(Z)-acetyloxymethoxyimino-[methyl-[2-[1-(4-methylsulfonylphenyl)-5-phenylpyrazole-3-carbonyl]oxyethyl]amino]-oxidoazanium | 1046152-08-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (Z)-acetyloxymethoxyimino-[methyl-[2-[1-(4-methylsulfonylphenyl)-5-phenylpyrazole-3-carbonyl]oxyethyl]amino]-oxidoazanium
• CAS: 1046152-08-2
• 化学式: C₂₃H₂₅N₅O₈S
• 分子量: 531.546
• InChiKey: QMZILJWJGOUAIQ-FVDSYPCUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  37
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  167
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  O2-acetoxymethyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate 、 1-(4-Methylsulfonylphenyl)-5-phenylpyrazole-3-carboxylic acid 在 sodium carbonate 作用下， 以 六甲基磷酰三胺 为溶剂， 反应 72.0h， 以39%的产率得到(Z)-acetyloxymethoxyimino-[methyl-[2-[1-(4-methylsulfonylphenyl)-5-phenylpyrazole-3-carbonyl]oxyethyl]amino]-oxidoazanium
  参考文献：
  名称：

  Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids: Synthesis, nitric oxide release studies and anti-inflammatory activities

  摘要：

  A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs) wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-c) NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids were synthesized. The diazen-1-ium-1,2-diolate compounds 11a-c all released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (7.7-9.3% range). In comparison, the percentage of NO released was significantly higher (67.5-73.6% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acid (9a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acids (9a-c) exhibited AI activities (ID(50) = 85.2-104.4 mg/kg po range) between that exhibited by the reference drugs aspirin (ID(50) = 128.7 mg/kg po) and celecoxib (ID(50) = 10.8 mg/kg po). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offers a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.05.028

文献信息

• Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids: Synthesis, nitric oxide release studies and anti-inflammatory activities
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Edward E. Knaus

  DOI：10.1016/j.bmc.2008.05.028

  日期：2008.7.1

  A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs) wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-c) NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids were synthesized. The diazen-1-ium-1,2-diolate compounds 11a-c all released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (7.7-9.3% range). In comparison, the percentage of NO released was significantly higher (67.5-73.6% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acid (9a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acids (9a-c) exhibited AI activities (ID(50) = 85.2-104.4 mg/kg po range) between that exhibited by the reference drugs aspirin (ID(50) = 128.7 mg/kg po) and celecoxib (ID(50) = 10.8 mg/kg po). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offers a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects. (c) 2008 Elsevier Ltd. All rights reserved.