Donetti A, Cereda E, Ezhaya A, Micheletti R
Department of Medicinal Chemistry, Istituto De Angeli, Milan, Italy.
J Med Chem. 1989 May;32(5):957-61. doi: 10.1021/jm00125a006.
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.
制备了三种N - 氟乙基取代的（咪唑基苯基）甲脒衍生物，即2 - 氟乙基（3b）、2,2 - 二氟乙基（3c）和2,2,2 - 三氟乙基（3d），以测试氟取代对碱性的影响，进而与未取代的N - 乙基衍生物（3a）相比，测试其对H2拮抗剂亲和力的影响，3a用作米芬替丁的模型。通过4 - （氨基苯基）咪唑与二硫化碳和氯甲酸乙酯反应得到的咪唑基苯基异硫氰酸酯（1），与所需的2 - 氟取代乙胺缩合得到中间体硫脲（2b - d）。这些硫脲经雷尼镍脱硫得到所需的甲脒（3b - d）。发现增加氟取代会使甲脒基的碱性大幅降低（3a，pKa = 8.65；3b，pKa = 8.12；3c，pKa = 6.60；3d，pKa = 6.14），而对咪唑部分的影响较小。通过对豚鼠心房组胺刺激的变时反应的拮抗作用评估的H2受体亲和力，在氟取代后增加（3a，KB = 177；3b，KB = 61；3c，KB = 21；3d，KB = 7.6）。得出的结论是，米芬替丁系列中的H2受体拮抗剂亲和力主要取决于中性物种的可用性。这些数据支持了米芬替丁与西咪替丁一样通过中性物种起作用的假设。
