N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]乙酰胺 | 848655-77-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]乙酰胺
• 英文名称: N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide
• 英文别名: N-[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-acetamide；N-(4-((3-Chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide；N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]acetamide
• CAS: 848655-77-6
• 化学式: C₂₀H₁₆ClFN₄O₂
• 分子量: 398.824
• InChiKey: FUUGSWZVLCMSJE-UHFFFAOYSA-N

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：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]乙酰胺 在 盐酸 、 potassium iodide 作用下， 以 乙醇 、 水 为溶剂， 生成 N-(4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl)-3-piperidin-1-ylpropanamide
  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
• 作为产物：
  描述：

  N-(3-氰基-7-乙氧基-4-羟基喹啉-6-基)乙酰胺 在 吡啶盐酸盐 、 三氯氧磷 作用下， 以 二乙二醇二甲醚 、 异丙醇 为溶剂， 生成 N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]乙酰胺
  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

• 喹啉及喹唑啉衍生物、制备方法、中间体、组 合物及应用
  申请人：上海医药集团股份有限公司

  公开号：CN103965120B

  公开（公告）日：2016-08-17

  本发明公开了喹啉及喹唑啉衍生物I、制备方法、中间体C、组合物及应用。该制备方法包括：方法一：①溶剂中，在碱1的作用下，将化合物A与化合物B进行反应，得到化合物C；②溶剂中，在碱2的作用下，将步骤①得到的产物C与化合物D进行反应；方法二：溶剂中，在碱1的作用下，将化合物A与化合物E进行反应。本发明还提供了上述式I化合物或上述药物组合物在制备EGFR酪氨酸激酶抑制剂、A431或H1975细胞增殖抑制剂、或者预防或治疗肿瘤疾病的药物中的应用。本发明提供的化合物具有较佳的抗肿瘤活性。。
• Process for the synthesis of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile
  申请人：Daigneault Sylvain

  公开号：US20050065181A1

  公开（公告）日：2005-03-24

  The present invention provides a process for the preparation of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile comprising the steps and products disclosed within this application.

  本发明提供了一种制备6-氨基-4-(3-氯-4-氟苯胺基)-7-乙氧基喹啉-3-羧腈的方法，包括本申请中披露的步骤和产品。
• [EN] QUINOLINE DERIVATIVES USED AS PET IMAGING AGENTS<br/>[FR] DÉRIVÉS DE LA QUINOLÉINE UTILISÉS COMME AGENTS D'IMAGERIE PET
  申请人：IMP INNOVATIONS LTD

  公开号：WO2011077095A1

  公开（公告）日：2011-06-30

  There is provided compounds of formula (I), wherein R1, R2, X1, X2, and X3 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful as positron emission tomography (PET) imaging agents, useful in the treatment of diseases in which inhibition of epidermal growth factor receptor tyrosine kinase activity or the inhibition of HER2 activity is desired and/or required, and useful in the treatment of cancer.

  提供化合物的化学式（I），其中R1、R2、X1、X2和X3的含义如描述中所述，并其药用盐，这些化合物可用作正电子发射断层扫描（PET）成像剂，适用于治疗需要或必须抑制表皮生长因子受体酪氨酸激酶活性或抑制HER2活性的疾病，并适用于癌症的治疗。
• Development of a new epidermal growth factor receptor positron emission tomography imaging agent based on the 3-cyanoquinoline core: Synthesis and biological evaluation
  作者：Federica Pisaneschi、Quang-De Nguyen、Elham Shamsaei、Matthias Glaser、Edward Robins、Maciej Kaliszczak、Graham Smith、Alan C. Spivey、Eric O. Aboagye

  DOI：10.1016/j.bmc.2010.08.004

  日期：2010.9

  97 ± 9.06 nM), low lipophilicity and good metabolic stability. ‘Click’ labeling afforded [18F]16 in 37.0 ± 3.6% decay corrected radiochemical yield based on azide [18F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [18F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a fourfold higher uptake in high

  表皮生长因子受体 (EGFR/c-ErbB1/HER1) 在许多癌症中过度表达，包括乳腺癌、卵巢癌、子宫内膜癌和非小细胞肺癌。EGFR 特异性显像剂可以促进原发肿瘤和/或转移瘤的临床评估。为了实现这一目标，我们设计并合成了一系列基于 3-氰基喹啉核心的含氟化合物。铅化合物，16，结合-2'-氟乙基-1,2,3-三唑被选择用于评价作为基于其对EGFR高亲和力放射性配体激酶（IC 50  = 1.81±0.18 nM）的，良好的细胞效力（IC 50  = 21.97 ± 9.06 nM)，低亲脂性和良好的代谢稳定性。提供“点击”标签 [ 18 F] 16在基于叠氮化物 [ 18 F] 14 的37.0 ± 3.6% 衰减校正放射化学收率和来自氟化物水溶液的 7% 合成结束 (EOS) 收率。在3小时的总合成时间内以>99%的放射化学纯度获得化合物[ 18 F] 16。与低表达 EGFR 的 HCT116
• Process for the synthesis of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile
  申请人：Daigneault Sylvain

  公开号：US20080161575A1

  公开（公告）日：2008-07-03

  The present invention provides a process for the preparation of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile comprising the steps and products disclosed within this application.

  本发明提供了一种制备6-氨基-4-(3-氯-4-氟-苯胺基)-7-乙氧基喹啉-3-羧腈的方法，包括本申请中披露的步骤和产品。