methyl 4-[N-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate | 441769-41-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: methyl 4-[N-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
• 英文别名: rac-tert-Butyl (2R,4S)-4-hydroxy-2-(((4-(methoxycarbonyl)cyclohexyl)oxy)methyl)pyrrolidine-1-carboxylate, AldrichCPR；tert-butyl (2S,4R)-4-hydroxy-2-[(4-methoxycarbonylcyclohexyl)oxymethyl]pyrrolidine-1-carboxylate
• CAS: 441769-41-1
• 化学式: C₁₈H₃₁NO₆
• 分子量: 357.447
• InChiKey: QFDFYKWVQMGLTE-RAFNIBEQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  85.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  苄基氯甲基醚 、 methyl 4-[N-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 17.0h， 以79%的产率得到methyl 4-[(4R)-benzyloxymethoxy-N-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
  参考文献：
  名称：

  Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist

  摘要：

  We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexinecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

  DOI：

  10.1021/jm901154c
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 methyl 4-[(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以100%的产率得到methyl 4-[N-(tert-butoxycarbonyl)-(4R)-hydroxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate
  参考文献：
  名称：

  Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist

  摘要：

  We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexinecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

  DOI：

  10.1021/jm901154c

文献信息

• Discovery of <i>trans</i>-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4<i>S</i>)-methoxy-(2<i>S</i>)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist
  作者：Fumihito Muro、Shin Iimura、Yuuichi Sugimoto、Yoshiyuki Yoneda、Jun Chiba、Toshiyuki Watanabe、Masaki Setoguchi、Yutaka Iigou、Keiko Matsumoto、Atsushi Satoh、Gensuke Takayama、Tomoe Taira、Mika Yokoyama、Tohru Takashi、Atsushi Nakayama、Nobuo Machinaga

  DOI：10.1021/jm901154c

  日期：2009.12.24

  We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexinecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.