(5Z)-1-羟基-3-(2-甲基丙基)-5-(2-甲基丙亚基)吡嗪-2,6-二酮 | 162666-34-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: (5Z)-1-羟基-3-(2-甲基丙基)-5-(2-甲基丙亚基)吡嗪-2,6-二酮
• 英文名称: Flutimide
• 英文别名: (5Z)-1-hydroxy-3-(2-methylpropyl)-5-(2-methylpropylidene)pyrazine-2,6-dione
• CAS: 162666-34-4
• 化学式: C₁₂H₁₈N₂O₃
• 分子量: 238.287
• InChiKey: SIXHCCPAJIVTOY-UITAMQMPSA-N

物化性质

• 沸点：
  354.8±25.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  70
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

Fluchine是一种新型的流感病毒核酸内切酶抑制剂，能够选择性地抑制该酶，IC50值为3μM。在细胞培养中，Flu胆怯表现出抗病毒活性，并可用于研究急性传染性呼吸道疾病，如流感[1]。

反应信息

• 作为反应物：
  描述：

  (5Z)-1-羟基-3-(2-甲基丙基)-5-(2-甲基丙亚基)吡嗪-2,6-二酮 在 palladium on activated charcoal 氢气 作用下， 生成
  参考文献：
  名称：

  新型流感病毒核酸内切酶抑制剂flutimide的分离和结构

  摘要：

  据报道，一种新物种Delfitschia confertaspora的一种荧光转录核酸内切酶抑制剂flutimide（1）的分离和结构阐明。该新颖的天然产物的特征在于N-羟基酰亚胺和环外烯胺官能团。

  DOI：

  10.1016/0040-4039(95)00213-v
• 作为产物：
  描述：

  N-p-methoxybenzyl-N-carboxymethyl-(S)-leucine methyl ester 在 4-二甲氨基吡啶 、 TEA 、 羟胺 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 六甲基磷酰三胺 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 30.0h， 生成 (5Z)-1-羟基-3-(2-甲基丙基)-5-(2-甲基丙亚基)吡嗪-2,6-二酮
  参考文献：
  名称：

  Synthesis of Natural Flutimide and Analogous Fully Substituted Pyrazine-2,6-diones, Endonuclease Inhibitors of Influenza Virus

  摘要：

  Flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione, is a fungal metabolite isolated from a new species of Delitschia. cofertaspora. It has been shown to selectively inhibit cap-dependent endonuclease activity of influenza virus A. The inhibition of this activity is a target for the potential development of a therapeutic agent to treat influenza infections. A convergent total synthesis of flutimide starting from L-leucine has been described. The synthetic methodology has been extended to include the synthesis of specifically designed aromatic analogues of flutimide, some of which exhibited greater than 7-fold improvement in activity, The most potent compounds were those with p-fluorobenzylidene or p-methoxybenzylidene substitutions at C-5 of 3H-pyrazine-2,6-dione and showed IC50 values of 0.9 and 0.8 muM, respectively. The details of the rationale for the synthetic design, syntheses, and biological activities of these analogues are described.

  DOI：

  10.1021/jo015665d

文献信息

• Total synthesis of flutimide, a novel endonuclease inhibitor of influenza virus
  作者：Sheo B. Singh

  DOI：10.1016/0040-4039(95)00214-w

  日期：1995.3

  Flutimide is a completely substituted 1-N-hydroxy-2,6-diketo-Delta 3-piperazine isolated from a new species of Delitschia cofertaspora. It selectively inhibits influenza virus A endonuclease activity without affecting any viral transcription activity. Total synthesis of flutimide starting from L-leucine has been described.
• Substituted 3,4,12,12a-Tetrahydro-1H-[1,4]Oxazino[3,4-c]Pyrido[2,1-f][1,2,4]Triazine-6,8-dione, Pharmaceutical Composition, Method for the Production and Use Thereof
  申请人：Ivachtchenko Alena Alexandrovna

  公开号：US20220048925A1

  公开（公告）日：2022-02-17

  Influenza is an acute infectious respiratory disease caused by the influenza virus. It is part of the group of Acute Respiratory Viral Infections (ARVI). It occasionally spreads in the form of epidemics and pandemics. Currently, more than 2000 variants of the influenza virus differing in the antigen spectrum have been identified. Given that influenza is a serious threat to public health (worldwide, these annual epidemics lead to 3-5 million cases of severe illness, millions of hospitalizations, and up to 650,000 deaths), it seems appropriate to search for new anti-influenza drugs with improved characteristics. The inventors surprisingly found out that the previously unknown substituted 3,4,12,12a-tetrahydro-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione of general formula 1, its stereoisomer, their prodrug, pharmaceutically acceptable salt, solvate, hydrate, and a crystalline or polycrystalline form thereof are effective agents for prophylaxis and treatment of viral diseases, including influenza where R 1 is (6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, (7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)-methyl; R 2 is hydrogen or a protective group selected from a series comprising (C1-C3 alkyl) oxycarbonyloxy, [(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, [2-(C1-C3 alkyl) oxyethoxy]carbonyl}oxy, ([(1R)-2-[(C1-C3alkyl)oxy]-1-methylethoxy} carbonyl)oxy, [(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy) carbonyl]oxy,[(1-acetylazetidine)-3-yloxy]carbonyl}oxy, [(C1-C3alkyl) oxycarbonyl]-oxy}methoxy, ([2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy) methoxy.
• Synthesis of Natural Flutimide and Analogous Fully Substituted Pyrazine-2,6-diones, Endonuclease Inhibitors of Influenza Virus
  作者：Sheo B. Singh、Joanne E. Tomassini

  DOI：10.1021/jo015665d

  日期：2001.8.1

  Flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione, is a fungal metabolite isolated from a new species of Delitschia. cofertaspora. It has been shown to selectively inhibit cap-dependent endonuclease activity of influenza virus A. The inhibition of this activity is a target for the potential development of a therapeutic agent to treat influenza infections. A convergent total synthesis of flutimide starting from L-leucine has been described. The synthetic methodology has been extended to include the synthesis of specifically designed aromatic analogues of flutimide, some of which exhibited greater than 7-fold improvement in activity, The most potent compounds were those with p-fluorobenzylidene or p-methoxybenzylidene substitutions at C-5 of 3H-pyrazine-2,6-dione and showed IC50 values of 0.9 and 0.8 muM, respectively. The details of the rationale for the synthetic design, syntheses, and biological activities of these analogues are described.
• Isolation and structure of flutimide, a novel endonuclease inhibitor of influenza virus
  作者：Otto D. Hensens、Michael A. Goetz、Jerrold M. Liesch、Deborah L. Zink、Susan L. Raghoobar、Gregory L. Helms、Sheo B. Singh

  DOI：10.1016/0040-4039(95)00213-v

  日期：1995.3

  The isolation and structure elucidation of flutimide (1), an inhibitor of flutranscription endonuclease from Delitschia confertaspora, a new species, is reported. The novel natural product is characterized by N-hydroxyimide and exocyclic enamine functionalities.

  据报道，一种新物种Delfitschia confertaspora的一种荧光转录核酸内切酶抑制剂flutimide（1）的分离和结构阐明。该新颖的天然产物的特征在于N-羟基酰亚胺和环外烯胺官能团。