3-chloro-4-[4-[ [2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide | 1346133-07-0

• 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: 3-chloro-4-[4-[ [2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide
• 英文别名: 3-chloro-4-[4-[[(2S)-2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide；3-chloro-4-[4-[(2-pyridin-3-ylpyrrolidin-1-yl)methyl]phenoxy]benzamide
• CAS: 1346133-07-0
• 化学式: C₂₃H₂₂ClN₃O₂
• 分子量: 407.9
• InChiKey: LOOCZNLSXJHWTG-UHFFFAOYSA-N

物化性质

• 沸点：
  532.4±50.0 °C(Predicted)
• 密度：
  1.287±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  68.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-chloro-4-[4-[ [2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide 在 Chiralpak AS-H 作用下， 以 甲醇 、 二甲基十二/十四烷基叔胺 为溶剂， 以40%的产率得到LY2795050(S型)
  参考文献：
  名称：

  Discovery of Aminobenzyloxyarylamides as κ Opioid Receptor Selective Antagonists: Application to Preclinical Development of a κ Opioid Receptor Antagonist Receptor Occupancy Tracer

  摘要：

  Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for K opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyppyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K-i = 0.565 nM for kappa opioid receptor binding while having a K-i = 35.8 nM for mu opioid receptors and a K-i = 211 nM for delta opioid receptor binding. Compound 25 was also a potent antagonist of K opioid receptors when tested in vitro using a [S-35]-guanosine 5'O-[3-thiotriphosphate] ([S-35]GTP-gamma-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl(pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.

  DOI：

  10.1021/jm200789r
• 作为产物：
  描述：

  3-chloro-4-(4-formylphenoxy)benzonitrile 在 双氧水 作用下， 以 水 、 二甲基亚砜 、 1,2-二氯乙烷 为溶剂， 反应 5.0h， 生成 3-chloro-4-[4-[ [2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide
  参考文献：
  名称：

  Discovery of Aminobenzyloxyarylamides as κ Opioid Receptor Selective Antagonists: Application to Preclinical Development of a κ Opioid Receptor Antagonist Receptor Occupancy Tracer

  摘要：

  Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for K opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyppyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K-i = 0.565 nM for kappa opioid receptor binding while having a K-i = 35.8 nM for mu opioid receptors and a K-i = 211 nM for delta opioid receptor binding. Compound 25 was also a potent antagonist of K opioid receptors when tested in vitro using a [S-35]-guanosine 5'O-[3-thiotriphosphate] ([S-35]GTP-gamma-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl(pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.

  DOI：

  10.1021/jm200789r

文献信息

• HETEROARYLPHENOXY BENZAMIDE KAPPA OPIOID LIGANDS
  申请人：Pfizer Inc.

  公开号：US20180148432A1

  公开（公告）日：2018-05-31

  The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof wherein the variables R 1 , R 2 , R 3 , R 4 , R 9 , X, m and n are as defined herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating kappa opioid (κ-opioid) associated disorders including, e.g., a neurological disorder, or psychiatric disorder such as a neurocognitive disorder, substance abuse disorder, depressive disorder, anxiety disorder, trauma and stressor related disorder and feeding and eating disorder.

  本发明提供了Formula I的化合物及其药用盐，其中变量R1、R2、R3、R4、R9、X、m和n如本文所定义；制备方法；用于制备的中间体；含有这些化合物或盐的组合物，以及它们用于治疗κ-阿片受体相关疾病的用途，例如神经系统疾病，或精神障碍，如神经认知障碍、物质滥用障碍、抑郁障碍、焦虑障碍、创伤和应激相关障碍以及进食障碍。
• Heteroarylphenoxy benzamide kappa opioid ligands
  申请人：Pfizer Inc.

  公开号：US10316021B2

  公开（公告）日：2019-06-11

  The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof wherein the variables R1, R2, R3, R4, R9, X, m and n are as defined herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating kappa opioid (κ-opioid) associated disorders including, e.g., a neurological disorder, or psychiatric disorder such as a neurocognitive disorder, substance abuse disorder, depressive disorder, anxiety disorder, trauma and stressor related disorder and feeding and eating disorder.

  本发明提供了式 I 的化合物： 及其药学上可接受的盐，其中变量 R1、R2、R3、R4、R9、X、m 和 n 如本文所定义；制备工艺；制备工艺中使用的中间体；以及含有此类化合物或盐的组合物，及其用于治疗卡巴阿片（κ-阿片）相关紊乱的用途，例如包括神经紊乱或精神紊乱，如神经认知紊乱、药物滥用紊乱、抑郁紊乱、焦虑紊乱、创伤和应激相关紊乱以及进食和饮食紊乱。
• [EN] HETEROARYLPHENOXY BENZAMIDE KAPPA OPIOID LIGANDS<br/>[FR] LIGANDS OPIOÏDES KAPPA HÉTÉROARYLPHÉNOXY BENZAMIDE
  申请人：PFIZER

  公开号：WO2018096510A1

  公开（公告）日：2018-05-31

  The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof wherein the variables R1, R2, R3, R4, R9, X, m and n are as defined herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compound s or s al ts, an d thei r uses for treating kappa opioid (κ-opioid) associated disorders including, e.g., a neurological disorder, or psychiatric disorder such as a neurocognitive disorder, substance abuse disorder, depressive disorder, anxiety disorder, trauma and stressor related disorder and feeding and eating disorder.
• Discovery of Aminobenzyloxyarylamides as κ Opioid Receptor Selective Antagonists: Application to Preclinical Development of a κ Opioid Receptor Antagonist Receptor Occupancy Tracer
  作者：Charles H. Mitch、Steven J. Quimby、Nuria Diaz、Concepcion Pedregal、Marta G. de la Torre、Alma Jimenez、Qing Shi、Emily J. Canada、Steven D. Kahl、Michael A. Statnick、David L. McKinzie、Dana R. Benesh、Karen S. Rash、Vanessa N. Barth

  DOI：10.1021/jm200789r

  日期：2011.12.8

  Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for K opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyppyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K-i = 0.565 nM for kappa opioid receptor binding while having a K-i = 35.8 nM for mu opioid receptors and a K-i = 211 nM for delta opioid receptor binding. Compound 25 was also a potent antagonist of K opioid receptors when tested in vitro using a [S-35]-guanosine 5'O-[3-thiotriphosphate] ([S-35]GTP-gamma-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl(pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.