methyl trans-4-[1-[[7-fluoro-2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetyl]-(5S)-methylthiomethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate | 1416961-28-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: methyl trans-4-[1-[[7-fluoro-2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetyl]-(5S)-methylthiomethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
• CAS: 1416961-28-8
• 化学式: C₃₁H₃₇F₂N₃O₅S
• 分子量: 601.715
• InChiKey: HQRAYVVZMIOTJJ-HCUBDLJJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.17
• 重原子数：
  42.0
• 可旋转键数：
  10.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  93.9
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  methyl trans-4-[1-[[7-fluoro-2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetyl]-(5S)-methylthiomethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以100%的产率得到methyl trans-4-[1-[[7-fluoro-2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetyl]-(5S)-methanesulfonylmethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
  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：

  methyl trans-4-[1-tert-butoxycarbonyl-(5S)-hydroxymethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 在 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 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 methyl trans-4-[1-[[7-fluoro-2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetyl]-(5S)-methylthiomethyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
  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