tert-butyl 4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-formyl-3-(4-fluorophenyl)-pyrrolidine-1-carboxylate | 945467-32-3

• 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: tert-butyl 4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-formyl-3-(4-fluorophenyl)-pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (2R,3S,4R)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)-2-formylpyrrolidine-1-carboxylate；tert-butyl (2R,3S,4R)-4-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-2-formylpyrrolidine-1-carboxylate
• CAS: 945467-32-3
• 化学式: C₂₆H₂₆F₇NO₄
• 分子量: 549.486
• InChiKey: PNLJPNCDKZXWJU-BNQVVEKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-formyl-3-(4-fluorophenyl)-pyrrolidine-1-carboxylate 在 lithium hexamethyldisilazane 、 盐酸 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 生成 methyl (1S,2R,8aS)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-(4-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-7-carboxylate
  参考文献：
  名称：

  WO2007/136570

  摘要：

  公开号：
• 作为产物：
  描述：

  tert-butyl 4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(hydroxymethyl)-3-phenylpyrrolidine-1-carboxylate 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以94%的产率得到tert-butyl 4-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-formyl-3-(4-fluorophenyl)-pyrrolidine-1-carboxylate
  参考文献：
  名称：

  WO2007/87224

  摘要：

  公开号：

文献信息

• 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。
• 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。
• 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。
• 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.
• Fused tricyclic pyrrolizinones that exhibit pseudo-irreversible blockade of the NK1 receptor
  作者：Gregori J. Morriello、Gary Chicchi、Tricia Johnson、Sander G. Mills、Julie DeMartino、Marc Kurtz、K.L.C. Tsao、Song Zheng、Xinchun Tong、Emma Carlson、Karen Townson、Alan Wheeldon、Susan Boyce、Neil Collinson、Nadia Rupniak、Robert J. DeVita

  DOI：10.1016/j.bmcl.2010.07.058

  日期：2010.10

  Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (< 10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (< 2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively. (C) 2010 Elsevier Ltd. All rights reserved.