N-(4-chloro-2,5-dimethoxyphenyl)-7-fluoro-6-methoxy-N-(4-methoxybenzyl)quinazolin-4-amine | 870962-22-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-(4-chloro-2,5-dimethoxyphenyl)-7-fluoro-6-methoxy-N-(4-methoxybenzyl)quinazolin-4-amine
• 英文别名: N-(4-chloro-2,5-dimethoxyphenyl)-7-fluoro-6-methoxy-N-[(4-methoxyphenyl)methyl]quinazolin-4-amine
• CAS: 870962-22-4
• 化学式: C₂₅H₂₃ClFN₃O₄
• 分子量: 483.927
• InChiKey: XYBSDUDERIWTON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  65.9
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-(4-chloro-2,5-dimethoxyphenyl)-7-fluoro-6-methoxy-N-(4-methoxybenzyl)quinazolin-4-amine 在 ammonium cerium(IV) nitrate 、 sodium hexamethyldisilazane 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 2.25h， 生成 2-chloro-5-({6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)benzo-1,4-quinone
  参考文献：
  名称：

  2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2

  摘要：

  A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,41benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.

  DOI：

  10.1021/jm050559f
• 作为产物：
  描述：

  4-氯-2,5-二甲氧基苯胺 在 吡啶 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 二氯甲烷 、 叔丁醇 为溶剂， 反应 26.5h， 生成 N-(4-chloro-2,5-dimethoxyphenyl)-7-fluoro-6-methoxy-N-(4-methoxybenzyl)quinazolin-4-amine
  参考文献：
  名称：

  [EN] QUINONE SUBSTITUTED QUINAZOLINE AND QUINOLINE KINASE INHIBITORS
  [FR] INHIBITEURS DE QUINAZOLINE ET QUINOLINE KINASE A SUBSTITUTION QUINONE

  摘要：

  公开号：

  WO2005115145A3

文献信息

• Quinone Substituted Quinazoline and Quinoline Kinase Inhibitors
  申请人：Floyd Jr Brawner Middleton

  公开号：US20070299092A1

  公开（公告）日：2007-12-27

  The present invention provides for compounds with the general formula: A compound of formula (1) having the structure (1) wherein Z is a radical selected from the group (a), (b), or (c) as well as methods and compositions containing these compounds useful for treatment of diseases that are characterized, at least in part, by excessive, abnormal, or inappropriate angiogenesis. These disease states, include but are not limited to, cancer, diabetic retinopathy, macular degeneration and rheumatoid arthritis. These compounds inhibit angiogenesis by inhibiting a tyrosine kinase receptor enzyme, specifically KDR, and binding to the KDR in an irreversible manner.

  本发明提供了一般式为：具有结构式（1）的化合物，其中Z是从（a）、（b）或（c）组中选择的基团，以及包含这些化合物的方法和组合物，用于治疗至少部分特征为过度、异常或不适当血管生成的疾病。这些疾病状态包括但不限于癌症、糖尿病视网膜病变、黄斑变性和类风湿性关节炎。这些化合物通过抑制酪氨酸激酶受体酶，特别是KDR，并以不可逆的方式与KDR结合来抑制血管生成。
• [EN] QUINONE SUBSTITUTED QUINAZOLINE AND QUINOLINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE QUINAZOLINE ET QUINOLINE KINASE A SUBSTITUTION QUINONE
  申请人：WYETH CORP

  公开号：WO2005115145A3

  公开（公告）日：2006-02-23
• 2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2
  作者：Allan Wissner、M. Brawner Floyd、Bernard D. Johnson、Heidi Fraser、Charles Ingalls、Thomas Nittoli、Russell G. Dushin、Carolyn Discafani、Ramaswamy Nilakantan、Joseph Marini、Malini Ravi、Kinwang Cheung、Xingzhi Tan、Sylvia Musto、Tami Annable、Marshall M. Siegel、Frank Loganzo

  DOI：10.1021/jm050559f

  日期：2005.12.1

  A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,41benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.