The synthesis of a series of adenosine A₃receptor agonists

Abstract

A series of 1-(6-aminopurin-9-yl)-1-deoxy-N-methyl--D-ribofuranuronamides characterised by 2-dialkylamino-7-methyloxazolo [4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised. This work involved the synthesis of 2-dialkylamino-5-aminomethyl-7-methyloxazolo [4,5-b]pyridines and analogues that were coupled with the known 1-(6-chloropurin-9-yl)-1-deoxy-N-methyl--D-ribofuranuronamide. The oxazolo [4,5-b]pyridines were synthesized by regioselective functionalisation of 2,4-dimethylpyridine N-oxides. The regioselectivities of these reactions were found to depend upon the nature of the heterocycle with 2-dimethylamino-5,7-dimethyloxazolo [4,5-b]pyridine-N-oxide undergoing regioselective functionalisation at the 7-methyl group on reaction with trifluoroacetic anhydride in contrast to the reaction of 4,6-dimethyl-3-hydroxypyridine-N-oxide with acetic anhydride that resulted in functionalisation of the 6-methyl group. To optimise selectivity for the A3 receptor, 5-aminomethyl-7-bromo-2-dimethylamino-4-[(3-methylisoxazol-5-yl)methoxy]benzo [d]oxazole was synthesised and coupled with the 1-(6-chloropurin-9-yl)-1-deoxy-Nmethyl--D-ribofuranuronamide. The products were found to act as adenosine A3 agonists but further work is required to optimise potency and selectivity.