W. V. van Bever, C. Niemegeers, P. Janssen
Oct 1, 1974
Citations
2
Influential Citations
130
Citations
Quality indicators
Journal
Journal of medicinal chemistry
Abstract
The synthesis of the respective diastereoisomers and enantiomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidylj-Nphenylpropanamide and N-[3-methyl-l-(l-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide is reported. Analgesic activity is evaluated in the tail withdrawal test in rats. cis-(+)-N-[3-Methyl-l-(2-phenylethyl)-4-piperidyll-N-phenylpropanamide (23) is found to be an extremely potent analgesic, up to 6684 times morphine. Compound 23 has a fast onset of action, a shorter duration of action than morphine, and an unusually high safety margin. As part of a continuing effort to develop novel analgesic agents a series of methyl-substituted derivatives of fentanyl (1) was prepared. Fentanyl, a well-known analgesic characterized by high potency, a rapid onset, and short duration of action,lg2 belongs to a series N-[l-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide~.~ At the time of the peak effect (Table IV) 1 is about 300 times more potent than morphine in the tail withdrawal test in rats..4 It is known that methyl substitution in the side chain (Y to the basic nitrogen of 1 (compound 2) enhances the analgesic a~tivity.~ On the other hand, the activity-enhancing effects of 3-methyl substitution in the piperidine ring of 4-phenylpiperidine analgesics are well documented.”* These considerations have led to synthesis of the different diastereoisomers and enantiomers of N-[3-methyl-l(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide (3, R = H) and N-[3-methyl-l-(l-methyl-2-phenylethyl)-4-piperidyll-N-phenylpropanamide (3, R = Me). The recent publication of Riley, et UL.,~ has prompted us to report our results.