Synthesis, anti-exudative and anti-inflammatory properties of substituted N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-1,4-dihydropyridin-3-carboxam

Abstract

One-pot reaction of cyanothioacetamide, N-(2,4-dichlorophenyl)acetoacetamide and furfural in the presence of excessive N-methylmorpholine in EtOH at 25 °C gives N-methylmorpholinium 5-[(2,4-dichlorophenyl)carbamoyl]-3-cyano-4-(2-furyl)-6-methyl-1,4-dihydropyridin-2-thiolate, yielding 82%. Subsequent S-alkylation of the prepared thiolate with N-substituted α-chloroacetamides occurs in a regiospecific way to form N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-[(2-oxo-2-{[substituted aryl]amino}ethyl)sulfanyl]-1,4-dihydropyridin-3-carboxamides 10–17. Compounds 10–17 were identified by means of IR and NMR spectroscopy, as well as by elemental analysis. Synthesized compounds 10–17 were examined for anti-exudative and anti-inflammatory activity. White laboratory rats numbering 112 individuals were divided into control (“acute formalin-induced paw edema”) and intact groups, 4 reference groups (acetylsalicylic acid, indomethacin, nimesulide, and paracetamol) and 8 experimental groups, according to the number of tested 1,4-dihydropyridine derivatives. The efficacy of the anti-inflammatory activity of the samples was evaluated in the model of “acute formalin paw edema” in rats, which was simulated by injecting 0.1 mL of 2% formalin solution into the aponeurosis of the right hind limb. The studied compounds were given intragastrically at a dose of 5 mg/kg 1.5 hours before the induction of the inflammatory process. Oncometric changes were measured quantitatively by limb girth. It was shown that the most pronounced anti-inflammatory activity was possessed by: N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-[(2-oxo-2-{[3-(trifluoromethyl)phenyl]-amino}ethyl)sulfanyl]-1,4-dihydropyridin-3-carboxamide 12 (1.09–1.81 times more effective than the reference drugs); 6-[(2-anilino-2-oxoethyl)sulfanyl]- N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-1,4-dihydropyridin-3-carboxamide 16, which reduced the induced paw edema by 42.91% compared to control; N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-({2-[(3-methylphenyl)amino]-2-oxoethyl}sulfanyl)-1,4-dihydropyridin-3-carboxamide 14 (1.65–2.85 times higher anti-inflammatory activity compared to the reference drugs in 18-hour experiments). N-(2,4-Dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-({2-[(3,5-dimethylphenyl)amino]-2-oxoethyl}sulfanyl)-1,4-dihydropyridin-3-carboxamide 11 was found to be the most active, reducing paw edema 2.9 times more effectively than nimesulide.