Design, Synthesis And Anti-inflammatory Activity Of Pyrazole Class Of COX-2 Selective Inhibitors

Background Nonsteroidal anti-inflammatory drugs(NSAIDs), the inhibitors of cyclooxygenase(COX) involved in the first step of biosynthesis of prostalandins(PGs), are extensively used in analgesic, antipyretic and anti-inflammation. However, treatment with classical NSAIDs, particularly in the individuals who have rheumatoid arthritis and osteoarthritis, often leads to gastric ulcers or other gastrointestinal complications, which considerably limits the therapeutic potential of this class of drugs. In fact, COX exists in two isoforms named COX-1 and COX-2, respectively. COX-1 is constitutively expressed in stomach, kidneys and platelets and is considered important in mucosal protection and platelet and kidney function. COX-2 is inducible and plays a major role in PGs biosynthesis in inflammatory cells. Classical NSAIDs inhibit both forms of the enzyme, some of which even preferentially inhibit COX-1. The discovery of COX-2 led to the recognition that selective inhibition of COX-2 would constitute a novel approach to the treatment of inflammation with diminished sideeffects. Therefore, there is an increasing interest in the research and development of COX-2 selective inhibitors.Methods (1) Based on the chemical structure of Celecoxib, the first approved new family of COX-2 inhibitors in the world, three series of pyrazole derivatives were designed by retaining the necessary activity part of benzenesulfonamide in the molecule and changing 5-position and 4-position in the pyrazole ring. The target compounds were synthesized through Claisen condensation and cyclization from the starting compounds B-diketone, ethyl trifluoroacetate and 4-hydrazinobenzenesulfonamide hydrochloride. The chemical structures of those target compounds and key intermediates were determined by HPLC, IR, UV, 1HNMR, 13CNMR, MS, et al. In addition, the synthetic methods of the pyrazole derivatives and their intermediates such as B-diketone and 4-hydrazinobenzenesulfonamide hydrochloride were improved.(2) By using xylene, the model of mouse ear edema was induced. All the pyrazole derivatives were tested for their anti-inflammatory activity in xylene-induced mouse ear edema assay. Aspirin and the synthesized compounds were administered to mice by oral gavage at the dose of 100, 200 and 400 mg/kg, respectively. Compared the edema of pyrazole derivatives-treated groups with that of model group, the percentage of inhibition and anti-inflammatory activity were obtained. The gastrotoxicity of those compounds was evaluated by determining the gastric mucosal lesion index at the dose of 400mg /kg.Results We have synthesized 14 pyrazole derivatives, 13 of which have never been reported. Confirmed by IR, UV, 1HNMR, 13CNMR and MS,chemical structures of the synthesized compounds are consistent with those of the target molecules. Moreover, after the improvement of the synthetic methods, the pyrazole derivatives could be obtained successfully and efficiently.When systematically evaluated by the xylene-induced mouse ear edema assay at the dose of 100, 200 and 400 mg/kg, all the synthesized compounds were found to possess the ability of anti-inflammation, and their anti-inflammatory activity increased in the dose-releated manner. Some pyrazole derivatives in this paper, such as PC406, PC408, PC409, PC410 and PC411, were found to have more potential activity than Celecoxib (PC401) in anti-inflammation. Compared with Aspirin, all the compounds have diminished gastrotoxicity side effects. Some compounds, such as PC401, PC403, PC405, PC407, PC408, PC409, PC410 and PC412, show no significant influence on the stomach mucosa.Conclusion Based on the chemical structure of Celecoxib, three series of pyrazole derivatives including necessary activity part of benzenesulfonamide were designed and synthesized. Two series of molecular structures and 13 derivatives among them have never been reported. All the data of anti-inflammatory activity and gastrotoxicity mentioned above showed that pyrazole ring including benzenesulfonamide group was a good essential original...