N-(3-氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺 | 612500-78-4

• 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: N-(3-氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺
• 英文名称: 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline
• 英文别名: N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine；N-(3-chloro-2-fluorophenyl)-7-methoxy-6-piperidin-4-yloxyquinazolin-4-amine
• CAS: 612500-78-4
• 化学式: C₂₀H₂₀ClFN₄O₂
• 分子量: 402.856
• InChiKey: DFNJBNWBONZOQL-UHFFFAOYSA-N

物化性质

• 沸点：
  524.7±50.0 °C(Predicted)
• 密度：
  1.348±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  68.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(3-氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 21.0h， 生成 3-[4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]propionic acid dihydrochloride
  参考文献：
  名称：

  Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

  摘要：

  Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.

  DOI：

  10.1021/ml400146c
• 作为产物：
  描述：

  2-氨基-4,5-二甲氧基苯甲酸乙酯 在 吡啶 、 4-二甲氨基吡啶 、 甲烷磺酸 、 L-蛋氨酸 、 氨 、 cesium fluoride 、 N,N-二乙基苯胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 N,N-二甲基乙酰胺 、 水 、 异丙醇 为溶剂， 反应 60.0h， 生成 N-(3-氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺
  参考文献：
  名称：

  The first radiosynthesis of [ 11 C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling

  摘要：

  The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl)oxy) piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [C-11] AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl)-N-[C-11] methylacetamide} ([C-11]11a) was prepared from N-desmethyl-AZD8931 (11b) with [C-11]CH3OTf under basic condition (NaH) through N-[11C] methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [C-11]CO2 and decay corrected to end of bombardment (EOB) with 370-1110 GBq/mu mol specific activity at EOB. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.07.092

文献信息

• [EN] QUINAZOLINE DERIVATIVES<br/>[FR] DERIVES DE QUINAZOLINE
  申请人：ASTRAZENECA AB

  公开号：WO2005028469A1

  公开（公告）日：2005-03-31

  The invention concerns quinazoline derivatives of Formula (I): wherein each of R1, X1, R2, R3, R5, n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

  这项发明涉及式(I)的喹唑啉衍生物：其中R1、X1、R2、R3、R5、n和m中的每一个具有描述中定义的任意含义；它们的制备方法，含有它们的药物组合物以及它们在制造用作抗增殖剂的药物时的用途，用于预防或治疗对EGF和erbB受体酪氨酸激酶抑制敏感的肿瘤。
• NOVEL SALT-554
  申请人：Dobson Andrew Hornby

  公开号：US20090286982A1

  公开（公告）日：2009-11-19

  4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate, pharmaceutical compositions containing the difumarate, the use of the difumarate in the treatment of hyperproliferative disorders such as cancer and processes for the manufacture of the difumarate are described.

  描述了含有二富马酸的4-(3-氯-2-氟苯胺基)-7-甲氧基-6-[1-(N-甲基氨甲酰基甲基)哌啶-4-基]氧基}喹唑啉的制药组合物，以及二富马酸在治疗癌症等高增殖性疾病中的用途，以及制备二富马酸的方法。
• [EN] 4-ANILINO QUINAZOLINE DERIVATIVES AS ANTIPROLIFERATIVE AGENTS<br/>[FR] DERIVES DE 4-ANILINO QUINAZOLINE UTILISES EN TANT QU'AGENTS ANTIPROLIFERATIFS
  申请人：ASTRAZENECA AB

  公开号：WO2003082831A1

  公开（公告）日：2003-10-09

  The invention concerns quinazoline derivatives of Formula (I) wherein each of Q1, Z, R1 and Q2 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases.

  该发明涉及式（I）的喹唑啉衍生物，其中Q1、Z、R1和Q2中的每一个具有描述中定义的任何含义；其制备方法，含有它们的药物组合物以及它们在制备用作抗增殖剂的药物中的使用，用于预防或治疗对erbB受体酪氨酸激酶抑制敏感的肿瘤。
• Design of a “Two-in-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites
  作者：Florian Wittlinger、David E. Heppner、Ciric To、Marcel Günther、Bo Hee Shin、Jaimin K. Rana、Anna M. Schmoker、Tyler S. Beyett、Lena M. Berger、Benedict-Tilman Berger、Nicolas Bauer、James D. Vasta、Cesear R. Corona、Matthew B. Robers、Stefan Knapp、Pasi A. Jänne、Michael J. Eck、Stefan A. Laufer

  DOI：10.1021/acs.jmedchem.1c00848

  日期：2022.1.27

  Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now

  针对表皮生长因子受体 (EGFR) 的抑制剂是治疗 EGFR 激酶结构域中具有药物敏感性激活突变的非小细胞肺癌患者的有效疗法。由于治疗获得性突变而产生的耐药性推动了在 ATP 位点结合的连续几代抑制剂的开发。第三代药物奥希替尼现已成为该病的一线治疗药物。最近，已经开发出变构抑制剂来克服赋予奥希替尼耐药性的耐药突变。在这里，我们介绍了突变选择性先导化合物的结构指导设计和合成，该先导化合物由同时占据正构和变构位点的吡啶基咪唑稠合苄基异二氢吲哚二酮支架组成。该化合物有效抑制 L858R/T790M/C797S 突变体 EGFR 中的酶活性 (4.9 nM)，对野生型 EGFR (47 nM) 的活性显着降低。此外，该化合物对 L858R (1.2 μM) 和 L858R/T790M (4.4 μM) 变体具有适度的非西妥昔单抗依赖性和突变体选择性细胞功效。
• [EN] PIPERIDYL-QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS<br/>[FR] DERIVEES DE PIPERIDYL-QUINAZOLINE UTILISES COMME INHIBITEURS DE LA TYROSINE KINASE
  申请人：ASTRAZENECA AB

  公开号：WO2005012290A1

  公开（公告）日：2005-02-10

  The invention concerns quinazoline derivatives of formula (I) wherein R1 and R2 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB, particularly EGF, receptor tyrosine kinases.

  该发明涉及式（I）的喹嗪啉衍生物，其中R1和R2具有描述中定义的任何含义；它们的制备方法，包含它们的制药组合物以及它们在制造抗增殖剂用药物方面的使用，用于预防或治疗对erbB，特别是EGF，受体酪氨酸激酶抑制敏感的肿瘤。