Synthesis of certain substituted pyrrolidines as analgesics

The synthesis of a series of N-[[2R]-1-ethyl or propyl-2-[4-methoxybenzyl]-pyrrolidin-3-yl]-N-phenyl acetamide or propionamide [la-d] was achieved, where R, R=methyl or ethyl with the aim to evaluate their analgesic activity. The adopted synthetic pathway of these compounds was illustrated Dieckmann cyclization of 2-[acyl-[2-ethoxycarboryl-ethyl]-amino]-3-[4-methoxy-phenyl]-propionic acid ethyl ester [7a, b] afforded [R]-ethyl 1-acetyl or propionyl-5-[4-methoxybenzyl]-4-oxopyrrolidine-3-carboxylate [6a and 6b], followed by deethoxycarboxylation. The target compounds 1a-d were synthesized Screening of the analgesic profile of the synthesized compounds showed that compounds 1b and 1c at dose level of 0.13mmol/kg. I p. exhibited the highest analgesic activity compared with morphine hydrochloride [0.004 mmol/kg. i.p]

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

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