(1R,3aR,4aS,6R,8aR,9S,9aS)-6-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1-methyl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-3-one | 618385-94-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并呋喃类
• 英文名称: (1R,3aR,4aS,6R,8aR,9S,9aS)-6-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1-methyl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-3-one
• CAS: 618385-94-7
• 化学式: C₃₂H₃₅F₃N₂O₄
• 分子量: 568.636
• InChiKey: UDDPGVXMJWBTOZ-UVAOQSGXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  41
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  79.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (1R,3aR,4aS,6R,8aR,9S,9aS)-1-methyl-3-oxo-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-carbaldehyde 在 sodium dihydrogen phosphate 、 双氧水 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium chloride 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.25h， 生成 (1R,3aR,4aS,6R,8aR,9S,9aS)-6-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-1-methyl-9-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-3-one
  参考文献：
  名称：

  Himbacine-Derived Thrombin Receptor Antagonists: C₇-Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

  摘要：

  We have synthesized several C-7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K-i = 5 nM). We have also synthesized a C-9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K-i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.

  DOI：

  10.1021/ml400452v

文献信息

• Himbacine-Derived Thrombin Receptor Antagonists: C₇-Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar
  作者：Mariappan V. Chelliah、Samuel Chackalamannil、Yan Xia、William J. Greenlee、Ho-Sam Ahn、Stan Kurowski、George Boykow、Yunsheng Hsieh、Madhu Chintala

  DOI：10.1021/ml400452v

  日期：2014.2.13

  We have synthesized several C-7-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound 6a from this series showed excellent PAR-1 activity (K-i = 5 nM). We have also synthesized a C-9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K-i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.