SKI-758

• 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: SKI-758
• 英文别名: 4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxy-7-[5-(4-methylpiperazin-1-ylmethyl)furan-3-yl]quinoline-3-carbonitrile；4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methyl piperazin-1-yl)methyl]-furan-3-yl}-3-quinolinecarbonitrile；4-[(2,4-dichloro-5-methoxy-phenyl)amino]-6-methoxy-7-{5-[(4-methyl-piperazin-1-yl)methyl]-3-furyl}-quinoline-3-carbonitrile；4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-quinolinecarbonitrile；4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}quinoline-3-carbonitrile；4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[5-[(4-methylpiperazin-1-yl)methyl]furan-3-yl]quinoline-3-carbonitrile
• 化学式: C₂₈H₂₇Cl₂N₅O₃
• 分子量: 552.46
• InChiKey: ANUHLKPVOXDYSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  86.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-溴-2-呋喃甲醛 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 正丁基锂 、 硼酸三异丙酯 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 溶剂黄146 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 正己烷 、 二氯甲烷 、 异丙醇 为溶剂， 反应 52.0h， 生成 SKI-758
  参考文献：
  名称：

  Synthesis and Src Kinase Inhibitory Activity of a Series of 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles

  摘要：

  Compound 1 (SKI-606, bosutinib), a 7-alkoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile, is a potent inhibitor of Src kinase activity. We previously reported that analogs of 1 with thiophene groups at C-7 retained the Src activity of the parent compound. The corresponding C-7 furan analogs were prepared and it was found that the 3,5-substituted furan analog had increased activity compared to that of the 2,5-substituted furan isomer. Addition of a methoxy group at C-6 decreased the Src inhibitory activity of the C-7 2,5-substituted furan analog but increased the activity of the C-7 3,5-substituted furan isomer. This compound, 10, was a more potent Src inhibitor than 1 in both enzymatic and cell-based assays. The kinase selectivity profile of 10 was similar to that of 1, with 10 also inhibiting the activity of Abl and Lck. When tested in a solid tumor xenograft model, 10 had comparable oral activity to that of 1.

  DOI：

  10.1021/jm061031t

文献信息

• Process for preparation of 4-amino-3-quinolinecarbonitriles
  申请人：Sutherland Wiggins Karen

  公开号：US20050043537A1

  公开（公告）日：2005-02-24

  This invention discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising combining an amine compound with a cyanoacetic acid and an acid catalyst to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline in an alcoholic solvent and a trialkylorthoformate to yield a 3-amino-2-cyanoacrylamide; combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile and also discloses a process for the preparation of a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile comprising combining a disubstituted 3-amino thiophene with a cyanoacetamide and trialkylorthoformate in an alcoholic solvent to obtain a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile and also discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile by combining an amine compound with a cyanoacetic acid and a peptide coupling reagent to obtain a suspension; filtering the suspension to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline, an alcoholic solvent, and triethylorthoformate to yield a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride to yield a 4-amino-3-quinolinecarbonitrile.

  这项发明揭示了一种制备4-氨基-3-喹啉碳腈的过程，包括将胺化合物与氰乙酸和酸催化剂结合以产生氰乙酰胺；将氰乙酰胺与醇溶剂和三烷基正甲酸酯中的一个或多个取代苯胺缩合以产生3-氨基-2-氰基丙烯酰胺；将3-氨基-2-氰基丙烯酰胺与氯化磷在乙腈、丁腈、甲苯或二甲苯中结合，可选地在催化剂存在的情况下以产生4-氨基-3-喹啉碳腈，并且还揭示了一种制备7-氨基噻吩[3,2-b]吡啶-6-碳腈的过程，包括将二取代的3-氨基噻吩与氰乙酰胺和三烷基正甲酸酯在醇溶剂中结合以获得3-氨基-2-氰基丙烯酰胺；将3-氨基-2-氰基丙烯酰胺与氯化磷和乙腈、丁腈、甲苯或二甲苯结合，可选地在催化剂存在的情况下以产生7-氨基噻吩[3,2-b]吡啶-6-碳腈，并且还揭示了一种通过将胺化合物与氰乙酸和肽偶联试剂结合以获得悬浮液；过滤悬浮液以产生氰乙酰胺；将氰乙酰胺与一个或多个取代苯胺、醇溶剂和三乙基正甲酸酯缩合以产生3-氨基-2-氰基丙烯酰胺；将3-氨基-2-氰基丙烯酰胺与氯化磷结合以产生4-氨基-3-喹啉碳腈的制备过程。
• 4-(2,4-dichloro-5-methoxyphenyl)amino-6-methoxy-7-{[5-substituted -amino)methyl]-3-furyl}-3-quinolinecarbonitriles as kinase inhibitors
  申请人：Boschelli Harris Diane

  公开号：US20060035930A1

  公开（公告）日：2006-02-16

  This invention relates to compounds having the structure of Formula I wherein R 1 , R 2 , R 3 , and R 4 are described herein.

  这项发明涉及具有Formula I结构的化合物，其中R1、R2、R3和R4如本文所述。
• 4-(2,4-dichloro-5-methoxyphenyl)amino-6-methoxy-7-{[5-substituted-amino)methyl]-3-furyl}-3-quinolinecarbonitriles as kinase inhibitors
  申请人：Wyeth

  公开号：US07479561B2

  公开（公告）日：2009-01-20

  This invention relates to compounds having the structure of Formula I wherein R1, R2, R3, and R4 are described herein.

  本发明涉及具有I式结构的化合物，其中R1、R2、R3和R4在此处描述。
• [EN] DEUTERATED 3-CYANO QUINOLINE COMPOUND, PHARMACEUTICAL COMPOSITION, PREPARATION METHOD AND USE THEREOF<br/>[FR] COMPOSÉ DE 3-CYANOQUINOLÉINE DEUTÉRÉ, COMPOSITION PHARMACEUTIQUE LE COMPRENANT, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION
  申请人：SHANGHAI PHARMACEUTICALS HOLDING CO LTD

  公开号：WO2014086284A1

  公开（公告）日：2014-06-12

  本发明公开了一类氘代3-氰基喹啉类化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物等和含有这类化合物的药物组合物，以及这些化合物或组合物在制备治疗或预防肿瘤的药物特别是蛋白激酶抑制剂类药物中的用途。与现有技术相比，本发明的化合物在血药浓度、半衰期、清除率、微粒体稳定性、生物利用度或者酶抑制等性质上具有明显的优异性，因此可以更有效地抑制一种以上的蛋白激酶活性和/或抑制肿瘤细胞的生长。
• METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS OR MUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF
  申请人：Del Mar Pharmaceuticals

  公开号：EP2872161A2

  公开（公告）日：2015-05-20