Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,3-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 (IC(50) = 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 (ED(50) for inhibition of exudate PGE2 of 3 mg/kg and gastric PGE2 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 ED(50) 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.

中文翻译：

---

1,3-二芳基-4,5,6,7-四氢-2H-异吲哚衍生物：一系列新的有效和选择性的COX-2抑制剂，其中磺酰基不是结构必需的。

已经制备了新型的四氢-2H-异吲哚并评价为COX-2同工酶的抑制剂。中央多环系统上的1,3-二芳基取代和不存在磺酰基部分是该化学系列的两个结构特征。短而简单的合成途径产生了几种衍生物，这些衍生物被证明是有效的和选择性的COX-2与COX-1抑制剂（IC（50）=0。对于COX-2为6-100 nM，对于COX-100为100-> 1000 nM 1）。结构上的修改表明，附加到吡咯核上的双环和苯环上的4,4'-二氟取代对于高抑制力而言是最佳的。在人全血测定中证实了活性，随后在鼠气袋模型中证实了活性，在鼠气袋模型中，针对胃耐受性（ED（50））评估了体内PGE2抑制活性，以抑制3 mg / kg的渗出液PGE2和胃PGE2 20 mg / kg）。对高剂量（最高400 mg / kg）抑制剂的小鼠给药后，通过测量胃损伤程度进一步评估了胃耐受性。该研究小组允许选择许多在佐剂诱导的关节炎模型中比较的四氢-2H-异吲哚。口服给药后，化合物32和37在未注射的爪中显示出最有效的抑制水肿的ED（50）值，分别为0. 35和0.15 mg / kg / day。此外，