N-{(1S)-1-[[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]-methyl]-2-methylpropyl}-5-phenoxypyridine-2-carboxamide | 1436378-76-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-{(1S)-1-[[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]-methyl]-2-methylpropyl}-5-phenoxypyridine-2-carboxamide
• 英文别名: N-[(2S)-1-[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]-3-methylbutan-2-yl]-6-phenoxypyridine-3-carboxamide
• CAS: 1436378-76-5
• 化学式: C₂₈H₃₄N₄O₃
• 分子量: 474.603
• InChiKey: WDCWWUWEPQIEKL-HFZDXXHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  77.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-苯氧基烟酸甲酯 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙腈 为溶剂， 反应 12.0h， 生成 N-{(1S)-1-[[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]-methyl]-2-methylpropyl}-5-phenoxypyridine-2-carboxamide
  参考文献：
  名称：

  Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

  摘要：

  There is continuing interest in the discovery and development of new kappa opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [S-35]GTP gamma S binding assay showed that neither compound showed the high potency and kappa opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [S-35]GTP gamma S binding stimulated by the selective kappa opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyll-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good kappa opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [S-35]GTP gamma S binding assay showed that several of the analogues were potent and selective kappa opioid receptor antagonists.

  DOI：

  10.1021/jm400275h

文献信息

• 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。
• US9512105B2
  申请人：——

  公开号：US9512105B2

  公开（公告）日：2016-12-06
• [EN] 1-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS<br/>[FR] 4-ARYLPIPÉRAZINE 1-SUBSTITUÉ À TITRE D'ANTAGONISTE DU RÉCEPTEUR OPIOÏDE KAPPA
  申请人：RES TRIANGLE INST

  公开号：WO2013086496A2

  公开（公告）日：2013-06-13

  Provided are compounds represented by the formula: where R, Y3, R1,R2, R3, R4, R6, G, R7, E1, E2, A, B, W, X, Y and Z are as defined herein.
• Discovery of <i>N</i>-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists
  作者：Chad M. Kormos、Chunyang Jin、Juan Pablo Cueva、Scott P. Runyon、James B. Thomas、Lawrence E. Brieaddy、S. Wayne Mascarella、Hernán A. Navarro、Brian P. Gilmour、F. Ivy Carroll

  DOI：10.1021/jm400275h

  日期：2013.6.13

  There is continuing interest in the discovery and development of new kappa opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [S-35]GTP gamma S binding assay showed that neither compound showed the high potency and kappa opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [S-35]GTP gamma S binding stimulated by the selective kappa opioid agonist U69,593. These studies led to N-[(1S)-1-[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyll-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good kappa opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [S-35]GTP gamma S binding assay showed that several of the analogues were potent and selective kappa opioid receptor antagonists.