Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands
2014
Abstract A new series of 1 H -benzofuro[3,2- c ]pyrazole-3-carboxamides was synthesized. The novel compounds ( 15 – 24 ) were evaluated for their affinity to CB 2 and CB 1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6-methyl-1 H -benzofuro[3,2- c ]pyrazol-3-carboxylate. All the obtained derivatives showed high affinity to CB 2 receptors. Moreover, significant selectivity for CB 2 over CB 1 receptors was highlighted for lead derivatives amongst the novel series. The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (K i CB 2 22 exhibited the highest selectivity for CB 2 receptors with K i values of 3.7 and 2398 nM for CB 2 and CB 1 receptors, respectively. Preliminary functional assays evidenced CB 2 agonism behaviour for all the assayed novel derivatives.
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