Synthesis and activity of novel 5-substituted pyrrolo[2,3-d]pyrimidine analogues as pp60c-Src tyrosine kinase inhibitors

Abstract

Therapy with receptor tyrosine kinase inhibitors provides an improved treatment option in a number of diseases such as cancer, myocardial infection, osteoporosis, stroke, and neurodegeneration. We have designed, synthesized, and evaluated a series of novel 2-amino-5-[(benzyl)imino] methyl-3,7-dihydro-4H- pyrrolo[2,3-d]pyrimidine-4-one 7a and 2-amino-5-[(substituted-benzyl)imino] methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one 7b-e derivatives as potential tyrosine kinase inhibitors. These compounds were synthesized by condensation reaction using 2-tritylamino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d] pyrimidine-5-carbaldehyde 5 and appropriate benzylamines followed by detritylation. Compounds were evaluated for their inhibitory activity toward tyrosine phosphorylation for the pp60c-Src tyrosine kinase. Compounds 7a, 7d, and 7e demonstrated potent inhibitory activities against pp60 c-Src tyrosine kinase with IC50 values of 13.9, 34.5, and 78.4 μM, respectively. Dihalogenated compounds 7d and 7e have 3 to 7-times lower IC50 values than that of the parent compound 7a. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.