3-chloro-8-methoxydibenzo[b,e]oxepin-11(6H)-one | 1482523-76-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: 3-chloro-8-methoxydibenzo[b,e]oxepin-11(6H)-one
• 英文别名: 3-chloro-8-methoxy-6H-benzo[c][1]benzoxepin-11-one
• CAS: 1482523-76-1
• 化学式: C₁₅H₁₁ClO₃
• 分子量: 274.704
• InChiKey: TVCYFFQDSHJVMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-chloro-8-methoxydibenzo[b,e]oxepin-11(6H)-one 在 palladium diacetate 、 三溴化硼 、 potassium carbonate 、 caesium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 丙酮 、 叔丁醇 为溶剂， 反应 9.0h， 生成 N-(2-fluoro-5-{[8-(2-morpholin-4-ylethoxy)-11-oxo-6,11-dihydrodibenzo[b,e]oxepin-3-yl]amino}phenyl)benzamide
  参考文献：
  名称：

  Metabolically Stable Dibenzo[b,e]oxepin-11(6H)-ones as Highly Selective p38 MAP Kinase Inhibitors: Optimizing Anti-Cytokine Activity in Human Whole Blood

  摘要：

  Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones were synthesized and tested in a p38 alpha enzyme assay for their inhibition of tumor necrosis factor-alpha (TNF-alpha) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein Xray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38 alpha, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-alpha from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.

  DOI：

  10.1021/jm401276h
• 作为产物：
  描述：

  2-溴甲基-4-甲氧基苯甲酸甲酯 在 氯化亚砜 、 potassium carbonate 、 三氟乙酸酐 、 potassium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 10.0h， 生成 3-chloro-8-methoxydibenzo[b,e]oxepin-11(6H)-one
  参考文献：
  名称：

  Metabolically Stable Dibenzo[b,e]oxepin-11(6H)-ones as Highly Selective p38 MAP Kinase Inhibitors: Optimizing Anti-Cytokine Activity in Human Whole Blood

  摘要：

  Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones were synthesized and tested in a p38 alpha enzyme assay for their inhibition of tumor necrosis factor-alpha (TNF-alpha) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein Xray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38 alpha, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-alpha from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.

  DOI：

  10.1021/jm401276h