming a cyclopropane ring, and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond; R.sup.3 is preferably hydrogen, halogen or lower alkyl, R.sup.4 is preferably hydrogen or lower alkyl, X is preferably CH.sub.2, Y is preferably hydrogen and Z is preferably CONR.sup.14 R.sup.15 and R.sup.14 and R.sup.15 are a variety of organic groups, and pharmaceutically acceptable salts thereof, preparation, medical use and pharmaceutical formulations.

  本发明涉及某些式(I)的取代17β-取代羰基-6-氮杂雄烯-4-酮化合物，其中R.sup.1和R.sup.2 i)独立地是氢或较低的烷基，且承载R.sup.1和R.sup.2的碳之间的键是单键或双键，或者ii)一起形成环丙烷环的--CH.sub.2--基团，且承载R.sup.1和R.sup.2的碳之间的键是单键；R.sup.3优选是氢、卤素或较低的烷基，R.sup.4优选是氢或较低的烷基，X优选是CH.sub.2，Y优选是氢，Z优选是CONR.sup.14R.sup.15，且R.sup.14和R.sup.15是各种有机基团，以及其药学上可接受的盐，制备、医疗用途和制药配方。
• Azasteroids for treatment of tuberculosis
  申请人：The Research Foundation for the State University of New York

  公开号：US11072633B2

  公开（公告）日：2021-07-27

  The present invention provides a compound having the structure: for use in combination with an anti-tuberculosis drug for treating a subject infected with M. tuberculosis.

  本发明提供了一种具有以下结构的化合物： 用于与抗结核药物联合使用，治疗感染结核杆菌的患者。
• 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
• 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.
• SUBSTITUTED 6-AZAANDROSTENONES
  申请人：GLAXO WELLCOME INC.

  公开号：EP0674651B1

  公开（公告）日：1998-10-28