1,2,4-triazino<4,3-b>benzimidazole-3,4-dione | 116577-85-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1,2,4-triazino<4,3-b>benzimidazole-3,4-dione
• 英文别名: [1,2,4]triazino[4,3-a]benzimidazol-3,4-(10H)-dione；[1,2,4]triazino[4,3-a]benzimidazole-3,4(10H)-dione；1,2,4-triazino[4,3-b]benzimidazole-3,4-dione；[1,2,4]Triazino[4,3-a][1,3]benzimidazole-3,4-dione, 2,10-dihydro-；1,2-dihydro-[1,2,4]triazino[4,3-a]benzimidazole-3,4-dione
• CAS: 116577-85-6
• 化学式: C₉H₆N₄O₂
• mdl: MFCD07657996
• 分子量: 202.172
• InChiKey: BOCXXBQCSYYJRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,2,4-triazino<4,3-b>benzimidazole-3,4-dione 在 盐酸 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 (2-Carboxymethyl-3,4-dioxo-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-c][1,2,4]triazin-10-yl)-acetic acid
  参考文献：
  名称：

  [1,2,4]Triazino[4,3-a]benzimidazole Acetic Acid Derivatives:  A New Class of Selective Aldose Reductase Inhibitors

  摘要：

  Acetic acid derivatives of [1,2,4]triazino[4,3-alpha ]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-alpha ]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC50 = 0.36 muM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational. changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.

  DOI：

  10.1021/jm0109210
• 作为产物：
  描述：

  2-肼基-1H-1,3-苯并咪唑 、 草酸二乙酯 以 乙醇 为溶剂， 反应 3.0h， 以80%的产率得到1,2,4-triazino<4,3-b>benzimidazole-3,4-dione
  参考文献：
  名称：

  2-肼基苯并咪唑、-苯并恶唑和-苯并噻唑的缩合和环化反应

  摘要：

  2-肼基苯并恶唑 (1)、-苯并咪唑 (2) 和苯并噻唑 (3) 与氯甲酸乙酯和/或草酸二乙酯缩合生成 1,2,4-三唑并和 1,2,4-三嗪酮稠合酮分别为标题唑。1 和 2 与芳香醛和/或乙酸酐缩合，分别产生 3-芳基和 3-甲基取代的 1,2,4-三唑并稠合唑。肼 1 和 2 与乙酰丙酮环化生成相应的 2-(1-吡唑基) 衍生物。2-乙酰噻唑并苯并咪唑与羟胺和/或烷基胺反应生成相应的缩合产物。它也与芳香醛缩合得到查耳酮。与重氮苯盐反应，得到相应的2-芳基偶氮取代化合物。

  DOI：

  10.1246/bcsj.61.1339

文献信息

• Geometrically Constrained Analogues of N-Benzylindolylglyoxylylamides: [1, 2, 4]Triazino[4, 3-a]benzimidazol-4(10H)-one Derivatives as Potential New Ligands at the Benzodiazepine Receptor
  作者：Giampaolo Primofiore、Federico Da Settimo、Sabrina Taliani、Anna Maria Marini、Francesca Simorini、Ettore Novellino、Giovanni Greco、Letizia Trincavelli、Claudia Martini

  DOI：10.1002/ardp.200300788

  日期：2003.9

  3‐ethoxycarbonyl [1, 2, 4]triazino [4, 3‐a]benzimidazol‐4(10H)‐one 14 and its N(10)‐methyl analogue 15 closely related to 3‐alkoxycarbonyl‐β‐carbolines I were also investigated. The title compounds exhibited a lower affinity compared with the corresponding indolylglyoxylylamide derivatives II. Attempts were made to rationalize these results taking into account the possible tautomeric equilibria involving

  合成了一系列 3 - 苄氨基 - 和 3 - 芳基烷基氨基羰基 [1, 2, 4] 三嗪基 [4, 3 - a] 苯并咪唑 1-12 并进行生物学分析，作为 N - 苄基吲哚基乙氧基酰胺 II 的几何受限类似物，它们是高亲和力配体在苯二氮卓受体（BzR）。中间体3-乙氧基羰基[1,2,4]三嗪基[4,3-a]苯并咪唑-4(10H)-one 14及其与3-烷氧基羰基-β-咔啉密切相关的N(10)-甲基类似物15 . 也被调查了。与相应的吲哚基乙醛酰胺衍生物 II 相比，标题化合物表现出较低的亲和力。考虑到涉及这些配体的可能的互变异构平衡，试图使这些结果合理化。
• BADR, M. Z. A.;MAHMOUD, A. M.;MAHGOUB, S. A.;HOZIEN, Z. A., BULL. CHEM. SOC. JAP., 61,(1988) N 4, 1339-1344
  作者：BADR, M. Z. A.、MAHMOUD, A. M.、MAHGOUB, S. A.、HOZIEN, Z. A.

  DOI：——

  日期：——
• Condensation and Cyclization Reactions of 2-Hydrazinobenzimidazole, -benzoxazole, and -benzothiazole
  作者：M. Z. A. Badr、A. M. Mahmoud、S. A. Mahgoub、Z. A. Hozien

  DOI：10.1246/bcsj.61.1339

  日期：1988.4

  2-Hydrazinobenzoxazole (1), -benzimidazole (2), and benzothiazole (3) were condensed with ethyl chloroformate and/or diethyl oxalate to produce, 1,2,4-triazolo- and 1,2,4-triazino-fused ketones of the title azoles respectively. Condensation of 1 and 2 with aromatic aldehydes and/or acetic anhydride produced, 3-aryl- and 3-methyl-substituted 1,2,4-triazolo-fused azoles respectively. The hydrazines 1

  2-肼基苯并恶唑 (1)、-苯并咪唑 (2) 和苯并噻唑 (3) 与氯甲酸乙酯和/或草酸二乙酯缩合生成 1,2,4-三唑并和 1,2,4-三嗪酮稠合酮分别为标题唑。1 和 2 与芳香醛和/或乙酸酐缩合，分别产生 3-芳基和 3-甲基取代的 1,2,4-三唑并稠合唑。肼 1 和 2 与乙酰丙酮环化生成相应的 2-(1-吡唑基) 衍生物。2-乙酰噻唑并苯并咪唑与羟胺和/或烷基胺反应生成相应的缩合产物。它也与芳香醛缩合得到查耳酮。与重氮苯盐反应，得到相应的2-芳基偶氮取代化合物。
• [1,2,4]Triazino[4,3-<i>a</i>]benzimidazole Acetic Acid Derivatives:  A New Class of Selective Aldose Reductase Inhibitors
  作者：Federico Da Settimo、Giampaolo Primofiore、Antonio Da Settimo、Concettina La Motta、Sabrina Taliani、Francesca Simorini、Ettore Novellino、Giovanni Greco、Antonio Lavecchia、Enrico Boldrini

  DOI：10.1021/jm0109210

  日期：2001.12.1

  Acetic acid derivatives of [1,2,4]triazino[4,3-alpha ]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-alpha ]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC50 = 0.36 muM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational. changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.