[8-(4-Chlorophenyl)-2-ethyl-5-[[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl]-3,6-dioxo-[1,2,4]triazolo[4,3-b]pyridazin-7-yl] trifluoromethanesulfonate | 1494218-39-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: [8-(4-Chlorophenyl)-2-ethyl-5-[[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl]-3,6-dioxo-[1,2,4]triazolo[4,3-b]pyridazin-7-yl] trifluoromethanesulfonate
• CAS: 1494218-39-1
• 化学式: C₂₂H₁₆ClF₆N₅O₅S
• 分子量: 611.909
• InChiKey: JQIINOSEIXBAMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.0
• 重原子数：
  40.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  117.56
• 氢给体数：
  0.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  2-甲基嘧啶-5-硼酸 、 [8-(4-Chlorophenyl)-2-ethyl-5-[[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl]-3,6-dioxo-[1,2,4]triazolo[4,3-b]pyridazin-7-yl] trifluoromethanesulfonate 在 potassium phosphate 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以0.03 g的产率得到8-(4-chlorophenyl)-2-ethyl-5-((2-methyl-6-(trifluoromethyl)-pyridin-3-yl)methyl)-7-(2-methylpyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione
  参考文献：
  名称：

  Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

  摘要：

  Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

  DOI：

  10.1021/jm4010835
• 作为产物：
  描述：

  6-bromo-4,5-dichloro-2-((2-methyl-6-(trifluoromethyl)-pyridin-3-yl)methyl)pyridazin-3(2H)-one 在 四(三苯基膦)钯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 三溴化硼 、 sodium carbonate 、 potassium carbonate 、 caesium carbonate 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 10.67h， 生成 [8-(4-Chlorophenyl)-2-ethyl-5-[[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl]-3,6-dioxo-[1,2,4]triazolo[4,3-b]pyridazin-7-yl] trifluoromethanesulfonate
  参考文献：
  名称：

  Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

  摘要：

  Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

  DOI：

  10.1021/jm4010835