O²-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate | 858135-01-0

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: O²-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
• 英文别名: O2-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate；(Z)-dimethylamino-(methylsulfanylmethoxyimino)-oxidoazanium
• CAS: 858135-01-0
• 化学式: C₄H₁₁N₃O₂S
• 分子量: 165.216
• InChiKey: VMYFKIJIEIGZLK-ALCCZGGFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  O²-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate 在 磺酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以100%的产率得到O²-(chloromethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  WO2006/125016

  摘要：

  公开号：
• 作为产物：
  描述：

  氯甲基甲硫醚 、 sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate 以 六甲基磷酰三胺 为溶剂， 反应 72.0h， 以21%的产率得到O²-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Novel Nonsteroidal Antiinflammatory Drugs Possessing a Nitric Oxide Donor Diazen-1-ium-1,2-diolate Moiety:  Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies

  摘要：

  A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.

  DOI：

  10.1021/jm050211k

文献信息

• WO2006/125016
  申请人：——

  公开号：——

  公开（公告）日：——
• Novel Nonsteroidal Antiinflammatory Drugs Possessing a Nitric Oxide Donor Diazen-1-ium-1,2-diolate Moiety:  Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies
  作者：Carlos Velázquez、P. N. Praveen Rao、Edward E. Knaus

  DOI：10.1021/jm050211k

  日期：2005.6.1

  A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.