Azacycloalkanes VIII. Aromatic amides of N-substitutedα-pyrrolidinedicarboxylic acids

Synthesis, local anaesthetic and antiarrhythmic activities of N-alkyl derivatives of proline anilides

“…1), introduction of a N-benzyl moiety into the pyrrolidine ring of ortho-toluidine derivative appeared to abolish anaesthetic activity. All the above observations were found to be very close to those earlier reported [22] for the analogous mesidides and seemed to be general for this class of local anaesthetics.…”

“…We believe that this fact was linked with a clearly observable local irritative effect of 4g. Similarly to the previously reported data [9,22], we found that increase in the number of methyl groups translated into increase of potency and duration of local anaesthetic effect. Interestingly, 2,4-and 2,6-xylidides (4d and 4e) demonstrated almost no difference in the activity.…”

“…Then arylamides of 2-bromo-5-chloropentanoic acid (3) were prepared by treatment of 2 with various anilines in mild conditions. The treatment of 3 with primary alkylamines under heating in toluene resulted in the intramolecular cyclization with formation of arylamides of N-alkylprolines, which were further converted into the corresponding hydrochloric salts 4. ortho-Toluidide of N-methylproline (4a) has been previously reported and its physicochemical and spectral characteristics are in agreement with the literature values [22].…”

“…Extension of the chain from n-butyl (4c) to n-pentyl (4k) and further to n-hexyl (4l) in Nalkyl proline ortho-toluidides led to some increase of the Regnier index and significantly lengthened the anaesthetic activity. Making the alkyl chain even longer seemed to be unnecessary due to local irritative effect and poor aqueous solubility, previously reported for the similar structures with longer N-alkyl chain in the pyrrolidine ring [22]. The cyclohexyl substituted derivatives 4n and 4o demonstrated practically the same level and duration of anaesthesia as their corresponding n-butyl analogues 4c, e. Interestingly, despite recent reports [25][26][27] on high in vitro sodium channel blocking potential of 2,6-xylidine analogue of 4m -NeP1 ( Fig.…”