Synthesis of benzocycloalkane derivatives as new conformationally restricted ligands for melatonin receptors

Article abstract of DOI:10.1016/S0960-894X(98)00601-5

Benzocycloalkane derivatives 1-4 were synthesized as new conformationally restricted melatoninergic ligands. They were prepared by the reaction of the ketones 5 with diethylcyanophosphonate and the reduction of the corresponding cyano compounds or by the Wittig reaction and Curtius degradation to obtain the amines 8. The 1-Cyanobenzocyclobutane derivative was obtained by the benzyne cyclisation reaction. The amines 8 were acylated with acetyl, propionyl or butyryl groups. The affinity of the compounds for chicken brain melatonin receptors was evaluated using 2-[¹²⁵I]- iodomelatonin as the radioligand. The indanyl (2b, c), tetralin (3a-c) and benzocyeloheptane (4c) derivatives were potent compounds with nanomolar affinity and an important enantioselectivity of the receptor was observed with the (+) enantiomers 2b and 3b.