(d,l)-1-(4-fluorophenyl)-3-[(4-methylsulphonyl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

• 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: (d,l)-1-(4-fluorophenyl)-3-[(4-methylsulphonyl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole
• 英文别名: 3-(4-Fluorophenyl)-5-(4-methylsulfonylphenyl)-4-azatricyclo[5.2.1.02,6]deca-2,5-diene
• 化学式: C₂₂H₂₀FNO₂S
• 分子量: 381.471
• InChiKey: RWQSFTYBEDOSHS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  58.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  氟苯 在 10percent Pd/C 二硫化碳 、 三氯化铝 、 Oxone 、 ammonium formate 、 环己烯 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 乙醇 、 水 、 二甲基亚砜 、 甲苯 、 乙腈 为溶剂， 反应 26.0h， 生成 (d,l)-1-(4-fluorophenyl)-3-[(4-methylsulphonyl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole
  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

• Nouveaux derives de pyrrole leur procédé de preparation et les compositions pharmaceutiques qui les contiennent
  申请人：ADIR ET COMPAGNIE

  公开号：EP0921119A1

  公开（公告）日：1999-06-09

  Composés de formule (I) : dans laquelle : Rreprésente un atome d'hydrogène, un groupement alkyle, un groupement amino éventuellement substitué ou un groupement acyle (C1-C6) linéaire ou ramifié, R1, R2,identiques ou différents, représentent chacun indépendamment l'un de l'autre un groupement aryle, hétéroaryle ou cycloalkyle (C5-C7), chacun de ces groupements pouvant être éventuellement substitué, A,avec les atomes communs du pyrrole, représente un cycloalkyle (C3-C12), monocyclique ou bicyclique, saturé ou insaturé, un hétérocycle saturé de 5 à 7 chaînons contenant un ou deux atomes d'azote ou un oxa-7 bicyclo[2.2.1]heptane, chacun de ces cycles pouvant être éventuellement substitué, leurs isomères ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable. Medicaments.

  式(I)化合物 其中： R 代表氢原子、烷基、任选取代的氨基或直链或支链（C1-C6）酰基、 R1 和 R2（可以相同或不同）各自独立地代表芳基、杂芳基或（C5-C7）环烷基，其中每个基团都有可能被任选取代、 A，连同吡咯的公共原子，代表饱和或不饱和、单环或双环（C3-C12）环烷基、含有一个或两个氮原子的饱和 5 至 7 元杂环或 7-氧杂双环[2.2.1]庚烷，其中每个环都可能被任选取代、 它们的异构体及其与药学上可接受的酸或碱的加成盐。 药物。
• US6063804A
  申请人：——

  公开号：US6063804A

  公开（公告）日：2000-05-16
• US6114360A
  申请人：——

  公开号：US6114360A

  公开（公告）日：2000-09-05
• 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.