6-[5-{[(2R)-2,3-dihydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one | 1397261-97-0

• 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: 6-[5-{[(2R)-2,3-dihydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one
• CAS: 1397261-97-0
• 化学式: C₂₃H₂₂FN₅O₃
• 分子量: 435.458
• InChiKey: XXLWXRVGLWSSGN-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  32.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  116.06
• 氢给体数：
  4.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  6-[5-{[(2R)-2,3-dihydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one 在 吡啶 、 甲基磺酰氯 作用下， 以 乙腈 为溶剂， 反应 24.0h， 以30%的产率得到6-[(6R)-2-(4-fluorophenyl)-6-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of 6-[(6R)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor

  摘要：

  Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1 beta, TNF alpha, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNF alpha production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.

  DOI：

  10.1021/jm3008008
• 作为产物：
  描述：

  3-氯-6-甲基哒嗪 在 吡啶 、 盐酸 、 pyridinium hydrobromide perbromide 、 水 、 copper diacetate 、 sodium acetate 、 对甲苯磺酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 56.5h， 生成 6-[5-{[(2R)-2,3-dihydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of 6-[(6R)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor

  摘要：

  Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1 beta, TNF alpha, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNF alpha production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.

  DOI：

  10.1021/jm3008008