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.

Advancements in Aminofluorination of Alkenes and Alkynes: Convenient Access to β‐Fluoroamines

“…The introduction of fluorine into a biologically active compound can dramatically change its properties owing to the high electronegativity and small size of fluorine 1. For instance, the introduction of a fluorine atom in a position vicinal to an amine was able to produce a decrease in the amine's basicity,2 resulting in improvements in biological activity,3 bioavailability,4 and lipophilicity (log D ) 5. Nitrogen‐containing molecules represent major classes of bioactive compounds and natural products.…”

Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-deoxyuridines

“…(1) Dex-NCS has reasonable affinity for glucocorticoid receptors in cell-free extracts and in whole cells (Table I). (2) It is biologically active for the induction of the glucocorticoid-inducible enzyme TAT (Table I and Figure 1). (3) The apparent whole cell affinity of Dex-NCS for receptors is higher than the cell-free affinity (Table I), in keeping with the differences in off-rates of covalently Introduction Substitution of the 5-methyl group of thymidine by other groups has led to a multitude of compounds with either cytostatic or antiviral properties,1 2i.e.…”

“…After 2 h, 5 mL of acetic acid was added and the mixture was evaporated. Chromatographic purification yielded 90 mg (59%) of the phenylisoxazolyl derivative, which was crystallized from acetone: mp >250 °C; UV (MeOH) 237 nm (e = 20250), 303 (« = 18450); NMR 2.27 (t, 2 , H-2'), 3.68 (br s, 2 , H-5'), 3.85 (m, 1 , H-4'), 4.33 (m, 1 H, H-3'), 5.23 (br s, 2 H, 3'-OH and 5'-OH), 6.23 (t, 1 , H-l'), 7.26 (s, 1 H, H-4"), 7.51 and 7.86 (2 X br s, 5 H, aromatic H), 8.76 (s, 1 , H-6), 11.81 (br s, 1 H, NH) ppm; 13C NMR 40.5 (C-2'), 60.9 (C-5'), 70.2 (C-3'), 85.4 (C-l'), 87.9 (C-4'), 99.4 (C-4"), 102.7 (C-5), 126.6,128.5,129.1 and 130.1 (aromatic C), 139.5 (C-6), 149.4 (C-2), 162.0, 159.7, and 163.6 (C-4, C-3", and C-5") ppm. Anal.…”

One‐Pot Preparation of Enantiopure Fluorinated β‐Amino Acid Precursors

“…For example, the introduction of one or more fluorine atoms vicinal to an amine, as seen in the compounds in Figure 1, decreases the basicity of the amine 3. This can have the result of increasing the biological activity,4 bioavailability,5 and/or lipophilicity (log D)6 of a drug.…”