Design and Synthesis of some isoxazole carboxylic acid derivatives as Antiinfammatory Agents

Design and Synthesis of Some Isoxazole Carboxylic acid Derivatives as Antiinflammatory AgentsThe present investigation is concerned with the synthesis of 5-substituted isoxazole-3-carboxylic acids as well as their esters, amides and the corresponding hydroxamic acids. The key intermediates, ethyl 2,4-dioxo-6-(aryl) hex-5-enoates 2a-h were prepared by reaction of the chalcone derivatives la-h with diethyl oxalate. The resulting esters 2a-h were then cyclized to ethyl 5-[2-(aryl)vinyl] isoxazole-3-carboxylates 3a-h using hydroxylamine hydrochloride. The targeted carboxylic acids 4a-h were produced by boiling with hydrochloric acid. The hydroxamic acid derivatives 5a-h were obtained either by reaction of the esters 3a-h with hydroxyl amine in slightly alkaline medium or from the reaction of carboxylic acids 4a-h in the form of mixed anhydride with ethyl chloroformate and subsequent treatment with hydroxylamine in neutral medium.The amide derivatives 6-29 were synthesized from selected carboxtlic acides 4a-4c and 4e-4f by treatment of their acid chlorides with the appropriate amine.The structure of the newly synthesized compounds were ascertained using IR, NMR and mass spectroscopy in addition to the elemental analysis for C, H. and N.The anti-inflammatory activity of the prepared carboxylic acids 4a-h, hydroxamic acids 5a-h, esters 3b, 3e-g and amides 22, 24 and 25 was achieved by determination of their inhibitory effect on carrageenan-induced rat paw edema according to the reported method and in comparison to indomethacin as a reference drug.All of these compounds exhibited significant activity in comparison to the control group. The 5-[2-(p-Flourophenyl) vinyl] isoxazole-3-carboxylic acid 4b, its p-dimethylamino analogue 4g as well as the hydroxamic acid derivative 5g being comparable with indomethacin in terms of potency. Meanwhile, some of the tested esters 3e and 3g as well as amides 22, 24 and 25 showed also moderate anti-inflammatory activity but characterized by slow onset of action.The ulceroginicity of the most active acid 4g and corresponding ester 3g, as well as hydroxamic acid derivative 5g in comparison to indomethacin were examined using scanning electron microscope. All of these compounds are less ulcerogenic than indomethacin. The acid derivative 4g is the more ulcerogenic than the corresponding ester 3g whereas the hydroxamic acid derivative 5g is the least.