Synthesis and analgesic activity of N-aryl/arylakyl 3- [1-pyrrolidinyl/piperidinyl] butyramides

ABSTRACT

Conjugate addition of pyrrolidine or piperidine to methyl crotonate and hydrolysis of the resulting methyl butyrates gave [ +/- ]-3-pyrrolidino or piperidino-butyric acids [17 and 18, respectively]. Coupling of these racemic acids to aralkylamines, L-phenylalaninamide, or L-phenylalanine methyl ester gave N-substituted butyramides 3-14 which were tested as analgesics using the hot-plate method. [ +/- ]-N-[2-phenethyl]-3-[1-pyrrolidinyl] butyramide [6] showed naloxone-attenuated analgesia but was considerably less potent than morphine and of shorter duration of action. Diastereomeric butyramides containing Phe residue [11-14] were less active analgesic than 6, but unlike N-aralkyl substituted derivatives, showed no toxic effects on locomotor activity at the high doses [30-60 mg/kg] used for testing. In all cases, analgesia was accompanied by inhibition of spontaneous motor activity and sedation