3,5-bis(3-methylamino-4-fluorophenyl)-4-azatricyclo[5.2.1.0^2,6]deca-2,5-diene

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 英文名称: 3,5-bis(3-methylamino-4-fluorophenyl)-4-azatricyclo[5.2.1.0^2,6]deca-2,5-diene
• 英文别名: 2-fluoro-5-[5-[4-fluoro-3-(methylamino)phenyl]-4-azatricyclo[5.2.1.02,6]deca-2,5-dien-3-yl]-N-methylaniline
• 化学式: C₂₃H₂₃F₂N₃
• 分子量: 379.453
• InChiKey: XDLLXWRQCJWCFB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  39.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  氟苯 在 10percent Pd/C 二硫化碳 、 lithium aluminium tetrahydride 、 三氯化铝 、 硝酸 、 铁粉 、 氯化铵 、 溶剂黄146 、 环己烯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 乙醇 、 水 、 甲苯 为溶剂， 反应 3.25h， 生成 3,5-bis(3-methylamino-4-fluorophenyl)-4-azatricyclo[5.2.1.0^2,6]deca-2,5-diene
  参考文献：
  名称：

  1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole Derivatives:  A New Series of Potent and Selective COX-2 Inhibitors in Which a Sulfonyl Group Is Not a Structural Requisite

  摘要：

  Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,S-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC50 = 0.6-100 nM for COX-2, 100->1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4'-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED50 for inhibition of exudate PGE2 of 3 mg/kg and gastric PGEB of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by measurement of gastric damage. This panel of studies allowed selection of a number of tetrahydro-2H-isoindoles which were compared in the adjuvant-induced arthritis model. Compounds 32 and 37 showed the most potent activity with ED50 values for edema inhibition in the noninjected paw of 0.35 and 0.15 mg/kg/day, respectively, after oral administration. In addition, this interesting antiinflammatory profile was accompanied by a protective effect against arthritis-induced osteopenia, the decrease being 50% with a dose of 0.25 mg/kg/day.

  DOI：

  10.1021/jm990965x

文献信息

• 1,3-Diaryl-4,5,6,7-tetrahydro-2<i>H</i>-isoindole Derivatives:  A New Series of Potent and Selective COX-2 Inhibitors in Which a Sulfonyl Group Is Not a Structural Requisite
  作者：Bernard Portevin、Charles Tordjman、Philippe Pastoureau、Jacqueline Bonnet、Guillaume De Nanteuil

  DOI：10.1021/jm990965x

  日期：2000.11.1

  Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,S-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC50 = 0.6-100 nM for COX-2, 100->1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4'-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED50 for inhibition of exudate PGE2 of 3 mg/kg and gastric PGEB of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by measurement of gastric damage. This panel of studies allowed selection of a number of tetrahydro-2H-isoindoles which were compared in the adjuvant-induced arthritis model. Compounds 32 and 37 showed the most potent activity with ED50 values for edema inhibition in the noninjected paw of 0.35 and 0.15 mg/kg/day, respectively, after oral administration. In addition, this interesting antiinflammatory profile was accompanied by a protective effect against arthritis-induced osteopenia, the decrease being 50% with a dose of 0.25 mg/kg/day.