phenylmethyl 2-(4-chloro-5-methoxy-2-methylindol-3-yl)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: phenylmethyl 2-(4-chloro-5-methoxy-2-methylindol-3-yl)acetate
• 英文别名: benzyl 2-(4-chloro-5-methoxy-2-methyl-1H-indol-3-yl)acetate
• 化学式: C₁₉H₁₈ClNO₃
• 分子量: 343.81
• InChiKey: QGCNXFCBRGQPKX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  51.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  phenylmethyl 2-(4-chloro-5-methoxy-2-methylindol-3-yl)acetate 、 4-氯苯甲酰氯 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以87%的产率得到phenylmethyl 2-{4-chloro-1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}acetate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Indomethacin Derivatives as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors

  摘要：

  Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.

  DOI：

  10.1021/jm0611861
• 作为产物：
  描述：

  苄基月桂酸酯 、 3-氯-4-甲氧基苯井盐酸盐 在 溶剂黄146 作用下， 反应 3.0h， 以33%的产率得到phenylmethyl 2-(6-chloro-5-methoxy-2-methylindol-3-yl)acetate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Indomethacin Derivatives as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors

  摘要：

  Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.

  DOI：

  10.1021/jm0611861

文献信息

• WO2006/99416
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] 2-METHYL INDOLE CYCLOOXYGENASE-2 SELECTIVE INHIBITORS, COMPOSITIONS AND METHODS OF USE<br/>[FR] INHIBITEURS SELECTIFS DE LA 2-METHYLE-INDOLE CYCLOOXYGENASE-2, COMPOSITIONS ET PROCEDES D'UTILISATION
  申请人：NITROMED INC

  公开号：WO2006099416A1

  公开（公告）日：2006-09-21

  [EN] The invention describes compositions and kits comprising 2-methyl indole cyclooxygenase 2 (COX-2) selective inhibitors or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The 2-methyl indole cyclooxygenase 2 selective inhibitors can be optionally substituted with at least one nitric oxide enhancing group. The invention also provides methods for (a) treating inflammation, pain and fever; (b) treating gastrointestinal disorders and/or improving the gastrointestinal properties of COX-2 selective inhibitors; (c) facilitating wound healing; (d) treating renal and/or respiratory toxicities; (e) treating disorders resulting from elevated levels of cyclooxygenase-2; (f) improving the cardiovascular profile of COX-2 selective inhibitors; (g) treating diseases resulting from oxidative stress; (h) treating endothelial dysfunctions; (j) treating diseases caused by endothelial dysfunctions; (k) treating inflammatory disease states and/or disorders; (1) treating ophthalmic disorders; and (m) treating peripheral vascular diseases. The nitric oxide enhancing groups are organic nitrates, organic nitrites, nitrosothiols, thionitrites, thionitrates, NONOates, heterocyclic nitric oxide donors and/or nitroxides. The heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  [FR] L'invention décrit des compositions et des kits comprenant des inhibiteurs 2-méthyle-indole sélectifs de la cyclooxygénase 2 (COX-2) ou des sels desdits inhibiteurs acceptables sur le plan pharmaceutique et, éventuellement au moins un composé renforçateur monoxyde d'azote et/ou au moins un agent thérapeutique. Les inhibiteurs 2-méthyle-indole sélectifs de la cyclooxygénase 2 peuvent éventuellement être substitués avec au moins un groupe renforçateur ***monoxyde d'azote. L'invention prévoit également des procédés destinés à (a) traiter l'inflammation, la douleur et la fièvre ; (b) traiter les troubles gastro-intestinaux et/ou améliorer les propriétés gastro-intestinales d'inhibiteurs sélectifs de COX-2 ; (c) faciliter la guérison des blessures ; (d) traiter les intoxications rénales et/ou respiratoires ; (e) traiter des troubles résultant de niveaux élevés de cyclooxygénase-2 ; (f) améliorer le profil cardiovasculaire des inhibiteurs sélectifs de COX-2 ; (g) traiter des maladies résultant de stress oxydatif ; (h) traiter les dysfontionnements endothéliaux ; (j) traiter des maladies dues aux dysfonctionnement endothéliaux ; (k) traiter des états et/ou des troubles dus à une maladie inflammatoire ; (l) traiter des troubles ophthalmiques ; et (m) traiter des maladies vasculaires périphériques. Les groupes renforçateurs monoxyde d'azote sont des nitrates organiques, des nitrites organiques, des nitrosothiols, des thionitrites, des thionitrates, des NONOates, des donneurs hétérocycliques d'acide nitrique et/ou des nitroxydes. Les donneurs de monoxyde d'azote hétérocycliques sont des furoxanes, des sydnonimines, des oxatriazole-5-ones et/ou des oxatriazole-5-imines.
• Structure-Based Design, Synthesis, and Biological Evaluation of Indomethacin Derivatives as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors
  作者：Shiow-Jyi Wey、Michael E. Augustyniak、Edward D. Cochran、James L. Ellis、Xinqin Fang、David S. Garvey、David R. Janero、L. Gordon Letts、Allison M. Martino、Terry L. Melim、Madhavi G. Murty、Steward K. Richardson、Joseph D. Schroeder、William M. Selig、A. Mark Trocha、Roseanne S. Wexler、Delano V. Young、Irina S. Zemtseva、Brian M. Zifcak

  DOI：10.1021/jm0611861

  日期：2007.12.13

  Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.