Regioselective synthesis of novel functionalized 2-pyridones, synthetic application and in vivo study of anti-inflammatory activity

2-pyridones are known for their pharmacological properties1, among them, anti-inflammatory property2. β-enamino diketones are very attractive as precursors for the synthesis of 2-pyridones3, may lead to different regioisomeric products. Thus, β-enamino diketones 2(a-g) were reacted with malononitrile and ethyl cyanoacetate to give 6-carboxyethyl-3-cyano-2-pyridones and 3,6-dicarboxyethyl-2-pyridones, respectively. The products were regioselectively obtained in the salt form 3(a-n) and free 4(a-n) form. In order to exploit the synthetic potential of the 2-piridones 4(a-n), the hydrolysis reaction of the ester group was carried out to give 3-cyano-6-carboxylic-2-pyridones acid 5(a-g), 3-carboxylic-6-carboxyethyl-2-pyridones acid 6(a-g) and 3,6-dicarboxylic-2-pyridones acid 7(a-g). It was also evaluated reactivity of 2-pyridones 4(a-n) with hydrazine monohydrate and phenylhydrazine, leading to new compounds pyridopyridazine-2,8-diones 8(a-n) and 9(a-g). Many of the compounds synthesized were sent to the evaluation of anti-inflammatory activity in vivo through ear edema assay in mice4, being that some compounds presented high inhibition levels at 1.25 mg/ear doses.