N-[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]hydrazinecarbothioamide | 1187575-48-9

• 分子结构分类: 有机化合物 - 有机金属化合物 - 有机类金属化合物
• 英文名称: N-[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]hydrazinecarbothioamide
• 英文别名: 1-amino-3-[(2S)-1-[tert-butyl(diphenyl)silyl]oxy-4-hydroxybutan-2-yl]thiourea
• CAS: 1187575-48-9
• 化学式: C₂₁H₃₁N₃O₂SSi
• 分子量: 417.648
• InChiKey: LSVJIKIFXPKKCS-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.65
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (RS)-6-[1-bromo-2-(4-fluorophenyl)-2-oxoethyl]-2-(2-tolyl)-2,3-dihydropyridazin-3-one 、 N-[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]hydrazinecarbothioamide 在 碳酸氢钠 作用下， 以 乙醇 、 溶剂黄146 、 水 为溶剂， 反应 2.0h， 以77%的产率得到6-[5-{[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]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
• 作为产物：
  描述：

  (6S)-N,N-dibenzyl-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodecan-6-amine 在 盐酸 、 10% Pd/C 、 甲酸铵 、 碳酸氢钠 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 7.5h， 生成 N-[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxybutan-2-yl]hydrazinecarbothioamide
  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

文献信息

• Identification, Synthesis, and Biological Evaluation of 6-[(6<i>R</i>)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-<i>a</i>]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2<i>H</i>)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor
  作者：Toru Asano、Hitoshi Yamazaki、Chiyoshi Kasahara、Hirokazu Kubota、Toru Kontani、Yu Harayama、Kazuki Ohno、Hidekazu Mizuhara、Masaharu Yokomoto、Keiji Misumi、Tomohiko Kinoshita、Mitsuaki Ohta、Makoto Takeuchi.

  DOI：10.1021/jm3008008

  日期：2012.9.13

  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.