title: The synthesis of a series of adenosine A3 receptor agonists.
abstract: A series of 1'-(6-aminopurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamides that were 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-β-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-N-methyl-β-d-ribofuranuronamide. The products were active as selective adenosine A3 agonists.
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Erica
authors.initials: E
authors.lastname: Burnell
authors.affiliation: Muscagen Limited, 10, North Road, Cardiff, CF10 3DY, UK.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Davies
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Alan T L
authors.initials: AT
authors.lastname: Lee
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Snee
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Thomas
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043684:Receptor, Adenosine A3 / Q000378:metabolism*
chemical_list: D058909:Adenosine A3 Receptor Agonists; D010080:Oxazoles; D011725:Pyridines; D043684:Receptor, Adenosine A3; C577918:oxazolo(3,2-a)pyridine; D000241:Adenosine