2-(3,4-dichlorophenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2,N-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butyramide | 1131738-29-8

• 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: 2-(3,4-dichlorophenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2,N-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butyramide
• 英文别名: 2-(3,4-dichlorophenyl)-N-(4-fluoro-3-trifluoromethylbenzyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide；2-(3,4-dichlorophenyl)-N-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butanamide
• CAS: 1131738-29-8
• 化学式: C₂₉H₃₃Cl₂F₄N₃O₂
• 分子量: 602.5
• InChiKey: XNEWLEJBYAVWCK-UHFFFAOYSA-N

物化性质

• 沸点：
  685.4±55.0 °C(predicted)
• 密度：
  1.321±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  43.9
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(3,4-dichlorophenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2,N-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butyramide 在 盐酸 作用下， 生成 (2S)-2-(3,4-dichlorophenyl)-N-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butanamide;hydrochloride 、 (2R)-2-(3,4-dichlorophenyl)-N-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-N,2-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butanamide;hydrochloride
  参考文献：
  名称：

  PIPERIDINE DERIVATIVES AS NK3 ANTAGONISTS

  摘要：

  该发明涉及一种化合物，其化学式为Ar1、Ar2、R1、R2、R3、R4、R5和R5′，或其药用活性盐。这些化合物是用于治疗抑郁症、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动障碍（ADHD）的高潜力NK-3受体拮抗剂。

  公开号：

  US20090076081A1
• 作为产物：
  描述：

  (3-fluoro-4-(trifluoromethyl)benzyl)methylamine, hydrochloride 、 2-(3,4-dichlorophenyl)-2-methyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butyric acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 以69%的产率得到2-(3,4-dichlorophenyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2,N-dimethyl-4-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]butyramide
  参考文献：
  名称：

  Identification of a Critical Residue in the Transmembrane Domain 2 of Tachykinin Neurokinin 3 Receptor Affecting the Dissociation Kinetics and Antagonism Mode of Osanetant (SR 142801) and Piperidine-Based Structures

  摘要：

  In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr 139(2.58) in human, corresponding to Ala 114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).

  DOI：

  10.1021/jm900948q

文献信息

• PIPERIDINE DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS
  申请人：F. Hoffmann-La Roche AG

  公开号：EP2200982B1

  公开（公告）日：2012-03-14
• [EN] PIPERIDINE DERIVATIVES AS NK3 RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS DE PIPÉRIDINE EN TANT QU'ANTAGONISTES DU RÉCEPTEUR NK3
  申请人：HOFFMANN LA ROCHE

  公开号：WO2009033995A1

  公开（公告）日：2009-03-19

  The invention relates to a compound of general formula (I) wherein Ar1/Ar2 are independently from each other phenyl or pyridinyl, which are optionally substituted by one or two substituents, selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by alkoxy, lower alkyl substituted by cyano, lower di-alkyl amino, pyridinyl or cyano; R1 is hydrogen, lower alkyl, -(CH2)2O-lower alkyl, or cycloalkyl: R2 is -S(O)2-lower alkyl or -C(O) -lower alkyl; or R1 and R2 form together with the N-atom to which they are attached a pyrrolidin-2- one or a piperidin-2-one group; R3 is hydrogen, halogen or lower alkyl; R4 is hydrogen or lower alkyl; R5/R5' are independently from each other hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or cycloalkyl; or R5 and R5' form together with the carbon-atom to which they are attached a cycloalkyl group; or to a pharmaceutically active salt thereof. It has been found that the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
• PIPERIDINE DERIVATIVES AS NK3 ANTAGONISTS
  申请人：Knust Henner

  公开号：US20090076081A1

  公开（公告）日：2009-03-19

  The invention relates to a compound of formula wherein Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 5′ or to a pharmaceutically active salt thereof. The compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

  该发明涉及一种化合物，其化学式为Ar1、Ar2、R1、R2、R3、R4、R5和R5′，或其药用活性盐。这些化合物是用于治疗抑郁症、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动障碍（ADHD）的高潜力NK-3受体拮抗剂。
• Identification of a Critical Residue in the Transmembrane Domain 2 of Tachykinin Neurokinin 3 Receptor Affecting the Dissociation Kinetics and Antagonism Mode of Osanetant (SR 142801) and Piperidine-Based Structures
  作者：Pari Malherbe、Claudia Kratzeisen、Anne Marcuz、Marie-Thérèse Zenner、Matthias H. Nettekoven、Hasane Ratni、Joseph G. Wettstein、Caterina Bissantz

  DOI：10.1021/jm900948q

  日期：2009.11.26

  In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr 139(2.58) in human, corresponding to Ala 114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).