Bis-methylamides of 1,2-dialkyl substituted imidazole-4,5-dicarboxylic acids: preparation and antinociceptive activity

BACKGROUND: Searching for substances with high analgesic activity is one of the main problems of modern medicine. N-methyl-D-aspartate receptors present in all areas of the central nervous system responsible for reaction on pain stimulation. Moreover, peripheral glutamate receptors may be directly involved in the genesis of pain reactions. Therefore, it is of interest to search for new analgesics among N-methyl-D-aspartate receptor ligands. AIM: To develop a preparative method of synthesis and to investigate the antinociceptive activity of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-methylamides on the example of 2-propyl-1-ethylimidazole-4,5-dicarboxylic acid bis-methylamide. MATHERIALS AND METHODS: 1-Ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide was obtained using methods of organic synthesis. The Gaffner test of mechanical irritation of the base of the tail and the hot water tail-flick test in mice were selected to study the antinociceptive activity. RESULTS: It was shown that the amidation of 2-substituted imidazole-4,5-dicarboxylic acids dimethyl ether followed by the alkylation of the resulting 2-substituted imidazole-4,5-dicarboxylic acids bis-amide is а preferable method of the two alternative for obtaining of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-amides. It was shown that 1-ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide exhibits pronounced antinociceptive activity exceeding the activity of the comparative drugs analgin and ketorolac. CONCLUSIONS: A preparative method for the synthesis of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-amides is proposed. The dose-dependent antinociceptive activity of 1-ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide was shown. 1-Ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide exhibits antinociceptive activity exceeding the activity of analgin and ketorolac.