6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈 | 361162-95-0

• 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: 6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈
• 中文别名: 6-氨基-4-(3-氯-4-氟苯基氨基)-7-乙氧基-喹啉-3-甲腈
• 英文名称: 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile
• 英文别名: 4-((3-chloro-4-fluorophenyl)amino)-6-amino-7-ethoxyquinoline-3-carbonitrile；6-Amino-4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethyloxyquinoline；6-amino-4-(3-chloro-4-fluoroanilino)-7-ethoxyquinoline-3-carbonitrile
• CAS: 361162-95-0
• 化学式: C₁₈H₁₄ClFN₄O
• 分子量: 356.787
• InChiKey: AIQFOGOHLOICRK-UHFFFAOYSA-N

物化性质

• 熔点：
  181 - 183°C (dec.)
• 溶解度：
  DMSO（少量）、甲醇（少量）

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  84
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈 在 potassium iodide 作用下， 以 乙醇 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：

  间氨基苯乙醚 在 diphenyl ether-biphenyl eutectic 、 亚硝酸铵 、 铁粉 、 氯化铵 、 三氟乙酸酐 、 三氯氧磷 作用下， 以 甲醇 、 异丙醇 、 甲苯 为溶剂， 反应 27.25h， 生成 6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

  摘要：

  A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm020241c
• 作为试剂：
  描述：

  4-(3-chloro-4-fluorophenylamino)-7-ethoxy-6-nitroquinoline-3-carbonitrile hydrochloride 、 氯化铵 、 甲醇 在 铁粉 氮气 、 甲醇 、 乙酸乙酯 、 碳酸氢钠 、 magnesium sulfate 、 CHCl3-hexanes 、 6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈 作用下， 以 水 为溶剂， 反应 4.0h， 生成 6-氨基-4-(3-氯-4氟苯氨基)-7-乙氧基喹啉-3-腈
  参考文献：
  名称：

  Method of treating or inhibiting colonic polyps

  摘要：

  本发明提供了一种治疗或抑制结肠息肉的方法，其包括提供公式1的化合物，其中：R1、R2、R3、R4、X、Y和n如前文所定义，或其药学上可接受的盐。

  公开号：

  US06384051B1

文献信息

• Antineoplastic combinations
  申请人：Wyeth

  公开号：US20030050222A1

  公开（公告）日：2003-03-13

  This invention provides the use of a combination of CCI-779 and EKB-569 in the treatment of neoplasms.

  这项发明提供了在肿瘤治疗中使用CCI-779和EKB-569的组合。
• Protein tyrosine kinase enzyme inhibitors
  申请人：Wissner Allan

  公开号：US20050059678A1

  公开（公告）日：2005-03-17

  This invention provides compounds of formula 1, having the structure wherein R 1 , R 2 , R 3 , R 4 , and R 5 are described within the specification.

  本发明提供了具有以下结构的公式1化合物，其中R1、R2、R3、R4和R5在说明书内描述。
• [EN] SUBSTITUTED QUINOLINES AS PROTEIN TYROSINE KINASE ENZYME INHIBITORS<br/>[FR] UTILISATION DE QUINOLINES SUBSTITUEES COMME INHIBITEURS DE LA TYROSINE KINASE
  申请人：WYETH CORP

  公开号：WO2005034955A1

  公开（公告）日：2005-04-21

  This invention provides compounds of formula (I), having the structure wherein R1, R2, R3 are described within the specification. The compounds act as anti-cancer agents by inhibition of HER-2 and EGFR.

  这项发明提供了一种具有公式(I)的化合物，其结构式中R1、R2、R3在说明书中有描述。这些化合物通过抑制HER-2和EGFR起到抗癌剂的作用。
• 1,2-DITHIOLANE AND DITHIOL COMPOUNDS USEFUL IN TREATING MUTANT EGFR-MEDIATED DISEASES AND CONDITIONS
  申请人：Sabila Biosciences LLC

  公开号：US20180208584A1

  公开（公告）日：2018-07-26

  Compositions of the invention comprise 1,2-dithiolane, dithiol and related compounds useful as therapeutic agents for the treatment and prevention of diseases and conditions associated with aberrant EGFR activity.

  该发明的组合物包括1,2-二硫杂环烷、二硫醇和相关化合物，可用作治疗剂，用于治疗和预防与EGFR活性异常相关的疾病和病况。
• QUINAZOLINE AND QUINOLINE DERIVATIVES AS IRREVERSIBLE PROTEIN TYROSINE KINASE INHIBITORS
  申请人：ZHANG Hesheng

  公开号：US20090105247A1

  公开（公告）日：2009-04-23

  A compound of formula (I), a pharmaceutically acceptable salt, or hydrate thereof, and a method of preparing the same. A method of treating or preventing a physiological disorder caused by abnormal protein tyrosine kinase activity in a mammal comprising administering to said mammal a pharmaceutical composition comprising a compound of formula (I).

  公式（I）的化合物，其药用盐或水合物，以及制备该化合物的方法。一种治疗或预防哺乳动物中由异常蛋白酪氨酸激酶活性引起的生理紊乱的方法，包括向该哺乳动物施用包含公式（I）化合物的药物组合物。