benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate | 1030899-57-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate
• CAS: 1030899-57-0
• 化学式: C₁₃H₁₅NO₃
• 分子量: 233.267
• InChiKey: SXRCSLUPXCTDRP-JTQLQIEISA-N

物化性质

• 沸点：
  373.4±42.0 °C(Predicted)
• 密度：
  1.198±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate 在 正丁基锂 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 三乙胺 作用下， 以 乙醚 、 正己烷 为溶剂， 生成 methyl 5-{(2S,3R)-1-[(benzyloxy)carbonyl]-3-hydroxy-2-methylpyrrolidin-3-yl}pyridine-2-carboxylate
  参考文献：
  名称：

  Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists

  摘要：

  We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R-2) of the pyrrolidine ring increased the AR binding affinity. The (2S, 3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R-1) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.001
• 作为产物：
  描述：

  氯甲酸苄酯 在 四丙基高钌酸铵 、 sodium bis(2-methoxyethoxy)aluminum dihydride 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 甲苯 、 乙腈 为溶剂， 反应 42.0h， 生成 benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate
  参考文献：
  名称：

  Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists

  摘要：

  We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R-2) of the pyrrolidine ring increased the AR binding affinity. The (2S, 3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R-1) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.001

文献信息

• Cyclic amine compounds
  申请人：Hasuoka Atsushi

  公开号：US20090042967A1

  公开（公告）日：2009-02-12

  The present invention relates to pharmaceutical agents which are agents for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis; the pharmaceutical agents frailty suppressants, muscle strength enhancers, muscle increasing agents, cachexia suppressants, body weight decrease suppressants, agents for the prophylaxis or treatment of prostate hypertrophy, amyotrophy or muscle loss caused by a disease or an agent for reducing the prostate weight. The present invention also relates to methods for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis in a mammal, which comprises administering an effective amount of the pharmaceutical agents of the present invention or a prodrug thereof; use of the pharmaceutical agents of the present invention or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis; and the like.

  本发明涉及用于预防或治疗性腺功能减退症、男性更年期障碍、虚弱、消瘦或骨质疏松症的药物剂，其中包括虚弱抑制剂、肌肉力量增强剂、肌肉增长剂、消瘦抑制剂、体重减少抑制剂、用于预防或治疗前列腺肥大、肌萎缩或疾病引起的肌肉流失或降低前列腺重量的药物剂。本发明还涉及一种在哺乳动物中预防或治疗性腺功能减退症、男性更年期障碍、虚弱、消瘦或骨质疏松症的方法，包括向其投予本发明的药物剂或其前药的有效量；使用本发明的药物剂或其前药生产用于预防或治疗性腺功能减退症、男性更年期障碍、虚弱、消瘦或骨质疏松症的药物剂；等等。
• Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives
  作者：Moriteru Asano、Takenori Hitaka、Takashi Imada、Masami Yamada、Megumi Morimoto、Hiromi Shinohara、Takahito Hara、Masuo Yamaoka、Takashi Santou、Masaharu Nakayama、Yumi Imai、Noriyuki Habuka、Jason Yano、Keith Wilson、Hisashi Fujita、Atsushi Hasuoka

  DOI：10.1016/j.bmcl.2017.03.038

  日期：2017.5

  tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us

  我们最近报道了一类新型的组织选择性雄激素受体调节剂（SARMs），以萘衍生物A为代表。但是，由于代谢稳定性低，它们的药代动力学（PK）状况很差。为了改善PK谱，我们修饰了4-（吡咯烷-1-基）苄腈衍生物B的羟基吡咯烷和苄腈取代基，其效力与化合物A相当。这种优化使我们进行了进一步的修饰，从而改善了代谢稳定性同时保持有效的雄激素激动活性。在合成的化合物中，（2S，3S）-2，3-二甲基-3-羟基吡咯烷衍生物1c表现出合适的PK曲线和改善的代谢稳定性。在体内研究中，化合物1c在提肛肌中显示出显着的功效，而没有增加前列腺的重量。
• CYCLIC AMINE COMPOUND
  申请人：Hasuoka Atsushi

  公开号：US20100087506A1

  公开（公告）日：2010-04-08

  Provision of a compound having a superior androgen receptor regulating action. A compound represented by the formula (I) wherein R 1 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom; R 2 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom; R 3 is an electron-withdrawing group; R 4 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom; R 5 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom; R 6 is a hydrogen atom, a halogen atom, a group via a carbon atom, a group via a nitrogen atom, a group via an oxygen atom or a group via a sulfur atom; R 7 is alkyl optionally having substituent(s); R 8 is a hydrogen atom, alkyl optionally having substituent(s), alkenyl optionally having substituent(s) or cycloalkyl optionally having substituent(s); R 9 is a group via an oxygen atom; and ring A is a 5- or 6-membered ring optionally having substituent(s) other than R 6 to R 9 (excluding 2-chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-3-methylbenzonitrile, 2-chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile, 4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile, 2-chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-5-methylbenzonitrile, 2-chloro-3-ethyl-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile, 4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, 2,3-dichloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-5-methylbenzonitrile, 2,3-dichloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile, 4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-3-(trifluoromethyl)benzonitrile, 4-[(2S,3S)-3-hydroxy-2-isopropylpyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, 4-[(2S,3R)-3-hydroxy-2-isopropylpyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, and 2-chloro-4-[(2S)-3-hydroxy-2-methylpiperidin-1-yl]benzonitrile), or a salt thereof.

  提供具有优良雄激素受体调节作用的化合物。化合物由公式(I)表示，其中R1为氢原子、卤素原子、通过碳原子、氮原子、氧原子或硫原子连接的基团; R2为氢原子、卤素原子、通过碳原子、氮原子、氧原子或硫原子连接的基团; R3为电子吸引基团; R4为氢原子、卤素原子、通过碳原子、氮原子、氧原子或硫原子连接的基团; R5为氢原子、卤素原子、通过碳原子、氮原子、氧原子或硫原子连接的基团; R6为氢原子、卤素原子、通过碳原子、氮原子、氧原子或硫原子连接的基团; R7为可选带有取代基的烷基; R8为氢原子、可选带有取代基的烷基、烯基或环烷基; R9为通过氧原子连接的基团; 环A为5-或6-成员环，可选带有R6到R9之外的取代基团（不包括2-氯-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]-3-甲基苯甲腈、2-氯-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]苯甲腈、4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]苯甲腈、2-氯-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]-5-甲基苯甲腈、2-氯-3-乙基-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]苯甲腈、4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]-2-(三氟甲基)苯甲腈、2,3-二氯-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]-5-甲基苯甲腈、2,3-二氯-4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]苯甲腈、4-[(2S,3S)-3-羟基-2-甲基吡咯烷-1-基]-3-(三氟甲基)苯甲腈、4-[(2S,3S)-3-羟基-2-异丙基吡咯烷-1-基]-2-(三氟甲基)苯甲腈、4-[(2S,3R)-3-羟基-2-异丙基吡咯烷-1-基]-2-(三氟甲基)苯甲腈和2-氯-4-[(2S)-3-羟基-2-甲基哌啶-1-基]苯甲腈）或其盐。
• PYRROLIDIN-2-ONE DERIVATIVES AS ANDROGEN RECEPTOR MODULATOR
  申请人：Hasuoka Atsushi

  公开号：US20110098336A1

  公开（公告）日：2011-04-28

  A compound represented by the formula (I) according to claim 1 or a salt thereof has a superior androgen receptor modulating action.

  根据权利要求1所述的公式（I）代表的化合物或其盐具有优异的雄激素受体调节作用。
• Cyclic amine compound
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08013008B2

  公开（公告）日：2011-09-06

  A compound represented by the formula (I) each symbol of which is defined in the specification, or a salt thereof which has a superior androgen receptor regulating activity.

  化合物(I)的化学式由规范中定义的每个符号表示，或其盐，具有优越的雄激素受体调节活性。