Synthesis and analgesic activity of N-aryl/arylalkyl 3- (1-pyrrolidinyl/piperidinyl) butyramides
Essawi, M.Y.
Die Pharmazie 54(8): 575-579
1999
ISSN/ISBN: 0031-7144 PMID: 10483611 Document Number: 501943
Conjugate addition of pyrrolidine or piperidine to methyl crotonate, and hydrolysis of the resulting methyl butyrates gave the (+-)-3-pyrrolidino or piperidinobutyric acids 17 and 18, respectively. Coupling of these racemic acids to aryl-alkylamines, L-phenylalaninamide or L-phenylalanine methyl ester gave the 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 than 6, but unlike N-arylalkylsubstituted 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 an inhibition of spontaneous motor activity and sedation.