5-bromo-N-(2,4-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide | 1223081-65-9

• 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: 5-bromo-N-(2,4-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide
• 英文别名: 5-bromo-N-[(2,4-dichlorophenyl)methyl]-8-hydroxy-1,6-naphthyridine-7-carboxamide
• CAS: 1223081-65-9
• 化学式: C₁₆H₁₀BrCl₂N₃O₂
• 分子量: 427.084
• InChiKey: AVQFKQPKBCZNAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  75.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bromo-N-(2,4-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 8-(((1r,4r)-4-aminocyclohexyl)amino)-5-bromo-N-(2,4-dichlorobenzyl)-1,6-naphthyridine-7-carboxamide
  参考文献：
  名称：

  Investigation on the 1,6-naphthyridine motif: discovery and SAR study of 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one-based c-Met kinase inhibitors

  摘要：

  1,6-萘啶结构是药物化学中的一种多价支架，在适当取代时表现出多种生物活性。通过在1,6-萘啶框架中引入一个环脲药效基，并通过对7、8位进行构象约束，所得到的1H-咪唑[4,5-h][1,6]萘啶-2(3H)-酮被确认为一种新的c-Met激酶抑制剂。全面的SAR研究表明，带有末端游离氨基的N-1烷基取代基、N-3位的疏水性取代苯基团以及三环核心对于保持1H-咪唑[4,5-h][1,6]萘啶-2(3H)-酮化合物的有效Met抑制至关重要。进一步在C-5位引入4′-氨甲酰基苯氧基基团显著提高了活性。最佳的c-Met激酶抑制活性由2t所体现，IC50 = 2.6 μM，同时在低微摩尔浓度下对TPR-Met磷酸化和BaF3-TPR-Met细胞增殖表现出有效抑制。

  DOI：

  10.1039/c2ob26710a
• 作为产物：
  描述：

  2,3-吡啶二羧酸酐 在 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 氯化亚砜 、 magnesium sulfate 、 N,N-二甲基甲酰胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 48.0h， 生成 5-bromo-N-(2,4-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide
  参考文献：
  名称：

  Repositioning HIV-1 Integrase Inhibitors for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold with Drug-like Properties

  摘要：

  Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.

  DOI：

  10.1021/jm300667v

文献信息

• Investigation on the 1,6-naphthyridine motif: discovery and SAR study of 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one-based c-Met kinase inhibitors
  作者：Yong Wang、Zhong-Liang Xu、Jing Ai、Xia Peng、Jian-Ping Lin、Yin-Chun Ji、Mei-Yu Geng、Ya-Qiu Long

  DOI：10.1039/c2ob26710a

  日期：——

  The 1,6-naphthyridine motif is a multivalent scaffold in medicinal chemistry presenting various bioactivities when properly substituted. By incorporating a cyclic urea pharmacophore into the 1,6-naphthyridine framework through conformationally constraining the 7,8-positions, the resulting 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one was identified as a new class of c-Met kinase inhibitor. A comprehensive SAR study indicated that an N-1 alkyl substituent bearing a terminal free amino group, a hydrophobic substituted benzyl group at the N-3 position and the tricyclic core were essential for retaining effective Met inhibition of the 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one chemotype. Further introduction of a 4′-carboxamide phenoxy group at the C-5 position significantly improved the potency. The best c-Met kinase inhibitory activity was exemplified by 2t with an IC50 = 2.6 μM, which also displayed effective inhibition against TPR-Met phosphorylation and the proliferation of the BaF3-TPR-Met cells at low micromolar concentrations.

  1,6-萘啶结构是药物化学中的一种多价支架，在适当取代时表现出多种生物活性。通过在1,6-萘啶框架中引入一个环脲药效基，并通过对7、8位进行构象约束，所得到的1H-咪唑[4,5-h][1,6]萘啶-2(3H)-酮被确认为一种新的c-Met激酶抑制剂。全面的SAR研究表明，带有末端游离氨基的N-1烷基取代基、N-3位的疏水性取代苯基团以及三环核心对于保持1H-咪唑[4,5-h][1,6]萘啶-2(3H)-酮化合物的有效Met抑制至关重要。进一步在C-5位引入4′-氨甲酰基苯氧基基团显著提高了活性。最佳的c-Met激酶抑制活性由2t所体现，IC50 = 2.6 μM，同时在低微摩尔浓度下对TPR-Met磷酸化和BaF3-TPR-Met细胞增殖表现出有效抑制。
• Repositioning HIV-1 Integrase Inhibitors for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold with Drug-like Properties
  作者：Li-Fan Zeng、Yong Wang、Roza Kazemi、Shili Xu、Zhong-Liang Xu、Tino W. Sanchez、Liu-Meng Yang、Bikash Debnath、Srinivas Odde、Hua Xie、Yong-Tang Zheng、Jian Ding、Nouri Neamati、Ya-Qiu Long

  DOI：10.1021/jm300667v

  日期：2012.11.26

  Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.