4-(3-氯苯胺基)-7-甲氧基喹唑啉-6-醇 | 655247-78-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 4-(3-氯苯胺基)-7-甲氧基喹唑啉-6-醇
• 英文名称: 4-(3-chlorophenylamino)-7-methoxyquinazolin-6-ol
• 英文别名: 4-(3'-chloroanilino)-6-hydroxy-7-methoxyquinazoline；6-Quinazolinol, 4-[(3-chlorophenyl)amino]-7-methoxy-；4-(3-chloroanilino)-7-methoxyquinazolin-6-ol
• CAS: 655247-78-2
• 化学式: C₁₅H₁₂ClN₃O₂
• 分子量: 301.732
• InChiKey: KJERUNBRZXIGDV-UHFFFAOYSA-N

物化性质

• 沸点：
  483.1±45.0 °C(Predicted)
• 密度：
  1.433±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  67.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(3-氯苯胺基)-7-甲氧基喹唑啉-6-醇 在 盐酸羟胺 、 potassium carbonate 、 potassium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 7-(4-(3-chlorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide
  参考文献：
  名称：

  Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

  摘要：

  A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50 = 84 nM) and HDAC (IC50 = 2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC50 of 1.2 mu M. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.10.006
• 作为产物：
  描述：

  2-氨基-4,5-二甲氧基苯甲酸乙酯 在 吡啶 、 氯化亚砜 、 甲烷磺酸 、 L-蛋氨酸 、 氨 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 水 、 异丙醇 为溶剂， 反应 24.0h， 生成 4-(3-氯苯胺基)-7-甲氧基喹唑啉-6-醇
  参考文献：
  名称：

  新型全氟化碳调节的4-苯胺基喹唑啉类似物的简便合成

  摘要：

  4-苯氨基喹唑啉类似物在许多抑制表皮生长因子受体（EGFR）酪氨酸激酶活性的小分子中脱颖而出，从而成为抗癌药物设计的重要分子靶标。本文中，通过各种苯胺喹唑啉与PFC衍生的甲磺酸盐的亲核取代反应，直接设计和制备了一系列新颖的全氟化碳（PFC）调节的4-苯胺基喹唑啉。在碱的存在下，反应平稳进行，从而以高收率或高收率得到了范围广泛的4-苯胺基喹唑啉，苯胺部分上具有不同的取代基。此外，吉非替尼和厄洛替尼的PFC修饰类似物也分别以93％和90％获得。19 F MRI。

  DOI：

  10.1002/cjoc.201700240

文献信息

• Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors
  作者：Bin Zhang、Zhikun Liu、Shengjin Xia、Qingqing Liu、Shaohua Gou

  DOI：10.1016/j.ejmech.2021.113300

  日期：2021.4

  especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized

  多靶标，尤其是双靶标的药物设计已成为癌症治疗的流行研究领域。通过杂交策略开发小分子双靶标抑制剂可提供高度有效和选择性的抗癌药。在这项研究中，设计并合成了三个系列的带有苯磺酰胺部分的喹唑啉衍生物，作为双重EGFR / CAIX抑制剂。评价了所有合成的化合物对表皮样癌（A431）和非小细胞肺癌（A549和H1975）细胞系的抵抗，这些细胞系显示出弱至有效的抗癌活性。特别是，化合物8v成为对抗突变型H1975细胞最有效的衍生物，该突变型细胞与osimertinib具有可比的活性。重要的是8v在缺氧条件下，对H1975细胞具有比osimertinib更强的抗增殖活性。激酶抑制研究表明8v对EGFR T790M酶具有优异的抑制作用，其效力是吉非替尼的41倍，几乎与奥西替尼相当。机理研究表明8v在H1975细胞中显示出与乙酰唑胺相当的CAIX抑制作用，并显着抑制p-EGFR及其下游p-AKT和p-ER
• Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold
  作者：Yilan Ju、Jintao Wu、Xi Yuan、Luqing Zhao、Ganlin Zhang、Chao Li、Renzhong Qiao

  DOI：10.1021/acs.jmedchem.8b01612

  日期：2018.12.27

  (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold

  表皮生长因子受体（EGFR）的三磷酸腺苷（ATP）竞争性抑制剂已大大改善了非小细胞肺癌（NSCLC）的疾病预后。不幸的是，某些市售药物会影响EGFR突变型NSCLC患者的短暂有益反应。我们通过将大环多胺掺入4-苯胺基喹唑啉支架中，报道了一系列潜在的EGFR抑制剂。预期苯胺基喹唑啉部分有效结合至EGFR域，而ATP分子被大环多胺部分捕获。体外实验显示，大多数测试化合物比吉非替尼和拉帕替尼（EGFR / HER2的双重抑制剂）抑制肿瘤细胞增殖的能力更强。在激酶测定中，化合物1f对EGFR WT（IC 50 = 1.4 nM）和HER2（IC 50 = 2.1 nM）表现出优异的双重抑制活性。1f的体内药理学评估显示，A549异种移植小鼠具有显着的抗肿瘤活性（TGI = 44.2％）。当前的工作为优化基于苯胺喹唑啉的抑制剂提供了可行的解决方案。
• Design, synthesis and anti-tumor activity evaluation of 4,6,7-substitute quinazoline derivatives
  作者：Honglin Dai、Xiaojie Si、Hao Wang、Lingling Chi、Chao Gao、Zhengjie Wang、Limin Liu、Zhuo Qian、Yu Ke、Qiurong Zhang、Hongmin Liu

  DOI：10.1007/s00044-022-02897-9

  日期：2022.8

  A series of novel 4,6,7-substituted quinazoline derivatives were designed, synthesized and evaluated for their antiproliferative activities against human cancer cell lines (PC-3, MGC-803, HGC-27, A549 and H1975). Among all the target compounds, compound 22s displayed the most potent anti-proliferative activity against MGC-803 cells in vitro. Further mechanism studies revealed that compound 22s could

  设计、合成了一系列新型 4,6,7-取代的喹唑啉衍生物，并评估了它们对人类癌细胞系（PC-3、MGC-803、HGC-27、A549 和 H1975）的抗增殖活性。在所有目标化合物中，化合物22s在体外对 MGC-803 细胞表现出最有效的抗增殖活性。进一步的机制研究表明，化合物22s可以明显抑制MGC-803细胞的集落形成和迁移。同时，化合物22s可诱导MGC-803细胞凋亡，诱导细胞周期停滞于G1期。总的来说，这些工作表明化合物22s可能是优化基于苯胺喹唑啉的抗肿瘤药物的有价值的解决方案。
• Design, synthesis and antitumor activity evaluation of 4,6,7-trisubstituted quinazoline derivatives containing benzothiazole moiety
  作者：Fuqiang Yu、Ying Xu、Hao Wang、Lingling Chi、Xiaojie Si、Chao Gao、Honglin Dai、Limin Liu、Zhengjie Wang、Yu Ke、Hongmin Liu、Qiurong Zhang

  DOI：10.1007/s00044-023-03117-8

  日期：2023.10

  A series of novel 4,6,7-trisubstituted quinazoline derivatives containing benzothiazole moiety were designed, synthesized and evaluated for their antitumor activity against four human cancer cells (PC-3, MGC-803, A549 and Eca-109) using MTT assay. Among them, compound 11k showed the most potent cytotoxicity against PC-3 cells (IC50 = 5.59 ± 0.78 μM). Compound 11k also significantly inhibited the colony

  设计、合成了一系列含有苯并噻唑部分的新型4,6,7-三取代喹唑啉衍生物，并使用MTT法评估了它们对四种人类癌细胞（PC-3、MGC-803、A549和Eca-109）的抗肿瘤活性。其中，化合物11k对PC-3细胞表现出最强的细胞毒性（IC 50  = 5.59 ± 0.78 μM）。化合物11k还显着抑制PC-3细胞的集落形成和迁移。同时，化合物11k诱导细胞周期停滞在S期和细胞凋亡，并增加细胞内活性氧的积累。所有研究结果表明化合物11k可能是针对前列腺癌细胞的抗肿瘤药物的一种有价值的先导化合物。
• Enhancement of EGFR tyrosine kinase inhibition by C–C multiple bonds-containing anilinoquinazolines
  作者：Hyun Seung Ban、Yuko Tanaka、Wataru Nabeyama、Masako Hatori、Hiroyuki Nakamura

  DOI：10.1016/j.bmc.2009.11.035

  日期：2010.1

  A series of 4-anilinoquinazolines with C-C multiple bond substitutions at the 6-position were synthesized and investigated for their potential to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Among the compounds synthesized, alkyne 6d and allenes 7d and 7f significantly inhibited EGFR tyrosine kinase activity. These compounds inhibited EGF-mediated phosphorylation of EGFR in A431 cells, resulting in cell-cycle arrest and apoptosis induction. The C-C multiple bonds substituted at the C-6 position of the anilinoquinazoline framework were essential for the significant inhibitory activity. Compounds with long carbon chains (n = 3-6), such as 6c-f, 7c-f, 11, and 12, displayed prolonged inhibitory activity. (C) 2009 Elsevier Ltd. All rights reserved.