tert-butyl (3aR,4R,5S,7aS)-5-{1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindole-2-carboxylate | 1070764-21-4

• 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: tert-butyl (3aR,4R,5S,7aS)-5-{1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindole-2-carboxylate
• 英文别名: tert-butyl (3aR,4R,5S,7aS)-5-[1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy]-4-(2-methylphenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindole-2-carboxylate
• CAS: 1070764-21-4
• 化学式: C₃₂H₃₇F₆NO₅
• 分子量: 629.64
• InChiKey: JCYGHNVXENNDLU-WKFVTGRVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  tert-butyl (3aR,4R,5S,7aS)-5-{1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindole-2-carboxylate 在 盐酸 、 4-二甲氨基吡啶 、 锂硼氢 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-(acetohydroxyethoxy)}-4-(2-methylphenyl)octahydro-1H-isoindole
  参考文献：
  名称：

  WO2008/124143

  摘要：

  公开号：
• 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 dirhodium tetraacetate 、 10 wt% Pd(OH)2 on carbon 、 氢气 作用下， 以 乙醇 、 二氯甲烷 、 苯 为溶剂， 20.0~140.0 ℃ 、344.75 kPa 条件下， 反应 27.0h， 生成 tert-butyl (3aR,4R,5S,7aS)-5-{1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindole-2-carboxylate
  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

• WO2008/124143
  申请人：——

  公开号：——

  公开（公告）日：——
• 2-[(3a<i>R</i>,4<i>R</i>,5<i>S</i>,7a<i>S</i>)-5-{(1<i>S</i>)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2<i>H</i>-isoindol-2-yl]-1,3-oxazol-4(5<i>H</i>)-one: A Potent Human NK₁ Receptor Antagonist with Multiple Clearance Pathways
  作者：Andrew J. Kassick、Jinlong Jiang、Jaime Bunda、David Wilson、Jianming Bao、Huagang Lu、Peter Lin、Richard G. Ball、George A. Doss、Xinchun Tong、Kwei-Lan C. Tsao、Hong Wang、Gary Chicchi、Bindhu Karanam、Richard Tschirret-Guth、Koppara Samuel、Donald F. Hora、Sanjeev Kumar、Maria Madeira、Waisi Eng、Richard Hargreaves、Mona Purcell、Liza Gantert、Jacquelyn Cook、Robert J. DeVita、Sander G. Mills

  DOI：10.1021/jm400751p

  日期：2013.7.25

  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.