Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6receptor ligands?

Organic & Biomolecular Chemistry Pub Date: 2008-08-11 DOI: 10.1039/B808641A

Abstract

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-HT6receptor 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-HT6receptor was with moderate affinity (Ki = 216.5 nM) for the (Z)-benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenylsulfonamide counterpart 13 (Ki = 50.6 nM). Selected indenylsulfonamides 14–17 were then tested, showing Ki values as low as 20.2 nM.

Graphical abstract: Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6receptor ligands
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