O2-(acetoxymethyl) 1-(2-(hydroxycarbonyl)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate | 955130-62-8

• 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
• 英文名称: O2-(acetoxymethyl) 1-(2-(hydroxycarbonyl)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
• CAS: 955130-62-8
• 化学式: C₈H₁₃N₃O₆
• 分子量: 247.208
• InChiKey: LCHYUQSHXFASIQ-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.13
• 重原子数：
  17.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  114.5
• 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-(hydroxycarbonyl)pyrrolidin-1-yl)diazen-1-ium-1,2-diolate 、 脱羟基溴塞来考昔 在 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 24.0h， 以45%的产率得到(S,Z)-2-(acetoxymethoxy)-1-(2-(((4-(1-(4-sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)oxy)carbonyl)pyrrolidin-1-yl)diazene 1-oxide
  参考文献：
  名称：

  Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its methanesulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies

  摘要：

  A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs 12a-b) wherein an O-2-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, O-2-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the bromomethyl group of 5-(4-bromomethylphenyl)1-( 4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (9a), and its methanesulfonyl analog (9b), were synthesized. The diazen-1-ium-1,2-diolate compounds 12a-b released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (6.1-8.2% range). In comparison, the percentage NO released was significantly higher (76-77% 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 12a-b were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (10a), and its methanesulfonyl analog (10b), would be released from the parent NONO-coxib 12a or 12b upon in vivo cleavage by non-specific serum esterases. The hydroxymethyl compounds 10a-b were weak inhibitors of the cyclooxygenase-1 (COX-1) and COX-2 isozymes (IC50 = 3.7-10.5 mu M range). However, the hydroxymethyl compounds 10a-b and the parent NONO-coxibs 12a-b exhibited good AI activities (ED50 = 76.7-111.6 mu mol/kg po range) that were greater than that exhibited by the reference drugs aspirin (ED50 = 710 mu mol/kg po) and ibuprofen (ED50 = 327 mu mol/kg po), but less than that of celecoxib (ED50 = 30.9 mu mol/kg po). These studies indicate hybrid ester AI/NO-donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.10.001
• 作为产物：
  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

文献信息

• NO-RELEASING NONOATE(NITROGEN-BOUND)SULFONAMIDE-LINKED-COXIB ANTI-CANCER AGENTS
  申请人：Euclises Pharmaceuticals, Inc.

  公开号：US20140018544A1

  公开（公告）日：2014-01-16

  The present invention provides NO-releasing NONOate(nitrogen bound)sulfonamide-linked-coxib anti-cancer agents, having the structure of Formula (I): wherein R 1 , X, L, R 2 , R 3 , R 4 , and Z are as defined in the detailed description; pharmaceutical compositions comprising at least one compound of Formula (I); and methods useful for healing wounds, preventing and treating cancer, or treating actinic keratosis, cystic fibrosis or acne, using a compound of Formula (I).

  本发明提供了一种NO释放的NONOate（氮结合）磺酰胺-联苯并咪唑类抗癌药物，具有以下结构式（I）：其中R1、X、L、R2、R3、R4和Z如详细说明中所定义；包括至少一种式（I）化合物的制药组合物；以及使用式（I）化合物有益于治疗伤口、预防和治疗癌症、或治疗光化性角化症、囊性纤维化或痤疮的方法。
• US8859781B2
  申请人：——

  公开号：US8859781B2

  公开（公告）日：2014-10-14
• [EN] NO-RELEASING NONOATE (NITROGEN-BOUND) SULFONAMIDE-LINKED-COXIB ANTI-CANCER AGENTS<br/>[FR] AGENTS ANTICANCÉREUX DE COXIB LIÉS À UN SULFONAMIDE (LIAISON À L'AZOTE) DE NONOATE À LIBÉRATION DE NO
  申请人：EUCLISES PHARMACEUTICALS INC

  公开号：WO2014012074A2

  公开（公告）日：2014-01-16

  The present invention provides NO-releasing NONOate(nitrogen bound)sulfonamide- linked-coxib anti-cancer agents, having the structure of Formula (I): wherein R1, X, L, R2, R3, R4, and Z are as defined in the detailed description; pharmaceutical compositions comprising at least one compound of Formula (I); and methods useful for healing wounds, preventing and treating cancer, or treating actinic keratosis, cystic fibrosis or acne, using a compound of Formula (I).