3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylthio)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide | 482344-46-7

• 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: 3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylthio)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide
• 英文别名: 3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide；3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]-2-methylsulfanylpyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide
• CAS: 482344-46-7
• 化学式: C₂₁H₂₈N₆O₂S
• 分子量: 428.558
• InChiKey: MCMHMGZBNVWWJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  129
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylthio)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide 在 Oxone 作用下， 以 甲醇 、 水 为溶剂， 反应 16.0h， 生成 3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylsulfonyl)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide
  参考文献：
  名称：

  5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

  摘要：

  A novel class of 5-cyanopyrimidine-based inhibitors of p38 alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (> 50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38 alpha.

  DOI：

  10.1021/jm0503594
• 作为产物：
  描述：

  4,6-二氯-5-氰基-2-甲硫基嘧啶 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 3-(5-cyano-6-(methyl(neopentyl)amino)-2-(methylthio)pyrimidin-4-ylamino)-N-methoxy-4-methylbenzamide
  参考文献：
  名称：

  5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

  摘要：

  A novel class of 5-cyanopyrimidine-based inhibitors of p38 alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (> 50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38 alpha.

  DOI：

  10.1021/jm0503594

文献信息

• N-heterocyclic inhibitors of TNF-alpha expression
  申请人：——

  公开号：US20030139435A1

  公开（公告）日：2003-07-24

  N-heterocyclic compounds that block cytokine production via inhibition of p38 kinase are disclosed. In one embodiment, compounds of the present invention are represented by Formula (I): 1 Methods of production, pharmaceutical compositions and methods of treating conditions associated with inappropriate p38 kinase activity or TNF-&agr; expression utilizing compounds of the present invention are also disclosed.

  本发明揭示了通过抑制p38激酶来阻断细胞因子产生的N-杂环化合物。在一种实施方式中，本发明的化合物由式(I)表示。还公开了利用本发明的化合物生产方法、制药组合物以及治疗与不当p38激酶活性或TNF-α表达相关的疾病的方法。
• N-heterocyclic inhibitors of TNF-α expression
  申请人：Bristol-Myers Squibb Company

  公开号：US07253174B2

  公开（公告）日：2007-08-07

  N-heterocyclic compounds that block cytokine production via inhibition of p38 kinase are disclosed. In one embodiment, compounds of the present invention are represented by Formula (I): Methods of production, pharmaceutical compositions and methods of treating conditions associated with inappropriate p38 kinase activity or TNF-α expression utilizing compounds of the present invention are also disclosed.

  本发明揭示了通过抑制p38激酶阻断细胞因子产生的N-杂环化合物。在一种实施方式中，本发明的化合物由公式（I）表示：还公开了利用本发明的化合物的生产方法、制药组合物以及治疗与不适当的p38激酶活性或TNF-α表达相关的疾病的方法。
• N-HETEROCYCLIC INHIBITORS OF TNF-ALPHA EXPRESSION
  申请人：Ahmed Gulzar

  公开号：US20080015185A1

  公开（公告）日：2008-01-17

  N-heterocyclic compounds that block cytokine production via inhibition of p38 kinase are disclosed. In one embodiment, compounds of the present invention are represented by Formula (I): Methods of production, pharmaceutical compositions and methods of treating conditions associated with inappropriate p38 kinase activity or TNF-α expression utilizing compounds of the present invention are also disclosed.

  本发明揭示了通过抑制p38激酶而阻断细胞因子产生的N-杂环化合物。在一种实施方案中，本发明的化合物由式（I）表示：还揭示了利用本发明的化合物制备方法、制药组合物和治疗与不适当的p38激酶活性或TNF-α表达相关的疾病的方法。
• US7253174B2
  申请人：——

  公开号：US7253174B2

  公开（公告）日：2007-08-07
• US8044040B2
  申请人：——

  公开号：US8044040B2

  公开（公告）日：2011-10-25