Synthesis of cyclic tert-amines and their salts based on dimethylaminopropylamine and aminoethylpiperazine and their biological activity

Objectives. The work set out to obtain cyclic tert-amines by alkylation of dimethylaminopropylamine (DMAPA) and aminoethylpiperazine (AEP) with cis-1,4-dichloro-2-butene and cis-2,3-di(chloromethyl)-gem-dichlorocyclopropane. Quaternary ammonium salts were synthesized from a cyclic amine base and the resulting compounds evaluated as substances influencing the hemostasis process. The effect of structural fragments in the resulting substances on their anticoagulation and antiplatelet properties was evaluated.

Methods. The target compounds were obtained by a classical method of organic synthesis: by alkylation of DMAPA and AEP with cis-1,4-dichloro-2-butene and cis-2,3-di(chloromethyl)-gem-dichlorocyclopropane. The qualitative and quantitative compositions of the reaction mixtures were determined by chromatography with a Khromatek-Kristall 5000M chromatograph fitted with a 30 m × 0.25 mm × 0.5 μm capillary column containing 5% phenyl/95% polydimethylsiloxane as the stationary phase, as well as by nuclear magnetic resonance spectroscopy using a Bruker AM-500 spectrometer having operating frequencies of 500 and 125 MHz.

Results. The corresponding tertiary amines were obtained upon heating with 70–88% yield by alkylation of DMAPA and AEP with cis-1,4-dichloro-2-butene and cis-2,3-di(chloromethyl)-gem-dichlorocyclopropane. It was determined that the synthesized amines react with benzyl bromide to form salts with a yield of more than 80%. Quaternary ammonium salts were found to exhibit anticoagulation activity at the level of the reference standard, acetylsalicylic acid, and the highest activity is demonstrated by the amide 1-benzyl-4-[2-(2,5-dihydro-1H-pyrrol-1-yl)ethyl]piperazine. Analysis of the structure–property relationship showed that, in the series of DMAPA derivatives, the presence of a benzyl group increases the antiplatelet activity (the value of the maximum amplitude of platelet aggregation), whereas for the AEP derivatives, the presence of a benzyl group reduces by more than half the maximum amplitude of platelet aggregation, thereby reducing antiplatelet activity.

Conclusions. DMAPA and AEP condense with cis-1,4-dichloro-2-butene and cis-2,3-di(chloromethyl)-gem-dichlorocyclopropane to form the corresponding spirocyclic derivatives with high yields. The resulting amines are shown to undergo a quaternization reaction under thermal heating to form quaternary ammonium salts. The synthesized salts are found to exhibit anticoagulation activity comparable to that of the acetylsalicylic acid reference standard.

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