N-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-chloropropanamide | 1233953-80-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-chloropropanamide
• 英文别名: N-(4-(3-bromoanilino)quinazolin-6-yl)-3-chloropropanamide；N-[4-(3-bromoanilino)quinazolin-6-yl]-3-chloropropanamide
• CAS: 1233953-80-4
• 化学式: C₁₇H₁₄BrClN₄O
• 分子量: 405.681
• InChiKey: IJXVXOWDYWQHOF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  66.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-chloropropanamide 、 二甲胺 在 sodium iodide 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 9.25h， 以86%的产率得到UPR 1157
  参考文献：
  名称：

  [EN] IRREVERSIBLE EGFR INHIBITOR COMPOUNDS WITH ANTIPROLIFERATIVE ACTIVITY
  [FR] COMPOSÉS INHIBITEURS IRRÉVERSIBLES DE L'EGFR DOTÉS D'UNE ACTIVITÉ ANTIPROLIFÉRATIVE

  摘要：

  本发明涉及Formule（VII）的衍生物，其中R27，R28分别独立地是氢，（C1-C6）烷基，（CH2）n- COOR33，（CH2）n-CONR33R34，（CH2）n-NR33R34或（CH2）n-吗啉；或NR27R28是所选自吗啉，哌啶和Formula（VIII）的— N N-R27，其中R33，R34独立地是氢或（C1-C6）烷基；R29是氢或（C1-C6）烷基；R30是氢或-OR35，其中R35是（C1-C6）烷基，（CH2）n-NR33R34或（CH2）n-哌啶或（CH2）n-吗啉，其中R33，R34独立地是氢或（C1-C6）烷基；Y是氮原子或被氰基取代的碳原子；R31和R32独立地是氢，溴，氯，氟，乙炔或甲基；X是氢，溴，氯，氟或-O（CH2）n-Q；Q是芳基或杂环芳基，可选地由一个或多个取代基取代，所选自氢，氯，氟，三氟甲基基团或-NO2；n是选自0，1，2，3，4，5或6的整数。本发明的衍生物被用作具有抗增殖活性的不可逆EGFR抑制剂。

  公开号：

  WO2010076764A1
• 作为产物：
  描述：

  6-硝基喹唑啉-4(3H)-酮 在 氯化亚砜 、 铁粉 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 5.0h， 生成 N-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-chloropropanamide
  参考文献：
  名称：

  Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

  摘要：

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

  DOI：

  10.1021/jm201507x

文献信息

• 6‐Aryl and Heterocycle Quinazoline Derivatives as Potent EGFR Inhibitors with Improved Activity toward Gefitinib‐Sensitive and ‐Resistant Tumor Cell Lines
  作者：Mostafa M. Hamed、Dalal A. Abou El Ella、Adam B. Keeton、Gary A. Piazza、Ashraf H. Abadi、Rolf W. Hartmann、Matthias Engel

  DOI：10.1002/cmdc.201300147

  日期：2013.9

  thiourea derivatives 6 a, 6 b and compound 10 b also retained significant activity toward the gefitinib‐insensitive EGFRT790M/L858R mutant, displaying up to 24‐fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild‐type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6 a were found to be more potent than the

  合成了一组在6位具有可变芳基和杂环取代基的新型苯并喹唑啉衍生物，并测试了它们的EGFR抑制活性。芳基和杂环通过不同的键（如亚胺，酰胺和硫脲）连接到喹唑啉支架上。大多数芳基和杂环衍生物均表现出对野生型EGFR的有效抑制作用，其IC 50值在低纳摩尔范围内。在这些当中，硫脲衍生物6，图6b和化合物10b中也保留显著活性朝向吉非替尼不敏感的EGFR T790M / L858R突变体，其功效比吉非替尼高24倍。此外，测试了针对野生型（KB细胞）和突变型EGFR（H1975细胞）癌细胞系的细胞生长抑制活性。包含数种化合物6a的被发现是比朝向这两个细胞系的参考化合物吉非替尼更有效，因为是对化合物的情况下10b中对H1975细胞。因此，化合物6a和10b尤其可以作为开发有效抗野生型EGFR抑制剂和吉非替尼耐药突变体的抑制剂的新先导。
• Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors
  作者：Federica Vacondio、Caterina Carmi、Elena Galvani、Michele Bassi、Claudia Silva、Alessio Lodola、Silvia Rivara、Andrea Cavazzoni、Roberta R. Alfieri、Pier Giorgio Petronini、Marco Mor

  DOI：10.1016/j.bmcl.2013.08.008

  日期：2013.10

  In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. (C) 2013 Elsevier Ltd. All rights reserved.