17β-hydroxy-4-methyl-4-aza-androst-5(6)-en-3-one | 92472-37-2

• 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-hydroxy-4-methyl-4-aza-androst-5(6)-en-3-one
• 英文别名: 17β-hydroxy-4-methyl-4-azaandrostan-5-en-3-one；17β-hydroxy-4-methyl-4-aza-5-androsten-3-one；17β-hydroxy-N-methyl-4-azaandrost-5-en-3-one；17β-hydroxy-4-methyl-4-aza-androst-5-ene-3-one；(1S,3aS,3bR,9aR,9bS,11aS)-1-hydroxy-6,9a,11a-trimethyl-2,3,3a,3b,4,8,9,9b,10,11-decahydro-1H-indeno[5,4-f]quinolin-7-one
• CAS: 92472-37-2
• 化学式: C₁₉H₂₉NO₂
• 分子量: 303.445
• InChiKey: MICZNRRTCUCNTP-BMSLSITRSA-N

物化性质

• 沸点：
  467.6±45.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  17β-hydroxy-4-methyl-4-aza-androst-5(6)-en-3-one 在 pyridinium chlorochromate 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以631 mg的产率得到4-甲基-4-氮杂-5-雄甾烯-3,17-二酮
  参考文献：
  名称：

  Azasteroids：抑制5α-还原酶和雄激素受体结合的构效关系。

  摘要：

  制备了一系列类固醇，主要是4-氮杂类固醇，并在体外进行了测试，以作为人和大鼠前列腺5α-还原酶以及二氢睾丸激素与大鼠雄激素受体结合的抑制剂。主要的结构修饰是类固醇核的C-17位置的A环和连接部分的变化。新的A环修改包括碳环系列中的4-cyano-3-oxo-delta 4系统和1 alpha-CN，1 alpha-CH3、1 alpha，2 alpha-CH2、2 beta-F，2-aza， 3-oxo-4-aza系列中的2-oxa和A-homo变化。另外，制备了在C-7（α和β）或C-16（α和β）具有D-高环或甲基取代的4-氮杂甾类。大多数C-17取代基是由衍生自17β-COOH的反应性中间体制备的。在人和大鼠酶试验中，通过在3-oxo-delta 4类固醇上进行4-CN取代和在4-aza-3上结合了亲脂性取代的半极性基团的C-17侧链，可以看到增强的5α-还原酶抑制作用-oxo-5α

  DOI：

  10.1021/jm00161a028
• 作为产物：
  描述：

  睾酮 在 臭氧 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 17β-hydroxy-4-methyl-4-aza-androst-5(6)-en-3-one
  参考文献：
  名称：

  氮杂类固醇作为大鼠前列腺5α-还原酶的抑制剂。

  摘要：

  已经制备了一系列A环杂环类固醇，并在体外测试了其对大鼠前列腺类固醇5α-还原酶的抑制作用。发现一组17个β-取代的4-甲基-4-氮杂-5α-雄甾烷-3-酮具有惊人的高抑制活性。这些化合物由3-酮-δ4前体通过氧化（O3或NaIO4-KMnO4）A环裂解，然后用胺闭环并在铂催化剂上氢化而制得。其他的A环氮杂甾类化合物是通过贝克曼重排2-oxo-A-nor，3-oxo-和4-oxo-5α-雄甾烷酮的肟制得的。通过用间氯过苯甲酸将前体2,3-二氧代-4-氮杂甾族化合物氧化脱羰制备A-正-2-氧代-3-氮杂甾族化合物。4-氮杂类固醇的A环修饰包括δ1-不饱和键，2-和4-取代基以及3-羰基取代基。

  DOI：

  10.1021/jm00378a028

文献信息

• 4-aza steroids
  申请人：Aventis Pharmaceuticals Inc.

  公开号：US06365597B1

  公开（公告）日：2002-04-02

  The invention related to 4-aza-17&bgr;-(cyclopropoxy)-androst-5&agr;-androstan-3-one, 4-aza-17&bgr;-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the inhibition of C17-20 lyase, 5&agr;-reductase and C17&agr;-hydroxylase and to the use of these compounds in the treatment of androgen and estrogen mediated disorders, including benign prostatic hyperplasia, androgen mediated prostate cancer, estrogen mediated breast cancer and to DHT-mediated disorders such as acne. Disorders relating to the oversynthesis of cortisol, for example, Cushing's Syndrome, are also included. The treatment of androgen-dependent disorders also includes a combination therapy with known androgen-receptor antagonists, such as flutamide. The compounds of the invention have the following general formula:

  与4-aza-17β-(环丙氧基)-雄烯-5α-雄烷-3-酮，4-aza-17β-(环丙基氨基)-雄烷-4-烯-3-酮及相关化合物以及含有这些化合物的组合物有关的发明，以及对C17-20裂解酶、5α-还原酶和C17α-羟化酶的抑制，以及利用这些化合物治疗雄激素和雌激素介导的疾病，包括良性前列腺增生、雄激素介导的前列腺癌、雌激素介导的乳腺癌以及DHT介导的疾病，如痤疮。与皮质醇过度合成有关的疾病，例如库欣综合征，也包括在内。治疗雄激素依赖性疾病还包括与已知雄激素受体拮抗剂（如氟他胺）的联合治疗。本发明的化合物具有以下一般公式：
• Photochemical Reactions. 21. Sensitized Photooxygenation of<i>N</i>-Methylated 4-Aza-5-androsten-3-one and 4-Aza-5-androstene Steroidal Systems
  作者：Joan Francesc Piniella、Jordi Estapé、Pilar Lupón、Luis Merino、Mariano Puig、Juan-Julio Bonet、José Luis Briansó、Gabriel Germain

  DOI：10.1246/bcsj.60.3011

  日期：1987.8

  Two steroidal ene lactams, N-methyl-4-aza-5-androsten-3,17-dione and N-methyl-6-methoxy-4-aza-5-androsten-3,17-dione, and an enamine, N-methyl-4-aza-5-androsten-17β-ol, have been synthetized and their sensitized photooxygenations were investigated. The two ene lactams yield fragmentation compounds via the corresponding dioxetanes. Comparison with the previously reported behavior of an analogous N-unsubstituted ene lactam, seems to indicate that N-substitution is essential for the fragmentation to take place. On the other hand, the enamine yields a ketol. All results are briefly discussed from the mechanistic point of view.

  我们合成了两种甾体烯丙基内酰胺（N-甲基-4-氮杂-5-雄烯-3,17-二酮和 N-甲基-6-甲氧基-4-氮杂-5-雄烯-3,17-二酮）和一种烯胺（N-甲基-4-氮杂-5-雄烯-17β-醇），并研究了它们的敏化光氧化反应。这两种烯内酰胺通过相应的二氧杂环丁烷产生碎片化合物。与之前报道的一种类似的 N-未取代烯丙内酰胺的行为相比，似乎表明 N-取代是发生碎片化的必要条件。另一方面，烯胺产生了酮醇。本文从机理角度对所有结果进行了简要讨论。
• Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor
  作者：Xun Li、Shankar M. Singh、Fernand Labrie

  DOI：10.1021/jm00007a013

  日期：1995.3

  A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza- 5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)(3)/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC(50)s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50S = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM) Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC(50)s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50S < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107). The inhibition of DHT action on the proliferation of the androgen-sensitive cancer cells by formamido compounds showed moderate to good activity, IC50 values ranging from 45 to 100 nM as compared to hydroxyflutamide (IC50 = 52.5 nM).
• 17-BETA-CYCLOPROPYL(AMINO/OXY) 4-AZA STEROIDS AS ACTIVE INHIBITORS OF TESTOSTERONE 5-ALPHA-REDUCTASE AND C17-20-LYASE
  申请人：Aventis Pharmaceuticals Inc.

  公开号：EP0880540B1

  公开（公告）日：2002-06-12
• Design, Synthesis, and Biological Evaluation of 16-Substituted 4-Azasteroids as Tissue-Selective Androgen Receptor Modulators (SARMs)
  作者：Helen J. Mitchell、William P. Dankulich、George D. Hartman、Thomayant Prueksaritanont、Azriel Schmidt、Robert L. Vogel、Chang Bai、Sheila McElwee-Witmer、Hai Z. Zhang、Fang Chen、Chih-Tai Leu、Donald B. Kimmel、William J. Ray、Pascale Nantermet、Michael A. Gentile、Mark E. Duggan、Robert S. Meissner

  DOI：10.1021/jm900880r

  日期：2009.8.13

  A novel series of 16-substiuted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential,and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited all osteoanabolic, tissue-selective profile.