(1S,2R,8aS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-(5-oxotetrahydrofuran-3-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

• 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: (1S,2R,8aS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-(5-oxotetrahydrofuran-3-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one
• 英文别名: (1S,2R,8aS)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-1-(4-fluorophenyl)-7-(5-oxooxolan-3-yl)-2,3,8,8a-tetrahydro-1H-indolizin-5-one
• 化学式: C₂₈H₂₄F₇NO₄
• 分子量: 571.492
• InChiKey: WBJKVEOYVSBOSF-SDKRTWCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (1S,2R,8aS)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-1-(4-fluorophenyl)-7-(5-hydroxytetrahydrofuran-3-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one 在 Ag₂CO₃-celite 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以78%的产率得到(1S,2R,8aS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-7-(5-oxotetrahydrofuran-3-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one
  参考文献：
  名称：

  Tetrahydroindolizinone NK1 antagonists

  摘要：

  A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P-450 inhibition and hPXR induction profiles. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.120

文献信息

• 5,6,Fused Pyrrolidine Compounds Useful as Tachykinin Receptor Antagonists
  申请人：Bao Jianming

  公开号：US20090286777A1

  公开（公告）日：2009-11-19

  The present invention is directed to certain 5,6-fused pyrrolidine compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

  本发明涉及某些5,6-融合吡咯烷化合物，其作为神经激肽-1（NK-1）受体拮抗剂和缓激肽，特别是物质P的抑制剂具有用途。本发明还涉及含有这些化合物作为活性成分的制药配方以及这些化合物和它们的配方在治疗某些疾病，包括恶心、尿失禁、抑郁症和焦虑症中的应用。
• WO2007/136570
  申请人：——

  公开号：——

  公开（公告）日：——
• Tetrahydroindolizinone NK1 antagonists
  作者：Jianming Bao、Huagang Lu、Gregori J. Morriello、Emma J. Carlson、Alan Wheeldon、Gary G. Chicchi、Marc M. Kurtz、Kwei-Lan C. Tsao、Song Zheng、Xinchun Tong、Sander G. Mills、Robert J. DeVita

  DOI：10.1016/j.bmcl.2010.01.120

  日期：2010.4

  A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P-450 inhibition and hPXR induction profiles. (C) 2010 Elsevier Ltd. All rights reserved.