Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives

A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo2,1-f]purine-2,4-dione (2–10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11–13) were synthesized. Compounds (2–10) evaluated in vitro were potent 5-HT_1A receptor ligands. Preclinical studies indicated that 8-3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-3-(N4-2′-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.