1-(2,5-difluoro-4-(8-azaspiro[bicyclo[3.2.1]octane-3,2'-[1,3]dioxolane]-8-yl)benzyl)-3-(1H-indazol-4-yl)urea | 946388-23-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(2,5-difluoro-4-(8-azaspiro[bicyclo[3.2.1]octane-3,2'-[1,3]dioxolane]-8-yl)benzyl)-3-(1H-indazol-4-yl)urea
• CAS: 946388-23-4
• 化学式: C₂₄H₂₅F₂N₅O₃
• 分子量: 469.491
• InChiKey: BFWAWXBJKZRNRK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.04
• 重原子数：
  34.0
• 可旋转键数：
  4.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  91.51
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  1-(2,5-difluoro-4-(8-azaspiro[bicyclo[3.2.1]octane-3,2'-[1,3]dioxolane]-8-yl)benzyl)-3-(1H-indazol-4-yl)urea 在 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以99%的产率得到1-(2,5-difluoro-4-(3-oxo-8-azaspiro[bicyclo[3.2.1]octan-8-yl])benzyl)-3-(1H-indazol-4-yl)urea
  参考文献：
  名称：

  In Vitro Structure−Activity Relationship and In Vivo Characterization of 1-(Aryl)-3-(4-(amino)benzyl)urea Transient Receptor Potential Vanilloid 1 Antagonists

  摘要：

  The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.

  DOI：

  10.1021/jm070276i
• 作为产物：
  描述：

  N-乙氧羰基-4-托品酮 在 氢氧化钾 、 sodium hydroxide 、 硼烷四氢呋喃络合物 、 对甲苯磺酸 、 一水合肼 、 乙二醇 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 25.0h， 生成 1-(2,5-difluoro-4-(8-azaspiro[bicyclo[3.2.1]octane-3,2'-[1,3]dioxolane]-8-yl)benzyl)-3-(1H-indazol-4-yl)urea
  参考文献：
  名称：

  In Vitro Structure−Activity Relationship and In Vivo Characterization of 1-(Aryl)-3-(4-(amino)benzyl)urea Transient Receptor Potential Vanilloid 1 Antagonists

  摘要：

  The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.

  DOI：

  10.1021/jm070276i

文献信息

• In Vitro Structure−Activity Relationship and In Vivo Characterization of 1-(Aryl)-3-(4-(amino)benzyl)urea Transient Receptor Potential Vanilloid 1 Antagonists
  作者：Richard J. Perner、Stanley DiDomenico、John R. Koenig、Arthur Gomtsyan、Erol K. Bayburt、Robert G. Schmidt、Irene Drizin、Guo Zhu Zheng、Sean C. Turner、Tammie Jinkerson、Brian S. Brown、Ryan G. Keddy、Kurill Lukin、Heath A. McDonald、Prisca Honore、Joe Mikusa、Kennan C. Marsh、Jill M. Wetter、Karen St. George、Michael F. Jarvis、Connie R. Faltynek、Chih-Hung Lee

  DOI：10.1021/jm070276i

  日期：2007.7.1

  The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.