ethyl 5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]pyridine-2-carboxylate | 1192603-03-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ethyl 5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]pyridine-2-carboxylate
• CAS: 1192603-03-4
• 化学式: C₂₀H₂₀ClN₃O₃
• 分子量: 385.85
• InChiKey: QTKQUYBJWCVJLC-RBZFPXEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  86.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]pyridine-2-carboxylate 在 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]-N-methylpyridine-2-carboxamide
  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：

  2-氯-4-氟苯腈 在 1,1'-双(二苯基膦)二茂铁 、 正丁基锂 、 sodium bis(2-methoxyethoxy)aluminum dihydride 、 palladium diacetate 、 三氧化硫吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 37.5h， 生成 ethyl 5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-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

文献信息

• [EN] SUBSTITUTED PYRROLIDINE DERIVATIVE AND USE THEREOF<br/>[FR] DÉRIVÉ DE PYRROLIDINE SUBSTITUÉE ET SES UTILISATIONS
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2009131196A1

  公开（公告）日：2009-10-29

  　式（Ｉ）〔式中、Ｒ１は置換基を有していてもよいシアノフェニル；Ｒ２はＨまたはＣ１－６アルキル；Ｒ３はＨ；Ｒ４は置換基を有していてもよい芳香環基、－ＮＲａ－Ｘ－（ＣＨ２）ｎ－Ｙ－Ｒｂ（式中、ＲａはＨまたはＣ１－６アルキル；Ｘは結合手、－ＣＯ－、－ＣＯＮＨ－または－ＳＯ２－；ｎは０ないし３の整数；Ｙは結合手、－Ｏ－、－ＮＨ－、－ＮＨＣＯ－、－ＮＨＳＯ２－または－ＣＨ＝ＣＨ－；Ｒｂは置換基を有していてもよい環状基を示す。）、または－Ｏ－Ｚ－Ｒｃ（式中、Ｚは結合手、－ＣＨ２－または－ＣＯＮＨ－；Ｒｃは置換基を有していてもよい環状基を示す。）；Ｒ５はＨ、ヒドロキシまたは置換基を有していてもよいＣ１－６アルコキシ；Ｒ６～Ｒ９はＨ、ハロゲン原子、炭素原子を介する基、窒素原子を介する基、酸素原子を介する基または硫黄原子を介する基を示す。〕で表される化合物またはその塩。
• Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists
  作者：Satoshi Yamamoto、Hiromi Kobayashi、Tomohiro Kaku、Katsuji Aikawa、Takahito Hara、Masuo Yamaoka、Naoyuki Kanzaki、Atsushi Hasuoka、Atsuo Baba、Mitsuhiro Ito

  DOI：10.1016/j.bmc.2012.11.001

  日期：2013.1

  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.