6-amino-4-(3-chloro-4-fluorophenylamino)-7-trifluoromethoxyquinoline-3-carbonitrile | 492456-58-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-amino-4-(3-chloro-4-fluorophenylamino)-7-trifluoromethoxyquinoline-3-carbonitrile
• 英文别名: 6-Amino-4-(3-chloro-4-fluoroanilino)-7-(trifluoromethoxy)quinoline-3-carbonitrile
• CAS: 492456-58-3
• 化学式: C₁₇H₉ClF₄N₄O
• 分子量: 396.731
• InChiKey: RNSKNWPWSFFSFH-UHFFFAOYSA-N

物化性质

• 沸点：
  489.4±45.0 °C(Predicted)
• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  84
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-咪唑甲醛 、 6-amino-4-(3-chloro-4-fluorophenylamino)-7-trifluoromethoxyquinoline-3-carbonitrile 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-imidazol-4-ylmethyl)-amino]-7-trifluoromethoxy-quinoline-3-carbonitrile
  参考文献：
  名称：

  Inhibition of Tpl2 kinase and TNFα production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis

  摘要：

  The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.

  DOI：

  10.1016/j.bmcl.2006.08.102
• 作为产物：
  描述：

  3-三氟甲氧基苯胺 在 diphenyl ether-biphenyl eutectic 、 亚硝酸铵 、 铁粉 、 氯化铵 、 三氟乙酸酐 、 三氯氧磷 作用下， 以 甲醇 、 异丙醇 、 甲苯 为溶剂， 反应 27.25h， 生成 6-amino-4-(3-chloro-4-fluorophenylamino)-7-trifluoromethoxyquinoline-3-carbonitrile
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

  摘要：

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm020241c

文献信息

• Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)
  作者：Allan Wissner、Elsebe Overbeek、Marvin F. Reich、M. Brawner Floyd、Bernard D. Johnson、Nellie Mamuya、Edward C. Rosfjord、Carolyn Discafani、Rachel Davis、Xiaoqing Shi、Sridhar K. Rabindran、Brian C. Gruber、Fei Ye、William A. Hallett、Ramaswamy Nilakantan、Ru Shen、Yu-Fen Wang、Lee M. Greenberger、Hwei-Ru Tsou

  DOI：10.1021/jm020241c

  日期：2003.1.1

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.
• Inhibition of Tpl2 kinase and TNFα production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis
  作者：Yonghan Hu、Neal Green、Lori K. Gavrin、Kristin Janz、Neelu Kaila、Huan-Qiu Li、Jennifer R. Thomason、John W. Cuozzo、J. Perry Hall、Sang Hsu、Cheryl Nickerson-Nutter、Jean-Baptiste Telliez、Lih-Ling Lin、Steve Tam

  DOI：10.1016/j.bmcl.2006.08.102

  日期：2006.12

  The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.