5-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy]-5-oxopentanoic acid | 113516-48-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy]-5-oxopentanoic acid
• 英文别名: metronidazole monoglutarate；1-[2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl] pentanedioate；5-[2-(2-methyl-5-nitroimidazol-1-yl)ethoxy]-5-oxopentanoic acid
• CAS: 113516-48-6
• 化学式: C₁₁H₁₅N₃O₆
• 分子量: 285.257
• InChiKey: GOUUBNFUMHHKMX-UHFFFAOYSA-N

物化性质

• 熔点：
  102 °C
• 沸点：
  556.2±40.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  20
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 5-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy]-5-oxopentanoic acid 以 乙腈 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Metronidazole prodrugs: Synthesis, physicochemical properties, stability, and ex vivo release studies

  摘要：

  The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning (C-13 NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 degrees C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.06.016
• 作为产物：
  描述：

  戊二酸酐 、 甲硝唑 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 5.0h， 以60%的产率得到5-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy]-5-oxopentanoic acid
  参考文献：
  名称：

  [EN] ANTIBACTERIAL AND/OR ANTIPROTOZOAL NITROIMIDAZOLE DERIVATIVE COMPOUNDS WITH UREASE INHIBITOR ACTIVITY, PROCESS FOR PREPARING THESE COMPOUNDS AND USE IN PHARMACEUTICAL COMPOSITIONS AND MEDICINES.
  [FR] COMPOSES DERIVES DE NITROIMIDAZOLE ANTIBACTERIENS ET/OU ANTIPROTOZOAIRES A ACTIVITE INHIBITRICE D'UREASE, PROCEDE DE PREPARATION DESDITS COMPOSES ET UTILISATION DANS DES COMPOSITIONS PHARMACEUTIQUES ET DANS DES MEDICAMENTS

  摘要：

  公开号：

  WO2005041853A3

文献信息

• Metronidazole twin ester prodrugs: synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity
  作者：Nadia M. Mahfouz、Tarek Aboul-Fadl、Ahmed K. Diab

  DOI：10.1016/s0223-5234(98)80026-3

  日期：1998.9

  A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R-m values, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 degrees C using HPLC. in all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k(1) and k(2)) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) similar to 25-72 h) and also at the physiological pH (t(1/2) similar to 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) similar to 10-150 min) and in rat liver homogenate (t(1/2) similar to 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) similar to 3-9 h and 1-11 h respectively). in vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery. (C) Elsevier, Paris.
• [EN] ANTIBACTERIAL AND/OR ANTIPROTOZOAL NITROIMIDAZOLE DERIVATIVE COMPOUNDS WITH UREASE INHIBITOR ACTIVITY, PROCESS FOR PREPARING THESE COMPOUNDS AND USE IN PHARMACEUTICAL COMPOSITIONS AND MEDICINES.<br/>[FR] COMPOSES DERIVES DE NITROIMIDAZOLE ANTIBACTERIENS ET/OU ANTIPROTOZOAIRES A ACTIVITE INHIBITRICE D'UREASE, PROCEDE DE PREPARATION DESDITS COMPOSES ET UTILISATION DANS DES COMPOSITIONS PHARMACEUTIQUES ET DANS DES MEDICAMENTS
  申请人：EMS SA

  公开号：WO2005041853A3

  公开（公告）日：2005-08-04
• Metronidazole prodrugs: Synthesis, physicochemical properties, stability, and ex vivo release studies
  作者：Carla Mura、Donatella Valenti、Costantino Floris、Roberta Sanna、Maria Antonietta De Luca、Anna Maria Fadda、Giuseppe Loy

  DOI：10.1016/j.ejmech.2011.06.016

  日期：2011.9

  The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning (C-13 NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 degrees C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole. (C) 2011 Elsevier Masson SAS. All rights reserved.