17β-(N-cyclopropylamino)-4-methyl-4-aza-5α-androstan-3-one | 153338-67-1

• 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-(N-cyclopropylamino)-4-methyl-4-aza-5α-androstan-3-one
• 英文别名: 17β-(N-cyclopropyl)-4-methyl-4-aza-5α-androstan-3-one；17β-cyclopropylamino-4-methyl-4-aza-5α-androstan-3-one；(1S,3aS,3bS,5aR,9aR,9bS,11aS)-1-(cyclopropylamino)-6,9a,11a-trimethyl-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1H-indeno[5,4-f]quinolin-7-one
• CAS: 153338-67-1
• 化学式: C₂₂H₃₆N₂O
• 分子量: 344.541
• InChiKey: WJNMKVVRMHOZLC-WREBCAICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  32.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  17β-(N-cyclopropylamino)-4-methyl-4-aza-5α-androstan-3-one 生成 2α-iodo-17β-cyclopropyloxy-4-methyl-4-aza-5α-androstan-3-one
  参考文献：
  名称：

  4-aza steroids

  摘要：

  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：

  公开号：

  US06365597B1
• 作为产物：
  描述：

  17β-cyclopropylamino-2α-bromo-4-aza-5α-androstan-3-one 生成 17β-(N-cyclopropylamino)-4-methyl-4-aza-5α-androstan-3-one
  参考文献：
  名称：

  4-aza steroids

  摘要：

  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：

  公开号：

  US06365597B1

文献信息

• Synthesis and in vitro study of 17β-[N-ureylene-N,N′-disubstituted]-4-methyl-4-aza-5α-androstan-3-ones as selective inhibitors of type I 5α-reductase
  作者：Mettilda Lourdusamy、Jean Côté、S. Laplante、Fernand Labrie、Shankar M. Singh

  DOI：10.1016/s0968-0896(96)00241-6

  日期：1997.2

  ids as inhibitors of human type I 5 alpha-reductase (5 alpha-Re) were prepared from 17 beta-N-alkyl-4-methyl-4-aza-5 alpha-androstan-3-ones and various isocyanates. For the measurement of 5 alpha-Re activity, 293 cells transfected with human type I 5 alpha-Re, cDNA were used. Azasteroids with an N-cyclopropyl ring exhibited potent inhibitory activity against type I 5 alpha-Re. As the chain length increased

  从17个beta-N-烷基-4-制备了一系列17种β-（N-脲基-N，N'-二取代）-4-氮杂甾类化合物作为人类I型5α-还原酶（5 alpha-Re）的抑制剂。甲基-4-氮杂-5α-雄烷-3-酮和各种异氰酸酯。为了测量5α-Re活性，使用了用人I型5α-Re，cDNA转染的293细胞。具有N-环丙基环的氮杂类固醇对I 5型α-Re表现出有效的抑制活性。随着链长的增加，从N'-乙基到N'-丁基链，化合物的活性也增加，带有N'-丁基链的氮杂甾类化合物表现出较强的抑制活性（IC50 = 5.3 nM）。烷基链的分支降低了化合物的效力。1,2-双键的引入显着降低了氮杂类固醇的活性。N'的替换 具有苯基部分的-烷基链给出了该系列中活性最高的化合物（IC50 = 1.3 nM）。其他变化，例如用N-甲基或N-丁基链取代N-环丙基环，会降低化合物的活性（与上述化合物相比，化合物的活性较低）。N-甲基-
• 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
• US6365597B1
  申请人：——

  公开号：US6365597B1

  公开（公告）日：2002-04-02
• [EN] 17-BETA-CYCLOPROPYL(AMINO/OXY) 4-AZA STEROIDS AS ACTIVE INHIBITORS OF TESTOSTERONE 5-ALPHA-REDUCTASE AND C17-20-LYASE<br/>[FR] 17-BETA-CYCLOPROPYL(AMINO/OXY) 4-AZA STEROIDES UTILISES EN QUALITES D'INHIBITEURS DE 5-ALPHA-REDUCTASE ET DE C17-20-LYASE DE TESTOSTERONE
  申请人：HOECHST MARION ROUSSEL, INC.

  公开号：WO1997030069A1

  公开（公告）日：1997-08-21

  (EN) The invention related to 4-aza-17$g(b)-(cyclopropoxy)-androst-5$g(a)-androstan-3-one, 4-aza-17$g(b)-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the inhibition of C17-20 lyase, 5$g(a)-reductase and C17$g(a)-hydroxylase and to the use of these compounds in the treatment of androgen and estrogen mediated disorders, including benign prostatic hyperplasia, androgen mediated prostate cancer, estrogen mediated breast cancer and to DHT-mediated disorders such as acne. Disorders relating to the oversynthesis of cortisol, for example, Cushing's Syndrome, are also included. The treatment of androgen-dependent disorders also includes a combination therapy with known androgen-receptor antagonists, such as flutamide. The compounds of the invention have general formula (I).(FR) Cette invention concerne des composés 4-aza-17$g(b)-(cyclopropoxy)-androst-5$g(a)-androstan-3-one, des composés 4-aza-17$g(b)-(cyclopropylamino)-androst-4-en-3-one, et leurs composés apparentés, ainsi que des compositions contenant ces composés. Cette invention concerne également l'inhibition de C17-20 lyase, de 5$g(a)-reductase et de C17$g(a)-hydroxylase, ainsi que l'utilisation des composés susmentionnés dans le traitement de troubles déclenchés par des androgènes et des oestrogènes comme, par exemple, l'hyperplasie prostatique bénigne, le cancer de la prostate déclenché par des androgènes, le cancer du sein déclenché par des oestrogènes et les troubles déclenchés par DHT tels que l'acné. Les troubles liés à une synthèse excessive de cortisol, tel que le syndrome de Cushing, peuvent également être traités de cette manière. Le traitement de troubles liés à des androgènes comprend également une thérapie combinatoire faisant appel à des antagonistes de récepteurs d'androgènes connus, tel que du flutamide. Les composés décrits dans la présente invention correspondent à la formule générale (I).