title: N-(fluoroethyl)(imidazolylphenyl)formamidines. The issue of the active species of mifentidine.
abstract: Three N-fluoroethyl-substituted (imidazolylphenyl)formamidine derivatives, namely, 2-fluoroethyl (3b), 2,2-difluoroethyl (3c), and 2,2,2-trifluoroethyl (3d), were prepared to test the effect of fluorine substitution on basicity and, then, on H2-antagonist affinity in comparison with the unsubstituted N-ethyl derivative (3a), taken as a model of mifentidine. Imidazolylphenyl isothiocyanate (1), obtained by reaction of 4-(aminophenyl)imidazole with carbon disulfide and ethyl chloroformate, was condensed with the requisite 2-fluoro-substituted ethylamines to give the intermediate thioureas (2b-d). Desulfurization of these thioureas by Raney nickel furnished the desired formamidines (3b-d). Increasing fluorine substitution was found to decrease basicity of the formamidino group substantially (3a, pKa = 8.65; 3b, pKa = 8.12; 3c, pKa = 6.60; 3d, pKa = 6.14), while having a modest effect on the imidazole portion. Affinity at the H2 receptors, evaluated from antagonism of histamine-stimulated chronotropic response on guinea pig atria, increased following fluorine substitution (3a, KB = 177; 3b, KB = 61; 3c, KB = 21; 3d, KB = 7.6). It is concluded that H2-receptor antagonist affinity in the mifentidine series is mostly dependent on the availability of the neutral species. These data support the hypothesis that mifentidine, like cimetidine, acts through the neutral species.
authors.affiliation: Department of Medicinal Chemistry, Istituto De Angeli, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Donetti
authors.forename: E
authors.initials: E
authors.lastname: Cereda
authors.forename: A
authors.initials: A
authors.lastname: Ezhaya
authors.forename: R
authors.initials: R
authors.lastname: Micheletti
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D013329:Structure-Activity Relationship
chemical_list: D006635:Histamine H2 Antagonists; D007093:Imidazoles; C039796:mifentidine