A series of 2-phenyl-1,8-naphthyridin-4(1H)-one (2-PN) derivatives has been synthesized and illustrated very potent cytotoxicity. However, most of them were quite lipophilic and poor pharmacokinetic characteristic for preclinical studies.
In order to improve the ADME properties of 2-PNs, several 3-carboxylic acid derivatives were designed and synthesized. The appropriate ethyl benzoylacetate 11-13 were obtained from commercially available 3-substituted acetophenones 8-10 treated with diethyl carbonate, respectively. The acylating agent of N-succinimide ester of aminonicotinic acid 6 was prepared from appropriate aminonicotinic acid and N-hydroxysuccinimide in the presence of DCC in dry THF. To cyclocondensation of compounds 11-13 and acylating agent used potassium t-butoxide as a base at reflux afforded 2-PNs 14-16, respectively, bearing the 3-carboxyl moiety on the 3-position. Finally, the hydrolysis of compounds 14-16 by treatment with 10% NaOH(aq) gave target compounds 17-19, respectively. We provided successfully the synthetic route for the preparation of 2-phenyl-1,8-naphthyridin-4(1H)-one-
3-carboxylic acid derivatives under smooth reaction conditions for drug development.
