Synthesis and histamine H2-agonistic activity of ring-substituted phenyl analogues of impromidine

Analogues of the H2-agonist impromidine, characterized by a substituted phenyl ring instead of the 5-methyl-4-imidazolyl group, were prepared and tested for their H2-agonistic and H1-antagonistic activity at the guinea-pig atrium and ileum, respectively. The compounds were synthetized via successive aminolysis of diphenyl benzoylcarbonimidate and final acid hydrolysis of the benzoylguanidines. The substituents (mono- or disubstitution with F, Cl, Br, CF3, Me, Et, NO2, NMe2, NEt2, PhCH2) were mainly selected according to the structure-activity relationships known from potent cardiohistaminergics such as arpromidine. While in the arpromidine series substitution of the phenyl ring, in particular halogenation, proved to be very useful for increasing potency, in the series of title compounds, except for the m-fluoro analogue 5g, these variations resulted in a decrease in H2-agonistic activity in the isolated guinea-pig right atrium up to 1.5 orders of magnitude related to the parent compound 5a, which is 10 times more potent than histamine.