The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.
To study the bioisosteric replacement of a 2-pyridyl ring for a phenyl nucleus in astemizole, a series of N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amines was synthesized and evaluated. The title compounds were obtained starting from either 8a or 8b by four synthetic methods. The in vivo antihistamine activity was evaluated by the compound 48/80-induced lethality test in rats and the histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. Compound 37, the isostere of astemizole, showed the most potent antihistaminic properties in the rat. However, astemizole is superior to 37 as to duration of action and total potency.
The synthesis of a series of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-ami nes and the preliminary evaluation of their in vivo antihistamine activity are described. The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods. Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches. The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action was studied in the guinea pig for three compounds (4, 51, and 55). Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems. Astemizole has been selected for clinical investigation.
Stokbroekx R.A., M.G.M. Luyckx, J.J.M. Willerns, M. Janssen, J.O.M.M. Bracke, R.L.P. Joosen, and J.P. Van Wauwe: Levocabastine (R 50547): The prototype of a chemical series of compounds with specific HI-antihistaminic activity. Drug Dev. Res. 8:87-93, 1986.The synthesis and the histamine HI antagonism of four racemates of l-[cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002-0.003 mglkg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mglkg of levocabastine, whereas a dose of 2.5 mglkg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.
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