Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands

A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT6 receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides 13-17 using an optimized procedure with AlH3-NMe2Et. The binding at the 5-HT6 receptor was with moderate affinity (K-i = 216.5 nM) for the (Z)-benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenyisulfonamide counterpart 13 (K-i = 50.6 nM). Selected indenylsulfonamides 14-17 were then tested, showing Ki values as low as 20.2 nM.