(6R,7S,7aS)-6-{(1R)-1-[3.5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-3-oxohexahydro-1H-pyrrolizin-2-yl methanesulfonate | 945467-38-9

• 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: (6R,7S,7aS)-6-{(1R)-1-[3.5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-3-oxohexahydro-1H-pyrrolizin-2-yl methanesulfonate
• 英文别名: (6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-3-oxohexahydro-1H-pyrrolizin-2-yl methanesulfonate；[(6R,7S,8S)-6-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-7-(4-fluorophenyl)-3-oxo-1,2,5,6,7,8-hexahydropyrrolizin-2-yl] methanesulfonate
• CAS: 945467-38-9
• 化学式: C₂₄H₂₂F₇NO₅S
• 分子量: 569.497
• InChiKey: WZMAZNHLHKBOPO-HNLJCYKZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  81.3
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (6R,7S,7aS)-6-{(1R)-1-[3.5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-3-oxohexahydro-1H-pyrrolizin-2-yl methanesulfonate 在 sodium azide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以65%的产率得到(6R,7S,7aS)-2-azido-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one
  参考文献：
  名称：

  Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists

  摘要：

  Previous work on human NK1 (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50's of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.065
• 作为产物：
  描述：

  (6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-2(R or S)hydroxyhexahydro-3H-pyrrolizin-3-one 、 甲基磺酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以82%的产率得到(6R,7S,7aS)-6-{(1R)-1-[3.5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-3-oxohexahydro-1H-pyrrolizin-2-yl methanesulfonate
  参考文献：
  名称：

  Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists

  摘要：

  Previous work on human NK1 (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50's of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.065

文献信息

• Hexahydro-3H-Pyrrolizin-3-Ones Useful as Tachykinin Receptor Antagonists
  申请人：Bao Jianming

  公开号：US20090042854A1

  公开（公告）日：2009-02-12

  The present invention is directed to certain hexahydrpyrrolidinone 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.

  本发明涉及某些六水合吡咯烷酮化合物，其可用作神经激肽-1（NK-1）受体拮抗剂，以及缓激肽和特别是物质P的抑制剂。本发明还涉及包含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，包括呕吐、尿失禁、抑郁症和焦虑症方面的用途。
• WO2007/87224
  申请人：——

  公开号：——

  公开（公告）日：——
• Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists
  作者：Gregori J. Morriello、Sander G. Mills、Tricia Johnson、Mikhail Reibarkh、Gary Chicchi、Julie DeMartino、Marc Kurtz、P. Davies、K.L.C. Tsao、Song Zheng、Xinchun Tong、Emma Carlson、Karen Townson、F.D. Tattersall、Alan Wheeldon、Susan Boyce、Neil Collinson、Nadia Rupniak、Stephen Moore、Robert J. DeVita

  DOI：10.1016/j.bmcl.2010.01.065

  日期：2010.3

  Previous work on human NK1 (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24 h with ID50's of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity. (C) 2010 Elsevier Ltd. All rights reserved.