N-(3-chloro-4-fluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine | 1360430-70-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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-(3-chloro-4-fluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine
• CAS: 1360430-70-1
• 化学式: C₁₆H₁₂ClFN₄O₃
• 分子量: 362.748
• InChiKey: JMGHGGXIWOGJQO-UHFFFAOYSA-N

物化性质

• 沸点：
  523.0±50.0 °C(Predicted)
• 密度：
  1.483±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  92.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(3-chloro-4-fluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine 在 5%-palladium/activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 以85%的产率得到N⁴-(3-chloro-4-fluorophenyl)-7-ethoxyquinazoline-4,6-diamine
  参考文献：
  名称：

  作为EGFR抑制剂的喹唑啉衍生物及其应用

  摘要：

  本发明公开了一种作为EGFR抑制剂的喹唑啉衍生物及其应用。该化合物为如式I所示的化合物、其药学上可接受的盐、或前药。该化合物能够用于制备成治疗和/或预防癌症的药物。

  公开号：

  CN109776433A
• 作为产物：
  描述：

  7-氯-4(3H)-喹唑啉酮 在 盐酸 、 硫酸 、 硝酸 、 sodium 、 三氯氧磷 作用下， 以 水 、 异丙醇 为溶剂， 反应 73.5h， 生成 N-(3-chloro-4-fluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine
  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

• [EN] AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF<br/>[FR] DÉRIVÉS D'AMINOQUINAZOLINE, LEURS SELS ET LEURS PROCÉDÉS D'UTILISATION
  申请人：SUNSHINE LAKE PHARMA CO LTD

  公开号：WO2014177038A1

  公开（公告）日：2014-11-06

  Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Also provided herein are pharmaceutical compositions containing the compounds disclosed herein, and uses of the compounds or the compositions for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient and for modulating the protein tyrosine kinase activity.

  本文提供了氨基喹唑啉化合物、盐及其用途。这些化合物具有式(I)，或其立体异构体、几何异构体、互变异构体、N-氧化物、水合物、溶剂合物、代谢物、药学上可接受的盐或其前药。本文还提供了含有上述化合物的药物组合物，以及利用这些化合物或组合物预防、管理、治疗或减轻患者体内增殖性疾病的严重程度，并调节蛋白酪氨酸激酶活性的用途。
• [EN] FUNCTIONALIZED TYROSINE KINASE INHIBITORS MODIFIED WITH PRECIOUS METAL ELECTROPHILES AND METHODS ASSOCIATED THEREWITH<br/>[FR] INHIBITEURS FONCTIONNALISÉS DE LA TYROSINE KINASE MODIFIÉS AVEC DES AGENTS ÉLECTROPHILES DE MÉTAL PRÉCIEUX ET LEURS PROCÉDÉS ASSOCIÉS
  申请人：UNIV WAKE FOREST

  公开号：WO2015142683A1

  公开（公告）日：2015-09-24

  Newly synthesized thiourea-modified 3-chloro-4-fluoroanilio-quinazoline derivatives have been studied, as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylarmino chain. One compound tested acts as a thiourea-S/quinazoline-Nl mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitmib in NCI-H1975 (with IC50 values of 1.7 and 30 μΜ, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.

  新合成的硫脲修饰的3-氯-4-氟苯胺喹唑啉衍生物已被研究，作为线性金(I)配合物中的末端载体配体。这些分子通过计算对接实验模拟了酪氨酸激酶抑制剂吉非替尼。硫脲基团直接连接到喹唑啉-C6上，或通过柔性的乙基氨链连接到该位置。其中一个化合物作为硫脲-S/喹唑啉-Nl混合供体配体，通过X射线晶体学和/或电喷雾质谱确定为非寻常的二核复合物。一个化合物形成所需的稳定线性配合物。在NCI-H460和NCI-H1975肺癌细胞中研究了载体配体和相应的金(I)配合物的生物活性。其中一个被测试的化合物在NCI-H1975中部分克服了对吉非替尼的抵抗（分别具有1.7和30μΜ的IC50值），相应的金配合物（13）在低微摩尔浓度范围内保持活性。
• AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
  申请人：SUNSHINE LAKE PHARMA CO., LTD.

  公开号：US20160039838A1

  公开（公告）日：2016-02-11

  Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Also provided herein are pharmaceutical compositions containing the compounds disclosed herein, and uses of the compounds or the compositions for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient and for modulating the protein tyrosine kinase activity.

  本文提供了氨基喹啉化合物、盐及其用途。该化合物具有式(I)、立体异构体、几何异构体、互变异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或其前药。本文还提供了含有上述化合物的制药组合物，并使用该化合物或组合物预防、管理、治疗或减轻患者的增生性疾病严重程度，并调节蛋白酪氨酸激酶活性。
• Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors
  作者：Long Zhang、Yingying Yang、Haojie Zhou、Qingmei Zheng、Yuhao Li、Shansong Zheng、Shuyong Zhao、Dong Chen、Chuanwen Fan

  DOI：10.1016/j.ejmech.2015.08.026

  日期：2015.9

  We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors
  作者：Mu Yang、Amanda J. Pickard、Xin Qiao、Matthew J. Gueble、Cynthia S. Day、Gregory L. Kucera、Ulrich Bierbach

  DOI：10.1021/ic502998a

  日期：2015.4.6

  Thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as potential receptor-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the epidermal growth factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib. Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex [Au(mu-7-S,N)}(2)]X-2 (X = Cl-, SCN-) (12a,b) (X-ray crystallography, electrospray mass spectrometry). Derivative 9 forms a stable linear complex, [Au(PEt3)(9-S)](NO3) (13). The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. Compound 9 partially overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 mu M, respectively). The corresponding gold complex (13) maintains activity in the low-micromolar concentration range similar to the metal-free carrier. Compound 9 and the corresponding [Au(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar IC50 values similar to those observed for gefitinib under the same assay conditions. Potential mechanisms of action and reactions in biological media of this new type of hybrid agent, as well as shortcomings of the current design are discussed.