(S)-4-(4-((2-(3,5-二甲基苯基)吡咯烷-1-基)甲基)苯氧基)-3-氟苯甲酰胺 | 1174130-61-0

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (S)-4-(4-((2-(3,5-二甲基苯基)吡咯烷-1-基)甲基)苯氧基)-3-氟苯甲酰胺
• 英文名称: JSPA06508
• 英文别名: 4-[4-[[ (2S)-2-(3,5-dimethylphenyl)pyrrolidin-1-yl]methyl]phenoxy]-3-fluorobenzamide；(S)-4-(4-((2-(3,5-dimethylphenyl)-pyrrolidin-1-yl)methyl)phenoxy)-3-fluorobenzamide；(S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide；(S)-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3-fluorobenzamide；JNJ-67953964；LY2456302；4-[4-[[(2S)-2-(3,5-dimethylphenyl)pyrrolidin-1-yl]methyl]phenoxy]-3-fluorobenzamide
• CAS: 1174130-61-0
• 化学式: C₂₆H₂₇FN₂O₂
• 分子量: 418.511
• InChiKey: ZHPMYDSXGRRERG-DEOSSOPVSA-N

物化性质

• 沸点：
  519.2±50.0 °C(Predicted)
• 密度：
  1.201±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：1mg/mL； DMSO：5mg/mL；乙醇：3mg/mL； PBS (pH 7.2)：不溶

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 储存条件：
  -20°C，密封保存，置于干燥处。

制备方法与用途

LY-2456302是一种有效且能够穿透中枢神经系统的κ-opioid受体拮抗剂，其Ki值为0.807纳摩尔。

反应信息

• 作为产物：
  描述：

  对羟基苯甲醛 在 双氧水 、 potassium carbonate 作用下， 以 水 、 二甲基亚砜 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 (S)-4-(4-((2-(3,5-二甲基苯基)吡咯烷-1-基)甲基)苯氧基)-3-氟苯甲酰胺
  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。
• KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST
  申请人：Buezo Nuria Diaz

  公开号：US20090186873A1

  公开（公告）日：2009-07-23

  A selective kappa opioid receptor antagonist useful for treating ethanol use disorder withdrawal and anxiety, and/or depression, or schizophrenia as independent comorbid conditions.

  一种选择性kappa阿片受体拮抗剂，可用于治疗乙醇使用障碍的戒断症状、焦虑症、抑郁症，或作为独立的并发症治疗精神分裂症。
• 1-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：US20150005315A1

  公开（公告）日：2015-01-01

  Provided are compounds represented by the formula: where R, Y 3 , R 1 , R 2 , R 3 , R 4 , R 6 , G, R 7 , E 1 , E 2 , A, B, W, X, Y and Z are as defined herein.

  提供的化合物由以下公式表示：其中R，Y3，R1，R2，R3，R4，R6，G，R7，E1，E2，A，B，W，X，Y和Z的定义如下。
• 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。
• Use of an opioid receptor antagonist with kappa-activity and vortioxetine for treatment of depressive disorder with melancholic features
  申请人：H. Lundbeck A/S

  公开号：US10376506B2

  公开（公告）日：2019-08-13

  The present invention relates to an opioid antagonist with κ-activity for use in treatment of depressive disorder with melancholic features. The invention further relates to the combination of an opioid antagonist with κ-activity and vortioxetine for use in treatment of depressive disorder with melancholic features. The invention also relates to pharmaceutical compositions comprising an opioid antagonist with κ-activity and vortioxetine.

  本发明涉及一种具有κ活性的阿片拮抗剂，用于治疗具有忧郁特征的抑郁障碍。本发明进一步涉及一种具有κ活性的阿片拮抗剂与伏替西汀的组合，用于治疗具有忧郁特征的抑郁障碍。本发明还涉及由具有κ活性的阿片拮抗剂和伏替西汀组成的药物组合物。