(3S)-4-[(4R)-7-cyano-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocin-2-yl]-3-(3,4-dichlorophenyl)butanoic acid | 367261-23-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (3S)-4-[(4R)-7-cyano-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocin-2-yl]-3-(3,4-dichlorophenyl)butanoic acid
• 英文别名: (3S)-4-[(13R)-9-cyano-13-methyl-16-oxo-12-oxa-15-azatricyclo[8.6.0.02,7]hexadeca-1(10),2,4,6,8-pentaen-15-yl]-3-(3,4-dichlorophenyl)butanoic acid
• CAS: 367261-23-2
• 化学式: C₂₆H₂₂Cl₂N₂O₄
• 分子量: 497.378
• InChiKey: YXUUGZCMQLNQIK-DNVCBOLYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  90.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S)-4-[(4R)-7-cyano-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocin-2-yl]-3-(3,4-dichlorophenyl)butanoic acid 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 (S)-4-((R)-6-Cyano-9-methyl-12-oxo-7,9,10,12-tetrahydro-8-oxa-11-aza-cycloocta[a]naphthalen-11-yl)-3-(3,4-dichloro-phenyl)-butyryl chloride
  参考文献：
  名称：

  Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

  摘要：

  We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.03.054
• 作为产物：
  描述：

  (R)-11-[(S)-2-(3,4-Dichloro-phenyl)-4-oxo-butyl]-9-methyl-12-oxo-9,10,11,12-tetrahydro-7H-8-oxa-11-aza-cycloocta[a]naphthalene-6-carbonitrile 在 jones reagent 作用下， 以 异丙醇 、 丙酮 为溶剂， 以97%的产率得到(3S)-4-[(4R)-7-cyano-4-methyl-1-oxo-1,3,4,6-tetrahydro-2H-naphtho[1,2-f][1,4]oxazocin-2-yl]-3-(3,4-dichlorophenyl)butanoic acid
  参考文献：
  名称：

  Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

  摘要：

  We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2004.03.054

文献信息

• Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties
  作者：Jeffrey S Albert、Cyrus Ohnmacht、Peter R Bernstein、William L Rumsey、David Aharony、Brian B Masek、Bruce T Dembofsky、Gerard M Koether、William Potts、John L Evenden

  DOI：10.1016/j.tet.2004.03.054

  日期：2004.5

  We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity. (C) 2004 Elsevier Ltd. All rights reserved.