(E)-N-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4-(dimethylamino)but-2-enamide | 1245555-42-3

• 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: (E)-N-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4-(dimethylamino)but-2-enamide
• 英文别名: (2E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl]-4-(dimethylamino)-2-butenamide；(E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide；(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide
• CAS: 1245555-42-3
• 化学式: C₂₁H₂₁ClFN₅O₂
• 分子量: 429.881
• InChiKey: DXCQAHHHTYQESK-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  79.4
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide 、 二甲胺 以 异丁酰胺 、 水 为溶剂， 生成 (E)-N-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4-(dimethylamino)but-2-enamide
  参考文献：
  名称：

  [EN] PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
  [FR] FORMES PROMÉDICAMENTS D'INHIBITEURS DE KINASE ET LEUR UTILISATION EN THÉRAPIE

  摘要：

  公开号：

  WO2010104406A8

文献信息

• PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
  申请人：Smaill Jeffrey Bruce

  公开号：US20120077811A1

  公开（公告）日：2012-03-29

  The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R 1 is a group of the formula —(CH 2 ) n Tr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH 2 ) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R 2 , R 3 and R 4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R 2 )(R 3 )(R 4 )N, or two of R 2 , R 3 , and R 4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R 2 , R 3 and R 4 may be absent and two of R 2 , R 3 and R 4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

  本发明提供了新型的前药化合物，包括一种激酶抑制剂和一种还原活化的破裂芳香族硝基杂环或芳香族硝基碳杂环触发剂，其中该化合物带有正电荷。在优选实施例中，该化合物为式I：其中：X是任何带负电的反离子；R1是公式—(CH2)nTr的基团，其中Tr是芳香族硝基杂环或芳香族硝基碳杂环，—(CH2)nTr作为还原活化的破裂触发器；n是0到6的整数；R2、R3和R4可以各自独立地选择来自三级胺激酶抑制剂的脂肪族或芳香族基团(R2)(R3)(R4)N，或者R2、R3和R4中的两个可以形成激酶抑制剂的脂肪族或芳香族杂环胺环，或者R2、R3和R4中的一个可以缺失，R2、R3和R4中的两个可以形成激酶抑制剂的芳香族杂环胺环。该发明的化合物可用于治疗增殖性疾病，如癌症。
• Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury
  作者：Davis H. Chase、Adrian M. Bebenek、Pengju Nie、Saul Jaime‐Figueroa、Arseniy Butrin、Danielle A. Castro、John Hines、Brian M. Linhares、Craig M. Crews

  DOI：10.1002/anie.202316496

  日期：2024.4.2

  Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed “undruggable”. Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA‐approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure‐based drug design approach, aided by mass‐spectrometry and X‐ray crystallography, to develop DHC‐156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase‐inhibition from this novel scaffold while demonstrating that DHC‐156 induces the post‐translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies.

  摘要brachyury是一种致癌转录因子，其过度表达会促进脊索瘤的生长。下调脊索瘤细胞中的 brachyury 已被证明具有治疗潜力，然而，作为一种转录因子，它通常被认为是 "不可药用的"。鉴于针对 brachyury 的直接药理干预已被证明是困难的，干预尝试转而针对上游激酶。最近，美国 FDA 批准的激酶抑制剂阿法替尼被证明可以调节多个脊索瘤细胞系中的 brachyury 水平。在本文中，我们以阿法替尼为先导，采用基于结构的药物设计方法，在质谱分析和 X 射线晶体学的帮助下，开发出了 DHC-156，一种能更有选择性地结合 brachyury 并像阿法替尼一样有效地降低其调节水平的小分子。我们消除了这种新型支架的激酶抑制作用，同时证明了 DHC-156 能够诱导 brachyury 翻译后的下调，从而导致脊索瘤肿瘤细胞生长受到不可逆的损害。因此，我们证明了直接调控 brachyury 的可行性，这种方法可进一步开发为更有效的工具化合物和疗法。
• Process for the preparation of N-[4-[(3-chloro-4-fluoro phenyl) amino]-7-[[(3s-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) and its polymorphs thereof
  申请人：MSN LABORATORIES PRIVATE LIMITED

  公开号：US10550107B2

  公开（公告）日：2020-02-04

  The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:

  本发明涉及一种制备 N-[4-[(3-氯-4-氟苯基)氨基]-7-[[(3S)-四氢-3-呋喃基]氧基]-6-喹唑啉基]-4-(二甲基氨基)-(2E)-2-丁烯酰胺 (2Z)-2-丁烯二酸盐 (1:2)的改进工艺，其结构式如下：
• US9073916B2
  申请人：——

  公开号：US9073916B2

  公开（公告）日：2015-07-07
• [EN] PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY<br/>[FR] FORMES PROMÉDICAMENTS D'INHIBITEURS DE KINASE ET LEUR UTILISATION EN THÉRAPIE
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2010104406A8

  公开（公告）日：2011-10-06