N-(2-(4-benzyl-4-(dimethylamino)piperidin-1-yl)-4-(trifluoromethyl)benzyl)-2-(3-fluoro-4-(methylsulfonamido)phenyl)propanamide | 1020724-99-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-(2-(4-benzyl-4-(dimethylamino)piperidin-1-yl)-4-(trifluoromethyl)benzyl)-2-(3-fluoro-4-(methylsulfonamido)phenyl)propanamide
• 英文别名: N-[[2-[4-benzyl-4-(dimethylamino)piperidin-1-yl]-4-(trifluoromethyl)phenyl]methyl]-2-[3-fluoro-4-(methanesulfonamido)phenyl]propanamide
• CAS: 1020724-99-5
• 化学式: C₃₂H₃₈F₄N₄O₃S
• 分子量: 634.738
• InChiKey: PDAXSLZUMLDCAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  90.1
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  tert-butyl 4-cyano-4-(dimethylamino)piperidine-1-carboxylate 在 dimethyl sulfide borane 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙腈 为溶剂， 反应 48.0h， 生成 N-(2-(4-benzyl-4-(dimethylamino)piperidin-1-yl)-4-(trifluoromethyl)benzyl)-2-(3-fluoro-4-(methylsulfonamido)phenyl)propanamide
  参考文献：
  名称：

  Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain

  摘要：

  In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo, 49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111634

文献信息

• VR1 Receptor Ligands and u-Opioid Receptor Ligands for the Treatment of Pain
  申请人：KOEGEL Babette-Yvonne

  公开号：US20090286831A1

  公开（公告）日：2009-11-19

  A pharmaceutical composition comprising i) at least one composition that has affinity to the μ-opioid receptor, and at least one compound that has affinity to the VR1 receptor, or ii) at least one compound, in particular at least one compound corresponding to formula (I), (II), (III), (IV) or (V), that has affinity to the μ-opioid receptor and to the VR1 receptor, and also to the use of the pharmaceutical compositions i) and ii) for the production of a drug for the treatment of pain.

  一种药物组合物，包括i) 至少一种具有与μ-阿片受体亲和力的组合物，和至少一种具有与VR1受体亲和力的化合物，或者ii) 至少一种化合物，特别是至少一种与公式(I)、(II)、(III)、(IV)或(V)相对应的化合物，该化合物具有与μ-阿片受体和VR1受体的亲和力，以及将药物组合物i)和ii)用于制备用于治疗疼痛的药物的用途。
• VR1-REZEPTOR-LIGANDEN UND µ-OPIOID-REZEPTOR-LIGANDEN ZUR BEHANDLUNG VON SCHMERZ
  申请人：Grünenthal GmbH

  公开号：EP2083922A1

  公开（公告）日：2009-08-05
• [DE] VR1-REZEPTOR-LIGANDEN UND µ-OPIOID-REZEPTOR-LIGANDEN ZUR BEHANDLUNG VON SCHMERZ<br/>[EN] VR1 RECEPTOR LIGANDS AND µ OPIOID RECEPTOR LIGANDS FOR THE TREATMENT OF PAIN<br/>[FR] LIGANDS DU RÉCEPTEUR VR1 ET LIGANDS DU RÉCEPTEUR µ-OPIOÏDE POUR LE TRAITEMENT DE LA DOULEUR
  申请人：GRUENENTHAL GMBH

  公开号：WO2008046647A1

  公开（公告）日：2008-04-24

  [EN] The invention relates to a pharmaceutical composition comprising: i) at least one compound which has affinity for the µ opioid receptor, and at least one compound which has affinity for the VR1 receptor, or ii) at least one compound of the general formulae (I), (II), (III), (IV) or (V) which has affinity for the µ opioid receptor and for the VR1 receptor, and to the use of the pharmaceutical compositions (i) and (ii) for the manufacture of a medicament for the treatment of pain.
  [FR] L'invention concerne une préparation pharmaceutique comprenant: i) au moins un composé présentant une affinité pour le récepteur µ-opioïde et au moins un composé présentant une affinité pour le récepteur VR1, ou ii) au moins un composé de formule générale (I), (II), (III), (IV) ou (V) présentant une affinité pour le récepteur µ-opioïde et pour le récepteur VR1. Elle concerne également l'utilisation des compositions pharmaceutiques (i) et (ii) pour préparer un médicament destiné au traitement de la douleur.
  [DE] Die Erfindung betrifft eine pharmazeutische Zusammensetzung umfassend: i) wenigstens eine Verbindung, die Affinität zum µ-Opioid-Rezeptor aufweist, und wenigstens eine Verbindung, die Affinität zum VR1-Rezeptor aufweist oder ii) wenigstens eine Verbindung der allgemeinen Formeln (I), (II), (III), (IV) oder (V), die Affinität zum µ-Opioid-Rezeptor und zum VR1-Rezeptor aufweist, sowie die Verwendung der pharmazeutischen Zusammensetzungen (i) und (ii) zur Herstellung eines Arzneimittels zur Behandlung von Schmerz.
• Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain
  作者：Hobin Lee、Songyeon Ahn、Jihyae Ann、Heejin Ha、Young Dong Yoo、Young Ho Kim、Ji-Young Hwang、Kwang-Hyun Hur、Choon-Gon Jang、Larry V. Pearce、Timothy E. Esch、Nancy E. Lewin、Peter M. Blumberg、Jeewoo Lee

  DOI：10.1016/j.ejmech.2019.111634

  日期：2019.11

  In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo, 49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic. (C) 2019 Elsevier Masson SAS. All rights reserved.