(2,5-Dioxopyrrolidin-1-yl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate | 1026091-18-8

• 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: (2,5-Dioxopyrrolidin-1-yl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate
• CAS: 1026091-18-8
• 化学式: C₂₄H₂₁ClN₂O₆
• 分子量: 468.894
• InChiKey: ABRACVZDVWXSPY-UHFFFAOYSA-N

物化性质

• 沸点：
  631.0±55.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 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：

  (2,5-Dioxopyrrolidin-1-yl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate 在 Tween 80 、 potassium chloride 作用下， 以 phosphate buffer 为溶剂， 生成 吲哚美辛
  参考文献：
  名称：

  Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index

  摘要：

  Ester prodrugs of aspirin 1a, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N-hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a-d and 6a-d were studied at 37 degrees C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t(1/2) congruent to 6.5-18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t1/2 congruent to 11.4-235 min) as well as in 10% rat liver homogenates (t(1/2) congruent to 12.0-90.0 min). As a general pattern, the HMSI esters 5a-d revealed higher chemical stability than the corresponding HMIS analogues 6a-d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2-8.0 and of the latter at pH = 1.2-4.0. The distribution coefficient (D-7.4) values of the prodrugs 5a-d, 6a-d and the parent drugs 1a-d in an n-octanol/phosphate buffer (pH =7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a-d are more lipophilic than the corresponding HMSI derivatives 5a-d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs. (C) 1999 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)80025-2
• 作为产物：
  描述：

  吲哚美辛 、 alkaline earth salt of/the/ methylsulfuric acid 在 4-二甲氨基吡啶 、 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 13.0h， 生成 (2,5-Dioxopyrrolidin-1-yl)methyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate
  参考文献：
  名称：

  Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index

  摘要：

  Ester prodrugs of aspirin 1a, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N-hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a-d and 6a-d were studied at 37 degrees C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t(1/2) congruent to 6.5-18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t1/2 congruent to 11.4-235 min) as well as in 10% rat liver homogenates (t(1/2) congruent to 12.0-90.0 min). As a general pattern, the HMSI esters 5a-d revealed higher chemical stability than the corresponding HMIS analogues 6a-d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2-8.0 and of the latter at pH = 1.2-4.0. The distribution coefficient (D-7.4) values of the prodrugs 5a-d, 6a-d and the parent drugs 1a-d in an n-octanol/phosphate buffer (pH =7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a-d are more lipophilic than the corresponding HMSI derivatives 5a-d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs. (C) 1999 Editions scientifiques et medicales Elsevier SAS.

  DOI：

  10.1016/s0223-5234(00)80025-2

文献信息

• Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index
  作者：Nadia M Mahfouz、Farghaly A Omar、Tarek Aboul-Fadl

  DOI：10.1016/s0223-5234(00)80025-2

  日期：1999.7

  Ester prodrugs of aspirin 1a, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N-hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a-d and 6a-d were studied at 37 degrees C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t(1/2) congruent to 6.5-18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t1/2 congruent to 11.4-235 min) as well as in 10% rat liver homogenates (t(1/2) congruent to 12.0-90.0 min). As a general pattern, the HMSI esters 5a-d revealed higher chemical stability than the corresponding HMIS analogues 6a-d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2-8.0 and of the latter at pH = 1.2-4.0. The distribution coefficient (D-7.4) values of the prodrugs 5a-d, 6a-d and the parent drugs 1a-d in an n-octanol/phosphate buffer (pH =7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a-d are more lipophilic than the corresponding HMSI derivatives 5a-d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs. (C) 1999 Editions scientifiques et medicales Elsevier SAS.