ethyl (1S,4r)-4-(((2S,5S)-5-(morpholinomethyl)pyrrolidin-2-yl)methoxy)cyclohexane-1-carboxylate | 877758-78-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: ethyl (1S,4r)-4-(((2S,5S)-5-(morpholinomethyl)pyrrolidin-2-yl)methoxy)cyclohexane-1-carboxylate
• CAS: 877758-78-6
• 化学式: C₁₉H₃₄N₂O₄
• 分子量: 354.49
• InChiKey: CTRCODBURMSBNW-XSLAGTTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.58
• 重原子数：
  25.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  60.03
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  ethyl (1S,4r)-4-(((2S,5S)-5-(morpholinomethyl)pyrrolidin-2-yl)methoxy)cyclohexane-1-carboxylate 在 水 、 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 、 sodium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 92.0h， 生成
  参考文献：
  名称：

  A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

  摘要：

  We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl) amino] methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 mu g/mL; JP2, 462 mu g/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.003
• 作为产物：
  描述：

  ethyl trans-4-[1-tert-butoxycarbonyl-(5S)-benzyloxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 在 盐酸 、 2,2,6,6-四甲基哌啶氧化物 、 三氯异氰尿酸 、 水 、 氢气 、 palladium(II) hydroxide 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 6.0h， 生成 ethyl (1S,4r)-4-(((2S,5S)-5-(morpholinomethyl)pyrrolidin-2-yl)methoxy)cyclohexane-1-carboxylate
  参考文献：
  名称：

  A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

  摘要：

  We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl) amino] methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 mu g/mL; JP2, 462 mu g/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.003