Isomeric N-methyl-7-deazaguanines: synthesis, structural assignment, and inhibitory activity on xanthine oxidase

The N-methyl isomers of 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (2a) have been synthesized regiospecifically and their structures assigned. The 3-methyl compound 3 was obtained by alkylation of the parent chromophore 2a with dimethyl sulfate, and the 1-methyl isomer 5b was obtained by condensation of ethyl 2-cyano-4,4-diethoxybutyrate with N-methylguanidine and subsequent cyclization. Methylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7b), however, with methyl iodide in the presence of 50% NaOH, by phase-transfer techniques, followed by the replacement of halide by hydroxyl, yielded the 7-methyl compound 2b. The N-methyl isomers of 2a were all found to be inhibitors of xanthine oxidase from cow's milk. While the 3-methyl isomer 3 exhibits a Ki of 40 microM, the 7- and 1-isomers show Ki values of 4.5 and 3 microM, respectively.