3-(羟基-p-甲磺酰苯甲撑基)-5-氯-2-吲哚酮-1-羧酰胺类化合物的合成及生物活性研究

Synthesis and Biological Activity of 5-Chloro-3-(hydroxy-p-methanesulfonylphenylmethylene)-2-oxo-2,3-dihydroindole-1-carboxamides

为了寻找高效低毒的非甾体抗炎药物,将5-氯-2-吲哚酮与氯甲酸苯酯经酯化及水解制得1-苯氧羰基-5-氯-2-吲哚酮,在4-N,N-二甲氨基吡啶作用下与对甲磺酰基苯甲酰氯反应,经酸化得1-苯氧羰基-3-[羟基-(p-甲磺酰基)苯甲撑基]-5-氯-2-吲哚酮(II1),最后与相应的胺(氨)反应,经盐酸中和制得未见文献报道的目标化合物II2～II15,其结构经IR,1HNMR,MS和元素分析确证.二甲苯致小鼠耳肿胀模型测试显示II10,II11,II15具有明显的抗炎活性;角叉菜胶致大鼠足跖肿胀模型试验结果表明,II10,II11抗炎活性与双氯芬酸钠和替尼达普钠相当(P>0.05);其中II11的胃肠道副作用显著小于双氯芬酸钠(P<0.05)和替尼达普钠(P<0.01).

In order to search for new compounds with stronger anti-inflammatory activity and less side effects, phenyl 5-chloro-2-oxindole-1-carboxylate, obtained from 5-chloro-2-oxindole via esterification with phenyl chloroformate and subsequent hydrolyzation, reacted with 4-（methylsulfonyl） benzoyl chloride and 4-dimethylaminopyridine, followed by acidification with hydrochloric acid to yield phenyl 5-chloro- 3-（hydroxy-p-methylsulfonylphenylmethylene）-2-oxo-2,3-dihydroindole-1-carboxylate （Ⅱ1）, which was condensed with corresponding amines, followed by acidification with hydrochloride acid to afford the target compounds Ⅱ2-Ⅱ15, respectively. Fifteen novel title compounds were synthesized, and their structures were confirmed by IR, ^1H NMR, MS spectra and elemental analyses. Ⅱ10, Ⅱ11 and Ⅱ15 exhibited marked anti-inflammatory activity in xylene-induced mice ear swelling model. Moreover, Ⅱ10 and Ⅱ11 showed significant anti-inflammatory activity comparable to diclofenac sodium and tenidap sodium （P〉0.05） in carrageenan-induced rat paw edema model. Ⅱ11 had less gastrointestinal side effect than diclofenac sodium （P〈0.05） and tenidap sodium （P〈0.01）.