3-氟-4-[4-[[(2S)-2-(3-氟苯基)吡咯烷-1-基]甲基]苯氧基]苯甲酰胺 | 1346133-11-6

• 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: 3-氟-4-[4-[[(2S)-2-(3-氟苯基)吡咯烷-1-基]甲基]苯氧基]苯甲酰胺
• 英文名称: LY2444296
• 英文别名: (S) 3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide；(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide；3-fluoro-4-[4-[[(2S)-2-(3-fluorophenyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide
• CAS: 1346133-11-6
• 化学式: C₂₄H₂₂F₂N₂O₂
• 分子量: 408.448
• InChiKey: WHHMECUDUQRPJT-QFIPXVFZSA-N

物化性质

• 沸点：
  491.6±45.0 °C(Predicted)
• 密度：
  1.276±0.06 g/cm3(Predicted)
• 溶解度：
  乙醇：27.5mg/mL（67.33mM）；甲醇：5 mg/mL (12.24 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

LY2444296 是一种具有口服生物活性、高亲和力且选择性的短效 KOPR 拮抗剂，其 Ki 值约为 1 nM。该化合物表现出类似抗焦虑的效果。

靶点

• Ki: ~1 nM (KOPR)

体内研究

LY2444296 在 EPM 测试中显示出抗焦虑样的作用。

• LY2444296（3 mg/kg；腹腔注射，给药前30分钟）可防止参考 κ 激动剂 U69,593 引起的行为和神经内分泌效应，在初次接触可卡因的实验动物中表现尤为显著。
• 在慢性扩展获取自体给予可卡因后测试焦虑样及抑郁样行为，以及皮质醇释放时，LY2444296 减轻了这些症状。然而，对于初次接触可卡因的动物则没有此效果。

具体实验数据如下：

动物模型	成年雄性 SD 猴鼠（体重 240–250 g）
剂量	3 mg/kg
给药方式	腹腔注射，给药前30分钟
结果	预防了 U69,593 引起的行为和神经内分泌效应。

反应信息

• 作为产物：
  描述：

  间溴氟苯 在 碘 、 magnesium 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， -78.0~30.0 ℃ 、1.01 MPa 条件下， 反应 36.0h， 生成 3-氟-4-[4-[[(2S)-2-(3-氟苯基)吡咯烷-1-基]甲基]苯氧基]苯甲酰胺
  参考文献：
  名称：

  通过分子内还原胺化对映选择性直接合成游离环胺

  摘要：

  可以通过一锅法通过N -Boc保护的氨基酮的分子内还原胺化来制备手性环胺。用铱和f-spiroPhos的配合物作为催化剂，可将一系列N -Boc保护的氨基酮顺利地转化为手性环状游离胺，产率高，对映选择性高（ee高达97％）。而且，该方法也可以成功地应用于κ-阿片受体选择性拮抗剂（S）-1的合成。

  DOI：

  10.1021/acs.orglett.7b01828

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。
• 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.
• [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.
• Enantioselective Direct Synthesis of Free Cyclic Amines via Intramolecular Reductive Amination
  作者：Ying Zhang、Qiaozhi Yan、Guofu Zi、Guohua Hou

  DOI：10.1021/acs.orglett.7b01828

  日期：2017.8.18

  intramolecular reductive amination of N-Boc-protected amino ketones in a one-pot process. With the complex of iridium and f-spiroPhos as the catalyst, a range of N-Boc-protected amino ketones are smoothly transformed into chiral cyclic free amines in high yields and excellent enantioselectivities (up to 97% ee). Moreover, this method can also be successfully applied to the synthesis of a κ-opioid receptor

  可以通过一锅法通过N -Boc保护的氨基酮的分子内还原胺化来制备手性环胺。用铱和f-spiroPhos的配合物作为催化剂，可将一系列N -Boc保护的氨基酮顺利地转化为手性环状游离胺，产率高，对映选择性高（ee高达97％）。而且，该方法也可以成功地应用于κ-阿片受体选择性拮抗剂（S）-1的合成。