ethyl (3R)-1-(2'-chloro-11'-oxo-11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)-3-piperidinecarboxylate | 1254542-65-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: ethyl (3R)-1-(2'-chloro-11'-oxo-11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)-3-piperidinecarboxylate
• CAS: 1254542-65-8
• 化学式: C₂₆H₂₈ClNO₄
• 分子量: 453.966
• InChiKey: RIMDLDLEEDJOGB-MCPCIJHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.39
• 重原子数：
  32.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  55.84
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  ethyl (3R)-1-(2'-chloro-11'-oxo-11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)-3-piperidinecarboxylate 在 水 、 potassium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 1.0h， 以21.3 mg的产率得到(3R)-1-(2'-chloro-11'-oxo-11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)-3-piperidinecarboxylic acid hydrochloride
  参考文献：
  名称：

  Novel Spirotetracyclic Zwitterionic Dual H₁/5-HT_2A Receptor Antagonists for the Treatment of Sleep Disorders

  摘要：

  Histamine H-1 and serotonin 5-HT2A receptors mediate two different mechanisms involved in sleep regulation: H-1 antagonists are sleep inducers, while 5-HT2A antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H-1/5-HT2A potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H-1/5-HT2A activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

  DOI：

  10.1021/jm100856p
• 作为产物：
  描述：

  2'-chloro-3H,11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3,11'-dione 、 (R)-3-哌啶甲酸乙酯 在 溶剂黄146 、 三乙酰氧基硼氢化钠 、 碳酸氢钠 作用下， 以 1,2-二氯乙烷 、 二氯甲烷 为溶剂， 以90 mg的产率得到ethyl (3R)-1-(2'-chloro-11'-oxo-11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)-3-piperidinecarboxylate
  参考文献：
  名称：

  Novel Spirotetracyclic Zwitterionic Dual H₁/5-HT_2A Receptor Antagonists for the Treatment of Sleep Disorders

  摘要：

  Histamine H-1 and serotonin 5-HT2A receptors mediate two different mechanisms involved in sleep regulation: H-1 antagonists are sleep inducers, while 5-HT2A antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H-1/5-HT2A potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H-1/5-HT2A activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

  DOI：

  10.1021/jm100856p