(S)-benzosuber-1-yloxycarbonyloxymethyl (1R,5S,6S)-2-{[(3S,5S)-1-acetyl-5-(N,N-dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate | 1450666-43-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (S)-benzosuber-1-yloxycarbonyloxymethyl (1R,5S,6S)-2-{[(3S,5S)-1-acetyl-5-(N,N-dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate
• 英文别名: [(5S)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]oxycarbonyloxymethyl (4R,5S,6S)-3-[(3S,5S)-1-acetyl-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
• CAS: 1450666-43-9
• 化学式: C₃₂H₄₁N₃O₉S
• 分子量: 643.758
• InChiKey: OPNIXCBPTHFAEK-MOASZYHXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  45
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  168
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (S)-benzosuber-1-yloxycarbonyloxymethyl (1R,5S,6S)-2-{[(3S,5S)-1-acetyl-5-(N,N-dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate 在 水 、 4-羟乙基哌嗪乙磺酸 作用下， 生成 聚合甲醛 、 二氧化碳 、 6,7,8,9-四氢-5H-苯并环庚烯-5-醇 、 (4R,5S,6S)-3-[(3S,5S)-1-acetyl-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  参考文献：
  名称：

  Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

  摘要：

  Meropenem, a broad-spectrum parenteral beta-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.05.024
• 作为产物：
  描述：

  (R)-tetral-1-yloxycarbonyloxymethyl (1R,5S,6S)-2-{[(3S,5S)-5-(N,N-dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate 在 水 、 caesium carbonate 、 4-羟乙基哌嗪乙磺酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.17h， 生成 (S)-benzosuber-1-yloxycarbonyloxymethyl (1R,5S,6S)-2-{[(3S,5S)-1-acetyl-5-(N,N-dimethylcarbamoyl)pyrrolidin-3-yl]thio}-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate
  参考文献：
  名称：

  Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

  摘要：

  Meropenem, a broad-spectrum parenteral beta-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.05.024

文献信息

• Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis
  作者：Aaron M. Teitelbaum、Anja Meissner、Ryan A. Harding、Christopher A. Wong、Courtney C. Aldrich、Rory P. Remmel

  DOI：10.1016/j.bmc.2013.05.024

  日期：2013.9

  Meropenem, a broad-spectrum parenteral beta-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem. (C) 2013 Elsevier Ltd. All rights reserved.