4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-ol | 1012058-27-3

• 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: 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-ol
• 英文别名: 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-hydroxy-7-methoxy-quinazoline；4-[3-Chloro-4-[(3-fluorophenyl)methoxy]anilino]-7-methoxyquinazolin-6-ol
• CAS: 1012058-27-3
• 化学式: C₂₂H₁₇ClFN₃O₃
• 分子量: 425.847
• InChiKey: YCGIPLMVLHSUHF-UHFFFAOYSA-N

物化性质

• 熔点：
  239-241 °C
• 沸点：
  591.4±50.0 °C(Predicted)
• 密度：
  1.422±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  76.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-ol 在 正丁基锂 、 potassium carbonate 、 potassium iodide 作用下， 以 四氢呋喃 、 正己烷 、 乙腈 为溶剂， 反应 16.5h， 生成 3-((4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

  摘要：

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.12.055
• 作为产物：
  描述：

  3-氯-4-(3-氟苄氧基)苯胺 在 ammonium hydroxide 作用下， 以 甲醇 、 异丙醇 为溶剂， 反应 4.0h， 生成 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-methoxyquinazolin-6-ol
  参考文献：
  名称：

  6-（硝基咪唑-1 H-烷氧基）-4-苯胺基喹唑啉类化合物的设计，合成及生物学评价

  摘要：

  通过将低氧活化的硝基咪唑基团引入EGFR抑制剂的喹唑啉骨架中，设计，合成和评估了一系列新型的6-（硝基咪唑-1 H-烷氧基）-4-苯胺基喹唑啉衍生物（15a – 15r），并将其评估为有效的EGFR抑制剂。这些新合成的化合物中的大多数在常氧和低氧条件下对吉非替尼表现出可比的EGFR抑制活性，对HT-29细胞具有中等至优异的抗增殖活性。最有前途的化合物15c中所显示的IC 50 0.47 nM的针对EGFR的激酶值和优异的细胞毒性作用对HT-29细胞在含氧量正常和低氧与IC 50值分别为2.21μM和1.62μM。模拟还原激活研究表明，化合物15c在缺氧条件下具有还原激活特性，这与体外代谢研究一致，在体外代谢研究中，15c在缺氧条件下易于还原激活，在常氧条件下稳定性更高。所有这些结果表明15c在常氧和低氧下都是潜在的癌症治疗剂，值得进一步开发。

  DOI：

  10.1016/j.ejmech.2014.11.010

文献信息

• Quinazoline Derivatives, Preparation Methods and Uses Thereof
  申请人：Guo Jianhui

  公开号：US20080300248A1

  公开（公告）日：2008-12-04

  The present invention has disclosed a compound of formula I and a pharmaceutically acceptable salt or a solvate thereof, wherein the substituents are as defined in the description. The invention has also disclosed a method for preparing the compound of formula I, the pharmaceutical compositions comprising the same and their uses in the preparation of an anti-tumor medicament.

  本发明公开了公式I的化合物以及药用可接受的盐或溶剂化物，其中取代基如描述中定义。本发明还公开了制备公式I化合物的方法，包含该化合物的药物组合物及其在制备抗肿瘤药物中的用途。
• 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。
• Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
  申请人：Himmelsbach Frank

  公开号：US20050182043A1

  公开（公告）日：2005-08-18

  The present invention relates methods for treating disease conditions selected from the list consisting of benign or malignant tumors, diseases of the airways and lungs, diseases of the gastrointestinal tract, the bile duct and the gall bladder by administration to a patient in need thereof of a therapeutically effective amount of a bicyclic heterocyclic groups of general formula wherein said substituents are as defined herein.

  本发明涉及一种治疗疾病的方法，所述疾病包括良性或恶性肿瘤、呼吸道和肺部疾病、胆道和胆囊疾病以及胃肠道疾病，通过向需要治疗的患者施用以下一般式的双环杂环基的治疗有效量：其中所述取代基如定义所述。
• QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Qian Changgeng

  公开号：US20080194578A1

  公开（公告）日：2008-08-14

  The present invention relates to quinazoline containing zinc-binding moiety based derivatives that have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及含有锌结合基团的喹唑啉衍生物，具有增强和意外的抑制表皮生长因子受体酪氨酸激酶（EGFR-TK）的性质，并可用于治疗EGFR-TK相关的疾病和疾病，如癌症。所述衍生物还可以作为HDAC抑制剂。