O2-acetoxymethyl 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate | 1016165-37-9

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: O2-acetoxymethyl 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate
• 英文别名: O2-acetoxymethyl-1-(2-hydroxymethylpyrrolidin-1-yl)diazen-1-ium-1,2-diolate；O2-(acetoxymethyl) 1-(2-(hydroxymethyl)-pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
• CAS: 1016165-37-9
• 化学式: C₈H₁₅N₃O₅
• 分子量: 233.224
• InChiKey: KWXPPKYIBVQUSS-QMMMGPOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.23
• 重原子数：
  16.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  97.43
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  O2-acetoxymethyl 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate 在 ruthenium trichloride sodium periodate 作用下， 以 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 2.0h， 生成 O2-(acetoxymethyl) 1-(2-(hydroxycarbonyl)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  DIAZENIUMDIOLATED NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COMPOSITIONS THEREOF, AND RELATED METHODS

  摘要：

  披露了释放一氧化氮的化合物，例如，式(I)的化合物，其中R1-10、X和n如本文所述，这些化合物是非甾体抗炎药（NSAID）衍生物，包含亚硝基二醇基团N2O2−。这些化合物是具有胃保护、镇痛、心脏保护和/或抗炎特性的化学预防剂。还披露了一种药物组合物，包括本发明的化合物和药用载体。还披露了一种预防或治疗癌症或治疗炎症或炎症相关状况的方法，包括向哺乳动物施用本发明的化合物的有效量。

  公开号：

  US20090186859A1
• 作为产物：
  描述：

  溴甲基乙酸酯 、 (S)-1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate sodium salt 在 sodium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 15.0h， 生成 O2-acetoxymethyl 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  DIAZENIUMDIOLATED NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COMPOSITIONS THEREOF, AND RELATED METHODS

  摘要：

  披露了释放一氧化氮的化合物，例如，式(I)的化合物，其中R1-10、X和n如本文所述，这些化合物是非甾体抗炎药（NSAID）衍生物，包含亚硝基二醇基团N2O2−。这些化合物是具有胃保护、镇痛、心脏保护和/或抗炎特性的化学预防剂。还披露了一种药物组合物，包括本发明的化合物和药用载体。还披露了一种预防或治疗癌症或治疗炎症或炎症相关状况的方法，包括向哺乳动物施用本发明的化合物的有效量。

  公开号：

  US20090186859A1

文献信息

• Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin, indomethacin and ibuprofen: Synthesis, biological evaluation and nitric oxide release studies
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Dipankar Das、Gang Yu、Carlos A. Velázquez、Mavanur R. Suresh、Edward E. Knaus

  DOI：10.1016/j.bmcl.2009.04.059

  日期：2009.6

  anti-inflammatory (AI) ester prodrugs (NONO-NSAIDs) wherein a 1,3-dinitrooxy-2-propyl (12a–c), or O2-acetoxymethyl-1-[2-(methyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (14a–c), NO-donor moiety is directly attached to the carboxylic acid group of aspirin, indomethacin or ibuprofen were synthesized. NO release from the dinitrooxypropyl, or diazen-1-ium-1,2-diolate, ester prodrugs was increased substantially

  混合一氧化氮的一组新的（NO）释放抗炎（AI）酯前药（NONO-的NSAIDs），其中1,3- dinitrooxy -2-丙基（12A - ç），或Ô 2 -acetoxymethyl -1- [ 2 - （甲基）吡咯烷-1-基]二氮烯-1-鎓-1,2-二醇盐（14A - ç），NO供体部分直接连接于阿司匹林的羧酸基团，吲哚美辛或布洛芬合成。在l-半胱氨酸（12a - c）或大鼠血清（14a - c）。不抑制COX-1同工酶的酯前药（12a – c，14a – c）对COX-2同工酶表现出适度的抑制活性。NONO-NSAID 12a – c和14a – c当给予相同的口服剂量（μmol/ kg）时，其体内AI活性类似于母体药物阿司匹林，吲哚美辛或布洛芬。口服药效学特征的这些相似性表明，这些NONO-NSAIDs是经典的前药，需要通过酯酶介导的水解作用来进行代谢活化。这种混合的NO供体/抗
• Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-carboxymethylphenyl)-1-(4-methanesulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its aminosulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Dipankar Das、Gang Yu、Carlos Velázquez、Mavanur R. Suresh、Edward E. Knaus

  DOI：10.1016/j.bmc.2009.05.046

  日期：2009.7

  A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs) wherein an O-2-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (13a-b), or O-2-acetoxymethyl-1-(2-methylpyrrolidin-1-yl)diazen-1-ium-1,2-diolate (16a-b), NO-donor moiety was covalently coupled to the COOH group of 5-(4-carboxymethylphenyl)-1-(4-methane(amino) sulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (11a-b) was synthesized. The percentage of NO released from these diazen-1-ium-1,2-diolates was significantly higher (59.6-74.6% of the theoretical maximal release of 2 molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer (PBS) at pH 7.4 (5.0-7.2% range). These incubation studies suggest that both NO and the AI compound would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. All compounds were weak inhibitors of the COX-1 isozyme (IC50 = 8.1-65.2 mu M range) and modest inhibitors of the COX-2 isozyme (IC50 = 0.9-4.6 mu M range). The most potent parent aminosulfonyl compound 11b exhibited AI activity that was about sixfold greater than that for aspirin and threefold greater than that for ibuprofen. The ester prodrugs 13b, 16b exhibited similar AI activity to that exhibited by the more potent parent acid 11b when the same oral mu mol/kg dose was administered. These studies indicate hybrid ester AI/NO donor prodrugs of this type (NONO-coxibs) constitute a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects. (C) 2009 Elsevier Ltd. All rights reserved.