1-benzyloxycarbonyl-(3S)-methoxy-(2R)-pyrrolidinemethanol | 441717-58-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-benzyloxycarbonyl-(3S)-methoxy-(2R)-pyrrolidinemethanol
• 英文别名: 2-hydroxymethyl-3-methoxy-pyrrolidine-1-carboxylic acid benzyl ester；benzyl (2R,3S)-2-(hydroxymethyl)-3-methoxypyrrolidine-1-carboxylate
• CAS: 441717-58-4
• 化学式: C₁₄H₁₉NO₄
• 分子量: 265.309
• InChiKey: ORPZCOYFTHANCW-OLZOCXBDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-benzyloxycarbonyl-(3S)-methoxy-(2R)-pyrrolidinemethanol 在 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 Rh/Al₂O₃ 、 氢气 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 为溶剂， 反应 80.0h， 生成 methyl 4-[[(2R,3S)-3-methoxypyrrolidin-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
• 作为产物：
  描述：

  3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 在 dimethyl sulfide borane 、 甲醇 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以83%的产率得到1-benzyloxycarbonyl-(3S)-methoxy-(2R)-pyrrolidinemethanol
  参考文献：
  名称：

  [EN] IAP INHIBITORS
  [FR] INHIBITEURS DE PROTÉINES D'APOPTOSE

  摘要：

  本发明描述了以下式的化合物：它们的制备方法，含有它们的药物组合物，以及它们在治疗中的应用。本发明的化合物抑制IAPs（凋亡抑制蛋白），因此在癌症、自身免疫疾病和其他凋亡缺陷相关疾病的治疗中具有用处。

  公开号：

  WO2009094287A1

文献信息

• IAP INHIBITORS
  申请人：Condon Stephen M.

  公开号：US20110288116A1

  公开（公告）日：2011-11-24

  The present invention describes compounds of the following formula: processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. The compounds of the present invention inhibit IAPs (inhibitors of apoptosis proteins) and thus are useful in the treatment of cancer, autoimmune diseases and other disorders where a defect in apoptosis is implicated.

  本发明描述了以下式子的化合物：它们的制备过程、含有它们的药物组合物以及它们在治疗中的应用。本发明的化合物抑制IAPs（凋亡抑制蛋白），因此在治疗癌症、自身免疫性疾病和其他涉及凋亡缺陷的疾病中很有用。
• [EN] IAP INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉINES D'APOPTOSE
  申请人：TETRALOGIC PHARMACEUTICAL CORP

  公开号：WO2009094287A1

  公开（公告）日：2009-07-30

  The present invention describes compounds of the following formula: processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. The compounds of the present invention inhibit IAPs (inhibitors of apoptosis proteins) and thus are useful in the treatment of cancer, autoimmune diseases and other disorders where a defect in apoptosis is implicated.

  本发明描述了以下式的化合物：它们的制备方法，含有它们的药物组合物，以及它们在治疗中的应用。本发明的化合物抑制IAPs（凋亡抑制蛋白），因此在癌症、自身免疫疾病和其他凋亡缺陷相关疾病的治疗中具有用处。
• 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
  作者：Masaki Setoguchi、Shin Iimura、Yuuichi Sugimoto、Yoshiyuki Yoneda、Jun Chiba、Toshiyuki Watanabe、Fumihito Muro、Yutaka Iigo、Gensuke Takayama、Mika Yokoyama、Tomoe Taira、Misato Aonuma、Tohru Takashi、Atsushi Nakayama、Nobuo Machinaga

  DOI：10.1016/j.bmc.2012.11.003

  日期：2013.1

  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.