摘要
目的 研究高效低毒的双氯芬酸 (DC)偶联化合物。方法 以酯键或酰胺键将一氧化氮 (NO)供体 3 ,4 二苯磺酰基呋咱氮氧化物与DC偶联 ,观察偶联物对二甲苯致炎小鼠和角叉菜胶致炎大鼠的抗炎活性及对大鼠胃肠道反应 ,研究体内外偶联物的NO释放。结果 合成了 11个新化合物 (I1 - 1 1 ) ,其结构经MS ,IR ,1 HNMR和元素分析确证。I1 - 5,I9显示抗炎活性 ,其中I4 和I5活性与DC相当 ,胃肠道副作用显著小于DC ,体内外均释放NO。结论 苯磺酰基呋咱氮氧化物与DC偶联的化合物可保留DC抗炎活性 ,降低DC胃肠道不良反应。
AIM To search for new derivatives of diclofenac (DC) having activity of the parent drug and lacking its undesirable effects. METHODS Coupling DC with NO donor 3,4-dibenzenesulfonylfuroxan through esterification and amidation, evaluating anti-inflammatory activity against xylene-induced mice ear swelling and carrageenan-induced rat paw edema, observing side effects in the rat gastrointestinal (GI) tract and assessing NO releasing ability both in vitro and in vivo . RESULTS Eleven new compounds (I 1-11 ) were synthesized, and the structures of I 1-11 were determined by IR, 1HNMR , MS and elemental analysis. Compared with DC, I 1-5 and I 9 showed no significant difference in anti-inflammatory activity against xylene-induced mice ear swelling. I 4 and I 5 showed potency comparable to DC in treatment of carrageenan-induced rat paw edema. In GI tract, only slight mucosa sulface erosion was found in both I 4 and I 5 treated rats, while deep ulcer was found in nitrofenac dosed rats and ulcer perforation was found in DC treated rats. Five of eleven rats treated with DC died, one of eight rats treated with nitrofenac died. However, no death was found in eight rats dosed with I 4 or I 5. The detection of occult blood in feces and hematology index also showed that the extent of GI tract bleeding in I 4 and I 5 treated rats was much less than that in both DC and nitrofenac treated rats. In addition, I 4 and I 5 released NO both in vitro and in vivo . CONCLUSION Benzenesulfonylfuroxan-coupled DC may possess potency comparable to DC and less GI side effect than DC.
出处
《药学学报》
CAS
CSCD
北大核心
2001年第11期821-826,共6页
Acta Pharmaceutica Sinica
