1-tert-butyl-3-(2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)phenyl)urea | 1022085-42-2

• 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: 1-tert-butyl-3-(2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)phenyl)urea
• CAS: 1022085-42-2
• 化学式: C₁₆H₁₆ClF₃N₄O
• 分子量: 372.777
• InChiKey: IYJJICRQAXHHSZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.74
• 重原子数：
  25.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  66.91
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  3-氨基-5-羟基喹喔啉-2-(1H)-酮 、 1-tert-butyl-3-(2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)phenyl)urea 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以51%的产率得到1-(2-(6-(3-Amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-3-tert-butylurea
  参考文献：
  名称：

  Design and Synthesis of Peripherally Restricted Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

  摘要：

  Transient receptor potential vanilloid 1 (TRPV 1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, this TRPV1 antagonist significantly increased body core temperature following oral administration in rodents. Here, we, report one of our approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists. Through modifications of our clinical candidate, 3 a series of potent and peripherally restricted TRPV1 antagonists have been prepared. These analogues demonstrated on-target coverage in vivo but caused increases in body core temperature, suggesting that peripheral restriction was not sufficient to separate antagonism mediated antihyperalgesia from hyperthermia. Furthermore, these studies demonstrate that the site of action for TRPV1 blockade elicited hyperthermia is outside the blood-brain barrier.

  DOI：

  10.1021/jm7014638
• 作为产物：
  描述：

  2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)benzeneamine 、 叔丁基异氰酸酯 在 magnesium chloride 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 18.0h， 以60%的产率得到1-tert-butyl-3-(2-(6-chloropyrimidin-4-yl)-5-(trifluoromethyl)phenyl)urea
  参考文献：
  名称：

  Design and Synthesis of Peripherally Restricted Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

  摘要：

  Transient receptor potential vanilloid 1 (TRPV 1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, this TRPV1 antagonist significantly increased body core temperature following oral administration in rodents. Here, we, report one of our approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists. Through modifications of our clinical candidate, 3 a series of potent and peripherally restricted TRPV1 antagonists have been prepared. These analogues demonstrated on-target coverage in vivo but caused increases in body core temperature, suggesting that peripheral restriction was not sufficient to separate antagonism mediated antihyperalgesia from hyperthermia. Furthermore, these studies demonstrate that the site of action for TRPV1 blockade elicited hyperthermia is outside the blood-brain barrier.

  DOI：

  10.1021/jm7014638