On the basis of the condensation products of the available pyrimidine-5-carbaldehydes, a number of new functionalized representatives of pyrido[2,3-d]pyrimidine were synthesized by intramolecular cyclization reactions.
It is shown that the interaction of 4,6-dichloropyrimidine-5-carbaldehyde with cyanomethyltriphenylphosphorane produces (2Е)-3-(4,6-dichloropyrimidine-5-уl)acrylonitrile, which proved to be promising for the preparation of new 4-substituted 7-iminopyrido[2,3-d]pyrimidine derivatives. The possibility of obtaining by one-pot two-stage method a number of substituted pyrido[2,3-d]pyrimidine-7-one derivatives has been demonstrated, containing residues of secondary amines at position 4 of the heterocyclic system, from ethyl (2Е)-3-(6-amino-4-chloropyrimidin-5-yl)acrylate. Developed a convenient method of synthesizing of pyrido[2,3-d]pyrimidin-7-one derivatives with various nitrogen-substituted in position 4 of heterocyclic systems. An effective approach to obtaining previously unavailable 7-amino-4-chloropyrido[2,3-d]pyrimidine useful for purposeful synthesis of pyrido[2,3-d]pyrimidine-4,7-diamines has been found. Reactions of 4,6-dichloropyrimidine-5-carbaldehyde with methyl- and tert-butylglycinates were investigated. It was found that the reaction of 4,6-dichloro-5-formylpyrimidine with glycine ester hydrochlorides in the presence of triethylamine results in new derivatives of N-(5-formylpyrimidin-4-yl)glycinate and cyclization products – 4-chloro-5-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate and 6-amino-4-chloropyrido[2,3-d]pyrimidine-7-one. For the first time, a simple, fast and convenient («one-pot») approach to the synthesis of previously unknown 6-aminopyrido[2,3-d]pyrimidine-7-ones by the reaction of 4-amino-substituted pyrimidine-5-carbaldehydes from methyl N-(4-methoxybenzylidene)glycinate was proposed. The inhibitors of human protein kinase CK2 was searched in a number of new amino-substituted derivatives of pyrido[2,3-d]pyrimidine. During biochemical testing in vitro of inhibitory activity protein kinase CK2 showed that of the 14 selected compounds the two exhibited inhibitory activity of protein kinase CK2. Methyl 2-[(7-aminopyrido[2,3-d]pyrimidin-4-yl)amino]benzoate and N-(4-anilino-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methoxybenzamide were determined to inhibit kinase CK2 in IC50 6,0 and 19,5 μМ respectively. Complexes of compounds with the ATP-binding site of human protein kinase CK2 have been analyzed to explain the data of biochemical testing. It was indicated to the further chemical optimization of pyrido[2,3-d]pyrimidines to increase for biologically active compounds in a number of amino-substituted pyrido[2,3-d]pyrimidine derivatives.
