Novel pyrrolocycloalkylpyrazole analogues as CB 1 ligands

Novel 1,4‐dihydropyrazolo[3,4‐ a ]pyrrolizine‐, 4,5‐dihydro‐1 H ‐pyrazolo[4,3‐ g ]indolizine‐ and 1,4,5,6‐tetrahydropyrazolo[3,4‐ c ]pyrrolo[1,2‐ a ]azepine‐3‐carboxamide‐based compounds were designed and synthesized for cannabinoid CB 1 and CB 2 receptor interactions. Any of the new synthesized compounds showed high affinity for CB 2 receptor with K i values superior to 314 n m , whereas some of them showed moderate affinity for CB 1 receptor with K i values inferior to 400 n m . 7‐Chloro‐1‐(2,4‐dichlorophenyl) ‐N‐ (homopiperidin‐1‐yl)‐4,5‐dihydro‐1 H ‐pyrazolo[4,3 ‐g ]indolizine‐3‐carboxamide ( 2j ) exhibited good affinity for CB 1 receptor ( K i CB 1  = 81 n m ) and the highest CB 2 / CB 1 selectively ratio (>12). Docking studies carried out on such compounds were performed using the hCB 1 X‐ray in complex with the close pyrazole analogue AM 6538 and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB 1 ligands.