(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-3-indolyl]acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-3-indolyl]acetate
• 英文别名: (1,3-dioxy-1,3-dihydro-2H-isoindol-2-yl)methyl [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate；(1,3-Dioxoisoindol-2-yl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate
• 化学式: C₂₈H₂₁ClN₂O₆
• 分子量: 516.938
• InChiKey: LSUMTUPZADIGGD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  94.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-3-indolyl]acetate 在 phosphate buffer pH 7.4 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 6.0h， 生成 邻苯二甲酸亚胺 、 吲哚美辛
  参考文献：
  名称：

  Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs

  摘要：

  N-Hydroxymethylphthalimide (HMPhI) esters 5a-d of some nonsteroidal anti-inflammatory drugs were synthesized and evaluated as potential prodrugs with the aim of depressing the gastrotoxicity of the parent drugs by temporarily masking the carboxylic acid function. The ester prodrugs were synthesized through condensation of N-hydroxymethylphthalimide and the mixed carboxylic-carbonic anhydride intermediate or the corresponding acid chloride of the parent acid. Their structures were confirmed by H-1-NMR spectra and the purity has been assessed by TLC and elemental analyses. An HPLC method has been developed for investigation of the hydrolysis kinetics in aqueous buffer solutions and in 80% rabbit plasma. The lipophilicity parameters log P and log k' were determined and showed that the prodrugs were found to be more lipophilic (log P > 2) than the parent drugs. A considerable chemical stability of all compounds (t(1/2) = 4.7-21.9 h) has been observed in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3), while at pH 7.4 only prodrugs 5b-d are sufficiently stable (t(1/2) similar to 3-5 h). Meanwhile, rapid conversion to the parent drugs 3a-d was observed in 80% rabbit plasma (t(1/2) similar to 1.0-11.5 min). Potential ulcerogenicity on rat stomach mucosa of the prodrugs and the parent drugs after oral administration for 4 days was studied using a scanning electron microscope. Gross observations and scanning electro-micrographs showed that the prodrugs are significantly less irritating to gastric mucosa than the parent NSAIDs. This result suggests that N-hydroxymethylphthalimide esters may be useful as nonulcerogenic prodrug forms for acidic NSAIDs. (C) Elsevier, Paris.

  DOI：

  10.1016/s0223-5234(98)80037-8
• 作为产物：
  描述：

  N-羟甲基邻苯二甲酰亚胺 、 吲哚美辛 在 4-二甲氨基吡啶 、 氯化亚砜 、 三乙胺 作用下， 生成 (1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-3-indolyl]acetate
  参考文献：
  名称：

  Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs

  摘要：

  N-Hydroxymethylphthalimide (HMPhI) esters 5a-d of some nonsteroidal anti-inflammatory drugs were synthesized and evaluated as potential prodrugs with the aim of depressing the gastrotoxicity of the parent drugs by temporarily masking the carboxylic acid function. The ester prodrugs were synthesized through condensation of N-hydroxymethylphthalimide and the mixed carboxylic-carbonic anhydride intermediate or the corresponding acid chloride of the parent acid. Their structures were confirmed by H-1-NMR spectra and the purity has been assessed by TLC and elemental analyses. An HPLC method has been developed for investigation of the hydrolysis kinetics in aqueous buffer solutions and in 80% rabbit plasma. The lipophilicity parameters log P and log k' were determined and showed that the prodrugs were found to be more lipophilic (log P > 2) than the parent drugs. A considerable chemical stability of all compounds (t(1/2) = 4.7-21.9 h) has been observed in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3), while at pH 7.4 only prodrugs 5b-d are sufficiently stable (t(1/2) similar to 3-5 h). Meanwhile, rapid conversion to the parent drugs 3a-d was observed in 80% rabbit plasma (t(1/2) similar to 1.0-11.5 min). Potential ulcerogenicity on rat stomach mucosa of the prodrugs and the parent drugs after oral administration for 4 days was studied using a scanning electron microscope. Gross observations and scanning electro-micrographs showed that the prodrugs are significantly less irritating to gastric mucosa than the parent NSAIDs. This result suggests that N-hydroxymethylphthalimide esters may be useful as nonulcerogenic prodrug forms for acidic NSAIDs. (C) Elsevier, Paris.

  DOI：

  10.1016/s0223-5234(98)80037-8

文献信息

• Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs
  作者：Farghaly A. Omar

  DOI：10.1016/s0223-5234(98)80037-8

  日期：1998.2

  N-Hydroxymethylphthalimide (HMPhI) esters 5a-d of some nonsteroidal anti-inflammatory drugs were synthesized and evaluated as potential prodrugs with the aim of depressing the gastrotoxicity of the parent drugs by temporarily masking the carboxylic acid function. The ester prodrugs were synthesized through condensation of N-hydroxymethylphthalimide and the mixed carboxylic-carbonic anhydride intermediate or the corresponding acid chloride of the parent acid. Their structures were confirmed by H-1-NMR spectra and the purity has been assessed by TLC and elemental analyses. An HPLC method has been developed for investigation of the hydrolysis kinetics in aqueous buffer solutions and in 80% rabbit plasma. The lipophilicity parameters log P and log k' were determined and showed that the prodrugs were found to be more lipophilic (log P > 2) than the parent drugs. A considerable chemical stability of all compounds (t(1/2) = 4.7-21.9 h) has been observed in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3), while at pH 7.4 only prodrugs 5b-d are sufficiently stable (t(1/2) similar to 3-5 h). Meanwhile, rapid conversion to the parent drugs 3a-d was observed in 80% rabbit plasma (t(1/2) similar to 1.0-11.5 min). Potential ulcerogenicity on rat stomach mucosa of the prodrugs and the parent drugs after oral administration for 4 days was studied using a scanning electron microscope. Gross observations and scanning electro-micrographs showed that the prodrugs are significantly less irritating to gastric mucosa than the parent NSAIDs. This result suggests that N-hydroxymethylphthalimide esters may be useful as nonulcerogenic prodrug forms for acidic NSAIDs. (C) Elsevier, Paris.