4-Phenylamino-3-quinolinecarbonitrile deriv. 25

• 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
• 英文名称: 4-Phenylamino-3-quinolinecarbonitrile deriv. 25
• 英文别名: 4-(2,4-dichloroanilino)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carbonitrile
• 化学式: C₂₄H₂₄Cl₂N₄O₃
• 分子量: 487.386
• InChiKey: BRHLUELBKABILP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  79.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-氯-7-(3-氯丙氧基)-3-氰基-6-甲氧基喹啉 在 吡啶盐酸盐 、 sodium iodide 作用下， 以 乙二醇乙醚 、 乙二醇二甲醚 为溶剂， 反应 13.0h， 生成 4-Phenylamino-3-quinolinecarbonitrile deriv. 25
  参考文献：
  名称：

  Synthesis and Src Kinase Inhibitory Activity of a Series of 4-Phenylamino-3-quinolinecarbonitriles

  摘要：

  Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC50 of 3.8 nM in the Src enzymatic assay and an IC50 of 940 nM for the inhibition of Src-dependent cell proliferation.

  DOI：

  10.1021/jm000420z

文献信息

• Three hybrid assay system
  申请人：GPC Biotech AG

  公开号：EP1975620A2

  公开（公告）日：2008-10-01

  The invention provides compositions and methods for isolating ligand binding polypeptides for a user-specified ligand, and for isolating small molecule ligands for a user-specified target polypeptide using an improved class of hypbrid ligand compounds.

  本发明提供了用于分离用户指定配体的配体结合多肽的组合物和方法，以及使用改良的低杂合配体化合物分离用户指定目标多肽的小分子配体的组合物和方法。
• Method of treatment of myocardial infarction
  申请人：——

  公开号：US20040214836A1

  公开（公告）日：2004-10-28

  Myocardial infarction in a mammal is treated by administering to the mammal a therapeutically effective amount of a chemical Src family tyrosine kinase protein inhibitor and the use of such inhibitor compounds for the preparation of a medicament for treating myocardial infarction. Myocardial infarction can be prevented by administering to the mammal a prophylactic amount of the inhibitor. The inhibitor preferably is an inhibitor of Src protein selected from the group consisting of a pyrazolopyrimidine class Src family tyrosine kinase inhibitor, a macrocyclic dienone class Src family tyrosine kinase inhibitor, a pyrido[2,3-d]pyrimidine class Src family tyrosine kinase inhibitor, a 4-anilino-3-quinolinecarbonitrile class Src family tyrosine kinase inhibitor, and a mixture thereof. In a particularly preferred embodiment, the Src family tyrosine kinase inhibitor is an ATP-competitive Src family tyrosine kinase inhibitor having a hydrophobic group that is less than about 6 angstroms in size situated adjacent to an ATP-mimicing heteroaromatic moiety. The Src family tyrosine kinase inhibitors can be used to prepare medicaments for the treatment of myocardial infarction. Also disclosed are articles of manufacture containing a chemical Src family tyrosine kinase inhibitor.

  通过向哺乳动物施用治疗有效量的化学Src家族酪氨酸激酶蛋白抑制剂和使用这种抑制剂化合物制备治疗心肌梗塞的药物，可以治疗哺乳动物的心肌梗塞。向哺乳动物施用预防量的抑制剂可预防心肌梗塞。该抑制剂优选为选自吡唑嘧啶类Src家族酪氨酸激酶抑制剂、大环二烯酮类Src家族酪氨酸激酶抑制剂、吡啶[2,3-d]嘧啶类Src家族酪氨酸激酶抑制剂、4-苯胺基-3-喹啉甲腈类Src家族酪氨酸激酶抑制剂及其混合物组成的组的Src蛋白抑制剂。在一个特别优选的实施方案中，Src 家族酪氨酸激酶抑制剂是一种 ATP 竞争性 Src 家族酪氨酸激酶抑制剂，其疏水基团的大小小于约 6 埃，与 ATP 拟合杂芳香族分子相邻。Src家族酪氨酸激酶抑制剂可用于制备治疗心肌梗塞的药物。还公开了含有化学Src家族酪氨酸激酶抑制剂的制造品。
• METHOD OF TREATMENT OF MYOCARDIAL INFARCTION
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：EP1744735A2

  公开（公告）日：2007-01-24
• [EN] METHOD OF TREATMENT OF MYOCARDIAL INFARCTION<br/>[FR] METHODE PERMETTANT DE TRAITER L'INFARCTUS DU MYOCARDE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2005089366A2

  公开（公告）日：2005-09-29

  Myocardial infarction in a mammal is treated by administering to the mammal a therapeutically effective amount of a chemical Src family tyrosine kinase protein inhibitor and the use of such inhibitor compounds for the preparation of a medicament for treating myocardial infarction. Myocardial infarction can be prevented by administering to the mammal a prophylactic amount of the inhibitor. The inhibitor preferably is an inhibitor of Src protein selected from the group consisting of a pyrazolopyrimidine class Src family tyrosine kinase inhibitor, a macrocyclic dienone class Src family tyrosine kinase inhibitor, a pyrido[2,3-d]pyrimidine class Src family tyrosine kinase inhibitor, a 4-anilino-3-quinolinecarbonitrile class Src family tyrosine kinase inhibitor, and a mixture thereof. In a particularly preferred embodiment, the Src family tyrosine kinase inhibitor is an ATP-competitive Src family tyrosine kinase inhibitor having a hydrophobic group that is less than about 6 angstroms in size situated adjacent to an ATP-mimicing heteroaromatic moiety. The Src family tyrosine kinase inhibitors can be used to prepare medicaments for the treatment of myocardial infarction. Also disclosed are articles of manufacture containing a chemical Src family tyrosine kinase inhibitor.
• Synthesis and Src Kinase Inhibitory Activity of a Series of 4-Phenylamino-3-quinolinecarbonitriles
  作者：Diane H. Boschelli、Yanong D. Wang、Fei Ye、Biqi Wu、Nan Zhang、Minu Dutia、Dennis W. Powell、Allan Wissner、Kim Arndt、Jennifer M. Weber、Frank Boschelli

  DOI：10.1021/jm000420z

  日期：2001.3.1

  Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC50 of 3.8 nM in the Src enzymatic assay and an IC50 of 940 nM for the inhibition of Src-dependent cell proliferation.