6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one | 945465-85-0

• 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: 6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one
• 英文别名: (6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one；(6R,7S,8S)-6-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-7-(4-fluorophenyl)-1,2,5,6,7,8-hexahydropyrrolizin-3-one
• CAS: 945465-85-0
• 化学式: C₂₃H₂₀F₇NO₂
• 分子量: 475.406
• InChiKey: SUITYIWBXSZXIQ-MJRZITLZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one 在 lithium hexamethyldisilazane 、 MoO5*pyridine*HMPA 作用下， 以 四氢呋喃 为溶剂， 生成 (6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-2(S)hydroxyhexahydro-3H-pyrrolizin-3-one 、 (6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-2(R)hydroxyhexahydro-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：

  3-[(2S,3S,4R)-4-{(1R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)pyrrolidin-2-yl]propanoic acid hydrochloride 在 4-二甲氨基吡啶 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以88%的产率得到6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one
  参考文献：
  名称：

  融合双环吡咯烷酮作为人类NK1拮抗剂的新支架。

  摘要：

  已经公开了关于人类NK（1）拮抗剂的先前工作，其中该结构的核心是取代的吡咯烷。这些化合物显示出良好的结合亲和力和功能性IP活性，但是，许多化合物没有表现出良好的体内活性所必需的大脑渗透性。本文介绍了新型5，5-稠合吡咯烷核的发现和制备。这种支架保持了先前报道的化合物的出色的结合亲和力和功能性IP活性，但在沙土鼠的脚踏试验中也观察到了出色的大脑渗透性。描述了确定最终导致单一活性非对映异构体最终合成的核心结构立体化学的确定。

  DOI：

  10.1016/j.bmc.2007.11.081

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。
• Asymmetric Synthesis of a Pyrrolizidinone‐Based hNK ₁ Antagonist through Reductive Ring Contraction of a Six‐Membered Cyclic Nitronate
  作者：Ilya V. Okladnikov、Yaroslav D. Boyko、Yulia V. Nelyubina、Sema L. Ioffe、Alexey Yu. Sukhorukov

  DOI：10.1002/ejoc.202200796

  日期：2022.11.7

  A seven-step asymmetric synthesis of a potent hNK1 antagonist has been accomplished through a stereoselective reductive recyclization of a properly functionalized six-membered cyclic nitronate.

  通过对适当官能化的六元环状硝酸盐进行立体选择性还原再循环，完成了强效 hNK 1拮抗剂的七步不对称合成。
• WO2007/87224
  申请人：——

  公开号：——

  公开（公告）日：——
• Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists
  作者：Gregori J. Morriello、Robert J. DeVita、Sander G. Mills、Jonathan R. Young、Peter Lin、George Doss、Gary G. Chicchi、Julie DeMartino、Marc M. Kurtz、Kwei-Lan C. Tsao、Emma Carlson、Karen Townson、Alan Wheeldon、Susan Boyce、Neil Collinson、Nadia Rupniak、Stephen Moore

  DOI：10.1016/j.bmc.2007.11.081

  日期：2008.3

  discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single

  已经公开了关于人类NK（1）拮抗剂的先前工作，其中该结构的核心是取代的吡咯烷。这些化合物显示出良好的结合亲和力和功能性IP活性，但是，许多化合物没有表现出良好的体内活性所必需的大脑渗透性。本文介绍了新型5，5-稠合吡咯烷核的发现和制备。这种支架保持了先前报道的化合物的出色的结合亲和力和功能性IP活性，但在沙土鼠的脚踏试验中也观察到了出色的大脑渗透性。描述了确定最终导致单一活性非对映异构体最终合成的核心结构立体化学的确定。
• 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.