4'-[3-methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-6-yl]biphenyl-2-carbaldehyde

• 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: 4'-[3-methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-6-yl]biphenyl-2-carbaldehyde
• 英文别名: 2-[4-[1-(4-Methoxyphenyl)-3-methylsulfonyl-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridin-6-yl]phenyl]benzaldehyde
• 化学式: C₂₇H₂₃N₃O₅S
• 分子量: 501.563
• InChiKey: OFHMEUSTASLSDF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4'-[3-methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-6-yl]biphenyl-2-carbaldehyde 、 (R)-3-吡咯烷醇 在 sodium cyanoborohydride 、 zinc(II) chloride 作用下， 以 甲醇 、 四氢呋喃 为溶剂， 反应 24.25h， 以46.9%的产率得到6-[4-(2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}phenyl)phenyl]-3-methanesulfonyl-1-(4-methoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin-7-one
  参考文献：
  名称：

  Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P-1 moieties that resulted in the identification of the p-methoxyphenyl P-1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P-4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidinl-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

  DOI：

  10.1021/jm070245n
• 作为产物：
  描述：

  6-(4-iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo(3,4-c)pyridin-7-one 、 2-甲酰基苯硼酸 在 四(三苯基膦)钯 sodium carbonate 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 24.0h， 以80%的产率得到4'-[3-methanesulfonyl-1-(4-methoxyphenyl)-7-oxo-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-6-yl]biphenyl-2-carbaldehyde
  参考文献：
  名称：

  Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P-1 moieties that resulted in the identification of the p-methoxyphenyl P-1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P-4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidinl-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

  DOI：

  10.1021/jm070245n