1,2,3-triazolo[4,5-d]pyridazines - Part VI. New 1-substituted-4-amino derivatives and their affinity towards A(1) and A(2A) adenosine receptors

Starting from the appropriate azides ( 4-chlorobenzyl-, 2-thiophenemethyl-, 2-fluorobenzyl-, and 4-fluorobenzylazides) agreeing with the substituent determining four series of derivatives (a-d), some 4-amino-substituted 1,2,3-triazolo[4,5-d]pyridazines (4a-d) corresponding to previously prepared derivatives were obtained by a well experimented synthetic route. Other new derivatives (6c,e) which were different from 4a-d because a chlorine atom had substituted the hydroxyl or the tautomeric oxamido group in the 7 position of the triazolopyridazine ring, were prepared from the suitable azides (2-fluorobenzyl and 2-chlorobenzyl), which similarly determine the series c and e, respectively, via the 4,7-dichloro derivatives 5. The radioligand binding assays at bovine brain adenosine A(1) and A(2A) receptors showed that some compounds 4 possessed high affinity and selectivity for the A(1) receptor subtype whilst binding affinity decreased in compounds 6 indicating the importance of a hydrogen bond donor in the 7 position of the triazolopyridazine ring. It is worth noting that compounds bearing the new lipophilic substituents 2-fluorobenzyl and 2-thiophenemethyl in the 1 position of the triazolopyridazine ring were the most active in the series. (C) 1999 Elsevier Science S.A. All rights reserved.