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N-(fluoroethyl)(imidazolylphenyl)formamidines. The Issue of the Active Species of Mifentidine

N-(fluoroethyl)(imidazolylphenyl)formamidines. The Issue of the Active Species of Mifentidine

A Donetti, E Cereda, A Ezhaya, R Micheletti

J Med Chem. 1989 May;32(5):957-61.

PMID: 2565401

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP462271	2-Fluoroethyl chloroformate		462-27-1	Price

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