Heilman W P, Battershell R D, Pyne W J, Goble P H, Magee T A
J Med Chem. 1978 Sep;21(9):906-13. doi: 10.1021/jm00207a013.
In an effort to develop nonacidic, nonsteroidal, antiinflammatory agents without gastrointestinal complications, a series of cyanobenzenes was synthesized for antiinflammatory evaluation. Twenty-seven substituted isophthalonitriles, 19 trimesonitriles, 30 benzonitriles, and 16 terephthalonitriles were tested in the rat utilizing the carrageenan-induced pedal edema assay. Based on the performance of phenylbutazone in this assay (43.8% reduction at 100 mg/kg), six compounds, dosed at 50 mg/kg, produced reductions in inflammation comparable to this standard. However, the LD50 value of each compound dosed at this level was in the range of 40--56 mg/kg in the mouse; therefore, further the LD50 value of each compound dosed at this level was in the range of 40--56 mg/kg in the mouse; therefore, further study was not warranted. Fifteen compounds possessed activity in excess of 20% reduction at 200 mg/kg and also possessed LD50 values greater than 300 mg/kg. Of these cyanobenzenes, trimesonitrile (16), 4-chlorobenzonitrile, 2-chloroterephthalonitrile, and 2-fluoroterephthalonitrile with reductions in edema of 32, 30, 46, and 49%, respectively, represent the best candidates for subsequent study.
为了开发无胃肠道并发症的非酸性、非甾体类抗炎药，合成了一系列氰基苯用于抗炎评估。利用角叉菜胶诱导的足爪肿胀试验在大鼠中测试了27种取代间苯二甲腈、19种均苯三甲腈、30种苯甲腈和16种对苯二甲腈。根据保泰松在该试验中的表现（100mg/kg时炎症减少43.8%），6种化合物以50mg/kg的剂量给药，产生的炎症减少程度与该标准相当。然而，在此剂量下给药的每种化合物在小鼠中的半数致死量（LD50）值在40 - 56mg/kg范围内；因此，没有必要进行进一步研究。15种化合物在200mg/kg时具有超过20%的炎症减少活性，并且半数致死量值大于300mg/kg。在这些氰基苯中，均苯三甲腈（16）、4 - 氯苯甲腈、2 - 氯对苯二甲腈和2 - 氟对苯二甲腈的水肿减少率分别为32%、30%、46%和49%，是后续研究的最佳候选化合物。
