Hydroxyalkylation with Cyclic Sulfates: Synthesis of Carbazole Derived CB₂ Ligands with Increased Polarity

In order to increase the polarity of the potent CB₂ ligand 1a, the homologous hydroxyalkyl carbazoles 2a–c were prepared and pharmacologically evaluated. An important step in the synthesis is the hydroxyalkylation of carbazole with cyclic sulfates providing the 2-hydroxyethyl and 3-hydroxypropyl derivatives 5a and 5b in a one-step reaction. The final propionamides 2a–c were prepared using the recently reported coupling reagent COMU1. The X-ray crystal structure of 2c displays an almost coplanar arrangement of the 3-phenyl-1,2,4-oxadiazole biaryl system. The increased polarity of 2a is associated with an almost 100-fold reduced CB₂ affinity. The 3-hydroxypropyl derivative 2b represents the best compromise between lipophilicity and CB₂ affinity (K_i=33 nM).