(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)-octahydro-1H-isoindol-5-yl]oxy}ethyl benzoate | 1070764-29-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)-octahydro-1H-isoindol-5-yl]oxy}ethyl benzoate
• 英文别名: (2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)octahydro-1H-isoindol-5-yl]oxy}ethyl benzoate；[(2S)-2-[[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-1,3-oxazol-2-yl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-5-yl]oxy]-2-[3,5-bis(trifluoromethyl)phenyl]ethyl] benzoate
• CAS: 1070764-29-2
• 化学式: C₃₅H₃₂F₆N₂O₅
• 分子量: 674.64
• InChiKey: HTBZSWICZWHQKO-JRHHORLMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  48
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  77.4
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)-octahydro-1H-isoindol-5-yl]oxy}ethyl benzoate 在 甲醇 、 sodium hydroxide 作用下， 反应 1.0h， 以55%的产率得到2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one
  参考文献：
  名称：

  2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK₁ Receptor Antagonist with Multiple Clearance Pathways

  摘要：

  Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenypoctahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.

  DOI：

  10.1021/jm400751p
• 作为产物：
  描述：

  [(1S,2R,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-diyl]bis(methylene)dipropane-1-sulfonate 在 吡啶 、 盐酸 、 dirhodium tetraacetate 、 锂硼氢 、 10 wt% Pd(OH)2 on carbon 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 苯 为溶剂， 140.0 ℃ 、344.75 kPa 条件下， 反应 50.5h， 生成 (2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)-octahydro-1H-isoindol-5-yl]oxy}ethyl benzoate
  参考文献：
  名称：

  2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK₁ Receptor Antagonist with Multiple Clearance Pathways

  摘要：

  Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenypoctahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.

  DOI：

  10.1021/jm400751p

文献信息

• HYDROXYMETHYL ETHER HYDROISOINDOLINE TACHYKININ RECEPTOR ANTAGONISTS
  申请人：DeVita Robert J.

  公开号：US20100105747A1

  公开（公告）日：2010-04-29

  The present invention is directed to certain hydroxymethyl ether hydroisoindoline 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, LUTS, depression, and anxiety.

  本发明涉及某些羟甲基醚羟异吲哚烷化合物，其作为神经激肽-1（NK-1）受体拮抗剂和快速激肽，特别是物质P的抑制剂有用。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，包括恶心、尿失禁、下尿路症状、抑郁症和焦虑症中的使用。
• Hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists
  申请人：Merck Sharp & Dohme Corp.

  公开号：US08124633B2

  公开（公告）日：2012-02-28

  The present invention is directed to certain hydroxymethyl ether hydroisoindoline 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, LUTS, depression, and anxiety.

  本发明涉及某些羟甲基醚羟异吲哚烷化合物，其作为神经激肽-1（NK-1）受体拮抗剂和快速激肽，特别是物质P的抑制剂而有用。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，包括恶心、尿失禁、下泌尿道症状、抑郁和焦虑方面的用途。
• WO2008/124143
  申请人：——

  公开号：——

  公开（公告）日：——
• 4-(octahydro-2H-isoindol-2-yl)-1,3-oxazol-4-one as TACHYKININ RECEPTOR ANTAGONISTS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2144503B1

  公开（公告）日：2013-03-27
• US8124633B2
  申请人：——

  公开号：US8124633B2

  公开（公告）日：2012-02-28