New antihistaminic N-heterocyclic 4-piperidinamines. 2. Synthesis and antihistaminic activity of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amines

Abstract

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.

A Panel of Cytochrome P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead Compounds

“…To assess enzyme activity on the metabolites produced by a single oxidation, all 120 enzymes were incubated with purified demethylated metabolites norverapamil 3 and desmethylastemizole [26] 11 . Product distributions and extents of reaction were determined by HPLC.…”

Synthesis and Anti‐Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole

“…The synthesis of monosubstituted analogues of astemizole having an unambiguous assignment of the substituent in the benzimidazole moiety could be accomplished following a multistep strategy that starts from the appropriately substituted 2-halo-nitrobenzenes and comprises amination with 4-fluorobenzyl amine, reduction of the nitro group, reaction with isothiocyanate 11, and ring closure. [24,25] On the other hand, the use of 4-substituted-1,2-phenylenediamine in the outlined synthetic scheme would lead to a mixture of 3-and 4-substituted thioureas, [26] and finally to a mixture of 5-and 6-monosubstituted regiosiomers of astemizole analogues. [24] With the view to avoid the complication arising from the separation of these regioisomers, two symmetrical 4,5-disubstituted-1,2-phenylenediamines, namely 4,5-dimethyl-1,2-phenylenediamine and 4,5-dichloro-1,2-phenylenediamine, were employed in the preparation of astemizole-like compounds with substituents on the benzimidazole moiety.…”

“…[24,25] On the other hand, the use of 4-substituted-1,2-phenylenediamine in the outlined synthetic scheme would lead to a mixture of 3-and 4-substituted thioureas, [26] and finally to a mixture of 5-and 6-monosubstituted regiosiomers of astemizole analogues. [24] With the view to avoid the complication arising from the separation of these regioisomers, two symmetrical 4,5-disubstituted-1,2-phenylenediamines, namely 4,5-dimethyl-1,2-phenylenediamine and 4,5-dichloro-1,2-phenylenediamine, were employed in the preparation of astemizole-like compounds with substituents on the benzimidazole moiety. In a manner similar to the one employed for the synthesis of compound 5, isothiocyanate 11 was reacted with these two symmetrical 4,5-disubstituted-1,2-phenylenediamines to give thioureas 13 (R = CH 3 ) and 14 (R = Cl), which were subsequently converted into corresponding benzimidazoles 15 and 16, respectively, using the cyclodesulfurization method.…”

“…The replacement of sodium hydride with lithium hydride and an increase in the reaction temperature to approximately 90 8C led to the unexpected 2-dimethylamino-1-(4-fluorobenzyl)benzimidazole (24), which presumably arose from substitution of the chlorine atom in the substrate with the dimethylamine, produced in situ from the solvent in the presence of the base, rather than the normal product. Finally, desired compound 25 was obtained, albeit in a modest yield, by reaction of 2-chloro-1-(4-fluorobenzyl)benzimidazole with ethyl 4-hydroxy-1-piperidinecarboxylate in DMSO in the presence of sodium hydride at 75-85 8C (Scheme 4).…”

Novel potential nonsedating H1 antagonists related to the gauche rotamer of PROS-NH-histamine

“…1) is postulated herein. This bears no relation to the classic first-generation molecular models of antihistamines (Janssens et al, 1985). It is concerned with the gauche monocation rotamer (1-GR), which might prove to be an adequate probe for nonclassic antihistaminic H 1 -receptor.…”