Synthesis, and structural, conformational and pharmacological studies of new fentanyl derivatives of the norgranatane system

A series of 9-phenethyl-3-α-(N-arylamido)norgranatanes have been synthesized and studied by 1H and 13C-NMR spectroscopy, and the crystal structure of 9-phenethyl-3-α-(N-p-tolyl-p-chlorobenzamido)norgranatane has been determined by X-ray diffraction. The compounds studied display in deuteriochloroform the same preferred chair–boat conformation with the disubstituted ring in a slightly distorted boat form. This bicycle conformation is similar to that found for compound 4f in the crystal state. In vivo pharmacological testing demonstrated that compounds 4a–h were inactive in the analgesic test, with the exception of compound 4b(the N-p-tolylpropanamido derivative) which showed an ED50 of 100 mg kg–1p.o.