Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives.

During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 {3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine} was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8-19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH3O) as well as in hydantoin N3 alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a-19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a {1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride} exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model.