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.
The synthesis of a series of N-1,4-disubstituted-1,4-dihydro-5H-tetrazol-5-one piperidinyl derivatives of fentanyl, carfentanil, and sufentanil is described. The 1-substituted tetrazolinones 2 were essentially prepared via the addition reaction of aluminium azide to isocyanates or acid chlorides in tetrahydrofuran. Alkylation of 2 under neutral or weakly basic conditions afforded almost exclusively the 1,4-disubstituted tetrazolinone isomer 3. N-Alkylation of the piperidine derivatives 4 with 3 in dimethylformamide yielded 9a-v. The morphinomimetic activity in rats, after intravenous injection of the compounds, was evaluated in the tail withdrawal reflex test. The fentanyl analogues 9a-c (R4 = H) are inactive at the measured dose of 2.5 or 10 mg/kg (iv). For the carfentanil analogues (R4 = COOCH3) maximal narcotic activity is found when R1 represents a lower alkyl group (9d-f) or a thienylethyl group (9n). The sufentanil analogues (R4 = CH2OCH3) show the same structure-activity relationship (SAR) profile as the carfentanil derivatives (R4 = COOCH3). The structural requirements for optimal activity are in good agreement with earlier observations in the series of 10-12. From the series the ethyl tetrazolinone derivative 9r, alfentanil (R 39209), was selected for clinical investigation. As an analgesic in rats, 9r is 140 times more potent than pethidine 15 and 72 times more potent than morphine 14. Alftentanil reaches its peak effect within 1 min after injection, and its duration of action is very short; at 2 times its MED50, 9r has a duration of action of 11 min. This duration is 30 min for 10 and 90 min for 14. Compared to 10, alfentanil 9r is about 4 times faster but 3 times shorter acting. Structurally, 9r shows most resemblance to sufentanil 12, since it differs only by substitution of a 4-ethyltetrazolinone ring for the thiophene ring. The considerable differences in their pharmacological profiles were explained in terms of marked variations in physicochemical and, hence, pharmacokinetic properties.
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.
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