Synthesis and pharmacochemistry of some new aminoketones with local anaesthetic activity

The synthesis of some new 1-indane- and 1-(1',2',3',4'-tetrahydronaphthalene-1-spiro-3''-ryrrolidino-2'',5 ''- dione)-3-amino-substituted-butanones-2, having the structural characteristics for local anaesthetic activity, is reported. These aminoketones were synthesized using a modified Mannich reaction. The structure of the intermediate and final products were identified by elemental and spectroscopic analyses (IR, 1H-NMR, MS). The physicochemical parametres pKa and logP were determined experimentally, and they were also calculated using the appropriate Taft's equation and the Rekker's hydrophobic fragmental constants, respectively. The local anaesthetic activity of the synthesized compounds was determined in vitro on isolated frog's nerve, using an improved evoked action potential technique. The biological results were expressed as relative activities (RA) to procaine, used as reference compound. These RA of the investigated compounds were found to lie between 0.50-0.85. An attempt was made to correlate the local anaesthetic activity with the values of the investigated physicochemical parameters.