The Study On The Synthesis And Activities Of New COX-2 Inhibitors Containing 5-aminothiazole Unit

Non-steroidal anti-inflammatory drugs?NSAIDs?are widely used in anti-inflammatory,analgesic,antipyretic,arthritis treatment and cancer prevention.However,using NSAIDs for long time can easily cause gastrointestinal bleeding and cardiovascular disease.In comparison,the side effects of Oxicam selective cyclooxygenase-2?COX-2?inhibitors are less than those of other NSAIDs.The synthesis and physiological activity of Oxicam NSAIDs have attracted much attention from drug developers.Aminothiazole compounds have a wide range of biophysiological activities and are a hot field in medicine and pesticide research,the2-aminothiazole derivatives,one branch of aminothiazole compounds have many compounds been marketed as medicines and pesticides.But the study of biophysiological activities of 5-aminothiazole derivatives are seriously lagging behind that of the 2-aminothiazole analogue.In order to find highly active 5-aminothiazole new drug molecules,using bioisosterism principle and active substructure splicing method and utilizing commercial Oxicam compounds?meloxicam,sudoxicam,tenoxicam,lornoxicam?as leading compounds,three new types of nine5-aminothiazole COX-2 inhibitors are designed.The structures of all target compounds were confirmed by 1H NMR,13C NMR and HRMS,and tested the cell viability of all target compounds.All target compounds were synthesized with the amine ester exchange reactions which are the 5-aminothiazole derivatives reacted with meloxicam methide,tenoxicam methoxide and lornoxicam methide separately.a new synthetic route for the 5-aminothiazole intermediates was designed,and three new derivatives of this type have not been reported in the literatures.The method has the characteristics of easy availability of raw materials,easy operation and high yield,and can be provided to reference for the subsequent research on the synthesis of5-aminothiazole compounds.Oxicam methides has been synthesized according to the industrialized routes.The cellular activities were evaluated using the lead compounds as positive controls with the concentration of 100 g/ml.The results showed that most compounds had good anti-inflammatory activities.Excitingly,Among them,compound A₁ diplayed higher inhibition of COX-2 activity significantly than that of the positive control?meloxicam?,In addition,its side effects?inhibition of COX-1 activity?is lower than that of the control drug,The animal activity,minimum inhibitory concentration,toxicity and safety will be studied in our research group,and a compound being entered possible clinical trial maybe expected.