17β-(N-amylamino)-4-methyl-4-aza-5α-androstan-3-one | 153338-66-0

• 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-amylamino)-4-methyl-4-aza-5α-androstan-3-one
• 英文别名: (1S,3aS,3bS,5aR,9aR,9bS,11aS)-6,9a,11a-trimethyl-1-(pentylamino)-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1H-indeno[5,4-f]quinolin-7-one
• CAS: 153338-66-0
• 化学式: C₂₄H₄₂N₂O
• 分子量: 374.61
• InChiKey: OEDKDUVRQIBRBG-KDTKDTIDSA-N

物化性质

• 沸点：
  493.1±45.0 °C(predicted)
• 密度：
  1.03±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 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：

  戊酰氯 、 17β-(N-amylamino)-4-methyl-4-aza-5α-androstan-3-one 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 以45%的产率得到17β-<(N-amyl)valeramido>-4-methyl-4-aza-5α-androstan-3-one
  参考文献：
  名称：

  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

  摘要：

  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).

  DOI：

  10.1021/jm00007a013
• 作为产物：
  描述：

  1-氨基戊烷 、 4-methyl-4-aza-5α-androstane-3,17-dione 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 48.0h， 以90%的产率得到17β-(N-amylamino)-4-methyl-4-aza-5α-androstan-3-one
  参考文献：
  名称：

  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

  摘要：

  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).

  DOI：

  10.1021/jm00007a013

文献信息

• INHIBITORS OF TESTOSTERONE 5$g(a)-REDUCTASE ACTIVITY
  申请人：ENDORECHERCHE INC.

  公开号：EP0641211A1

  公开（公告）日：1995-03-08
• US5494914A
  申请人：——

  公开号：US5494914A

  公开（公告）日：1996-02-27
• [EN] INHIBITORS OF TESTOSTERONE 5 alpha -REDUCTASE ACTIVITY<br/>[FR] INHIBITEURS D'ACTIVITE DE LA TESTOSTERONE 5 alpha -REDUCTASE
  申请人：ENDORECHERCHE INC.

  公开号：WO1993023053A1

  公开（公告）日：1993-11-25

  (EN) Inhibitors of testosterone 5$g(a)-reductase activity, for example those of formula (I) wherein novel substituents are provided at the R4, R6, R7, R17$g(a) and/or R17$g(b) positions are useful for the treatment of diseases whose progress is aided by activation of androgen receptors, e.g., prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia and the like.(FR) Des inhibiteurs de l'activité de la testosérone 5$g(a)-réductase, par exemple ceux répondant à la formule (I) dans laquelle de nouveaux substituants sont prévus au niveau des positions R4, R6, R7, R17$g(a) et/ou R17$g(b), peuvent être utilisés pour le traitement de maladies dont la progression est favorisée par l'activation de récepteurs d'androgène, telles que le cancer de la prostate, l'hyperplasie prostatique bénigne, l'acné, la séborrhée, l'hirsutisme, l'alopécie androgène et les maladies analogues.
• 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).