5-bromo-N-(4-fluorobenzyl)-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxamide | 500129-84-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-bromo-N-(4-fluorobenzyl)-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxamide
• 英文别名: [5-bromo-7-[(4-fluorophenyl)methylcarbamoyl]-1,6-naphthyridin-8-yl] 4-methylbenzenesulfonate
• CAS: 500129-84-0
• 化学式: C₂₃H₁₇BrFN₃O₄S
• 分子量: 530.374
• InChiKey: SHBKPWWLFZSVLT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-bromo-N-(4-fluorobenzyl)-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxamide 在 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 56.0h， 生成 8-(((1r,4r)-4-aminocyclohexyl)amino)-N-(4-fluorobenzyl)-5-(piperidin-1-yl)-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
• 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 、 三乙胺 、 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 、 氯仿 、 甲苯 为溶剂， 反应 53.17h， 生成 5-bromo-N-(4-fluorobenzyl)-8-(p-toluenesulfonyloxy)-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

• Process for preparing 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides
  申请人：Maligres E. Peter

  公开号：US20050014780A1

  公开（公告）日：2005-01-20

  The preparation of 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides is disclosed. A 5-halo-8-hydroxy-1,6-napthyridine-7-carboxylic acid or acid ester in which the hydroxy is derivatized with a protecting group is reacted with a sulfonamide (e.g., an alkanesulfonamide, N-alkyl alkanesulfonamide, or alkanesultam) in the presence of a copper promoter and a chelating agent, followed by deprotection of the hydroxy group, and then coupling with an amine to obtain the 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamide. Alternatively, the hydroxy-protected 5-halo-8-hydroxy-1,6-napthyridine-7-carboxylic acid (or ester) is first coupled with an amine, the resulting carboxamide reacted with a sulfonamide followed by deprotection of the hydroxy group to obtain the 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamide. The 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides are inhibitors of HIV integrase and are useful for treating HIV infection, preventing HIV infection, delaying the onset of AIDS, and treating AIDS.

  本文公开了制备5-磺酰胺基-8-羟基-1,6-萘啶-7-羧酸酰胺的方法。首先将5-卤代-8-羟基-1,6-萘啶-7-羧酸或酸酯与保护羟基的衍生物反应，加入磺酰胺（例如，烷基磺酰胺，N-烷基磺酰胺或烷基磺酰胺）和铜催化剂以及螯合剂，去除保护羟基，然后与胺偶联，得到5-磺酰胺基-8-羟基-1,6-萘啶-7-羧酸酰胺。或者，先将保护羟基的5-卤代-8-羟基-1,6-萘啶-7-羧酸（或酯）与胺偶联，然后将产生的羧酰胺与磺酰胺反应，去除保护羟基，得到5-磺酰胺基-8-羟基-1,6-萘啶-7-羧酸酰胺。5-磺酰胺基-8-羟基-1,6-萘啶-7-羧酸酰胺是HIV整合酶的抑制剂，可用于治疗HIV感染，预防HIV感染，延缓艾滋病的发作和治疗艾滋病。
• PROCESS FOR PREPARING 5-SULFONAMIDO-8-HYDROXY-1, 6-NAPHTHYRIDINE-7-CARBOXAMIDES
  申请人：Merck & Co., Inc.

  公开号：EP1427726A1

  公开（公告）日：2004-06-16
• [EN] PROCESS FOR PREPARING 5-SULFONAMIDO-8-HYDROXY-1, 6-NAPHTHYRIDINE-7-CARBOXAMIDES<br/>[FR] PROCEDE DE PREPARATION DE 5-SULFONAMIDO-8-HYDROXY-1, 6-NAPHTYRIDINE-7-CARBOXAMIDES
  申请人：MERCK & CO INC

  公开号：WO2003016309A1

  公开（公告）日：2003-02-27

  The preparation of 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides is disclosed. A 5-halo-8-hydroxy-1,6-napthyridine-7-carboxylic acid or acid ester in which the hydroxy is derivatized with a protecting group is reacted with a sulfonamide (e.g., an alkanesulfonamide, N-alkyl alkanesulfonamide, or alkanesultam) in the presence of a copper promoter and a chelating agent, followed by deprotection of the hydroxy group, and then coupling with an amine to obtain the 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamide. Alternatively, the hydroxy-protected 5-halo-8-hydroxy-1,6-napthyridine-7-carboxylic acid (or ester) is first coupled with an amine, the resulting carboxamide reacted with a sulfonamide followed by deprotection of the hydroxy group to obtain the 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamide. The 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides are inhibitors of HIV integrase and are useful for treating HIV infection, preventing HIV infection, delaying the onset of AIDS, and treating AIDS.
• 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.