4-nitro-N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide | 623900-99-2

• 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: 4-nitro-N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide
• 英文别名: (4-Nitrophenyl)-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)-amino]phenyl}-carboxamide；(4-Nitrophenyl)-N-{4-methyl-3-[(4-(pyridin-3-yl)pyrimidin-2-yl)-amino]phenyl}-carboxamide；N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]-4-nitrobenzamide
• CAS: 623900-99-2
• 化学式: C₂₃H₁₈N₆O₃
• 分子量: 426.434
• InChiKey: RBQQJBMCMDRKLD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-nitro-N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide 在 palladium on activated charcoal 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 6.0h， 以79%的产率得到4-amino-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide
  参考文献：
  名称：

  4-（（N-（2-（二甲基氨基）乙基）丙烯酰胺基）甲基）-N-（4-甲基-3-（（4-（吡啶-3-基）嘧啶-2-基）氨基）苯基的发现苯甲酰胺（CHMFL-PDGFR-159）作为高选择性的II型PDGFRα激酶抑制剂，可抑制PDGFRα驱动慢性嗜酸性粒细胞白血病。

  摘要：

  通过探索由DFG移出非活性构象而产生的非高度保守的变构疏水口袋，我们发现了一种高度选择性的II型PDGFRα激酶抑制剂15i（CHMFL-PDGFRα-159），对纯化的PDGFRα（IC50）具有很强的效力：132 nM），但结构上不相似的PDGFRβ，ABL，c-KIT和VEGFR2激酶。此外，它在KINOMEscan分析中的468个激酶/突变体中浓度为1μM时，显示出高选择性（S评分（10）= 0.02）。与PDGFRα配合的15i的X射线晶体结构在变构疏水口袋中显示出独特的结合特征，这可能有助于扩大II型激酶抑制剂的多样性。化合物15i通过强烈阻断PDGFRα介导的信号通路，阻止细胞周期进程并诱导凋亡，有效抑制PDGFRα驱动慢性嗜酸性粒细胞白血病（CEL）细胞系EOL-1的增殖。此外，化合物15i在异种移植模型中有效地抑制了EOL-1肿瘤的进展，并提高了移植瘤模型中的存活率。

  DOI：

  10.1016/j.ejmech.2018.03.003
• 作为产物：
  描述：

  4-硝基苯甲酰氯 、 N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 生成 4-nitro-N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide
  参考文献：
  名称：

  Optimization of novel combi-molecules: Identification of balanced and mixed bcr-abl/DNA targeting properties

  摘要：

  Steps toward the identification of combi-molecules with strong abl tyrosine kinase (TK) inhibitory property and significant DNA damaging potential are described. The optimized combi-molecule 13a was shown to induce approximately twofold stronger abl TK inhibitory activity than Gleevec (TM) and high levels of DNA damage in chronic myelogenous leukemic cells. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.05.067

文献信息

• Phenylaminopyrimidine derivatives and methods of use
  申请人：——

  公开号：US20040224967A1

  公开（公告）日：2004-11-11

  The present invention relates to phenylaminopyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states such as cancers associated with tyrosine kinases, especially Bcr-Abl, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of inhibition of tyrosine kinase reducing effects in warm-blooded animals such as humans.

  本发明涉及苯基氨基嘧啶衍生物、其制备方法、含有其作为活性成分的制药组合物、用于治疗与酪氨酸激酶相关的癌症，特别是Bcr-Abl的疾病状态的方法，以及它们作为药物的用途和它们用于制造药物以用于在温血动物，如人类中产生酪氨酸激酶抑制作用的生产。
• Optimization of novel combi-molecules: Identification of balanced and mixed bcr-abl/DNA targeting properties
  作者：Zakaria Rachid、Athanasia Katsoulas、Christopher Williams、Anne-Laure Larroque、James McNamee、Bertrand J. Jean-Claude

  DOI：10.1016/j.bmcl.2007.05.067

  日期：2007.8

  Steps toward the identification of combi-molecules with strong abl tyrosine kinase (TK) inhibitory property and significant DNA damaging potential are described. The optimized combi-molecule 13a was shown to induce approximately twofold stronger abl TK inhibitory activity than Gleevec (TM) and high levels of DNA damage in chronic myelogenous leukemic cells. (c) 2007 Elsevier Ltd. All rights reserved.
• Synthesis of pyrimidinopyridine–triazene conjugates targeted to abl tyrosine kinase
  作者：Zakaria Rachid、Athanasia Katsoulas、Fouad Brahimi、Bertrand Jacques Jean-Claude

  DOI：10.1016/s0960-894x(03)00553-5

  日期：2003.10

  The synthesis and abl tyrosine kinase inhibitory activities of alkyltriazenes conjugated to phenylaminopyrimidines are described. Significant abl inhibitory activities were observed only when a benzamido spacer was inserted between the 1,23-triazene chain and the 2-phenyaminopyridopyrimidine moiety. (C) 2003 Elsevier Ltd. All rights reserved.
• Synthesis and docking study of 2-phenylaminopyrimidine Abl tyrosine kinase inhibitors
  作者：Shuang Lü、Qun Luo、Xiang Hao、Xianchan Li、Liyun Ji、Wei Zheng、Fuyi Wang

  DOI：10.1016/j.bmcl.2011.09.127

  日期：2011.12

  Six analogs of imatinib, an Abl kinase inhibitor clinically used as a first-line therapeutic agent for chronic myeloid leukaemia (CML), have been synthesized and characterized. And their potency as Abl kinase inhibitors have been screened by a robust virtual screening method developed based on the crystal structure (PDB code 2hyy) of Abl-imatinib complex using Surflex-Docking. The docking results are consistent with the inhibitory potency of the compounds characterized by MS method. And the H-bonds between imatinib analogs and Thr315 and Met318 residues in Abl kinase are shown to be crucial for achieving accurate poses and high binding affinities for the ATP-competitive kinase inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.
• Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia
  作者：Qiang Wang、Feiyang Liu、Shuang Qi、Ziping Qi、Xiao-E. Yan、Beilei Wang、Aoli Wang、Wei Wang、Cheng Chen、Xiaochuan Liu、Zongru Jiang、Zhenquan Hu、Li Wang、Wenchao Wang、Tao Ren、Shanchun Zhang、Cai-Hong Yun、Qingsong Liu、Jing Liu

  DOI：10.1016/j.ejmech.2018.03.003

  日期：2018.4

  selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFRα revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFRα driving Chronic Eosinophilic

  通过探索由DFG移出非活性构象而产生的非高度保守的变构疏水口袋，我们发现了一种高度选择性的II型PDGFRα激酶抑制剂15i（CHMFL-PDGFRα-159），对纯化的PDGFRα（IC50）具有很强的效力：132 nM），但结构上不相似的PDGFRβ，ABL，c-KIT和VEGFR2激酶。此外，它在KINOMEscan分析中的468个激酶/突变体中浓度为1μM时，显示出高选择性（S评分（10）= 0.02）。与PDGFRα配合的15i的X射线晶体结构在变构疏水口袋中显示出独特的结合特征，这可能有助于扩大II型激酶抑制剂的多样性。化合物15i通过强烈阻断PDGFRα介导的信号通路，阻止细胞周期进程并诱导凋亡，有效抑制PDGFRα驱动慢性嗜酸性粒细胞白血病（CEL）细胞系EOL-1的增殖。此外，化合物15i在异种移植模型中有效地抑制了EOL-1肿瘤的进展，并提高了移植瘤模型中的存活率。