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A series of 2-(4-substituted-1-(homo)piperazinyl)benzimidazoles was prepared and tested for H1-antihistaminic activity in vitro and in vivo. Most of the compounds showed antihistaminic activity and some of the 1-[2-(substituted-oxy)ethyl] derivatives exhibited potent activity. In a structure-activity comparison it was found that the oxygen atom in the 2-(substituted-oxy)ethyl group at the 1-position of the benzimidazole nucleus played an important role for potent antihistaminic activity, especially in vivo. One of the most potent compounds, 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole (69), was 39 times more potent than chlorpheniramine maleate in H1-antihistaminic activity in vivo and was selected for clinical evaluation. The structure of compound 69 is of interest because it provides only a single aromatic unit linked through a chain to a basic nitrogen, while most H1-antihistaminic agents have structures that comprise a double-aromatic unit linked through a chain to a basic tertiary amino group.

With the aim of obtaining new H1-antihistaminic agents, transformations of previously reported antihistaminic benzimidazoles were performed on the basis of the concept of bioisosterism. Among the compounds prepared, imidazo[4,5-b]pyridine (8) and 4(3H)-quinazolinone (11) exhibited significant H1-antihistaminic activity.

Effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazol e difumarate (KB-2413) on chemical mediators were investigated in vitro and in vivo. Antihistaminic activity of KB-2413 in vitro was about 2, 7 and 5 times more potent than those of chlorpheniramine, diphenhydramine and clemastine, respectively, and equipotent to that of ketotifen. This antihistaminic activity of KB-2413 was competitive antagonism to histamine. In the study preventing histamine-induced mortality in guinea pigs, the antihistaminic potency of KB-2413 (p.o.) was about 39, 780, 68 and 3 times more potent than those of chlorpheniramine, diphenhydramine, clemastine and ketotifen, respectively. In the study preventing histamine-induced increase in vascular permeability, the antihistaminic potency of KB-2413 (p.o.) was about 27 and 4 times greater than those of chlorpheniramine and ketotifen, respectively. The preventing activity of KB-2413 (i.v.) on histamine-induced increase in airway resistance was about 10 and 2 times more potent than those of chlorpheniramine and ketotifen, respectively. These results indicate that the antihistaminic potency of KB-2413 is stronger than that of chlorpheniramine and that of ketotifen which has the strongest antihistaminic activity of all reference drugs. On the other hand, KB-2413 had only very weak anticholinergic, antibradykinin and antiserotonin activity in the study in vitro or in vivo, so that KB-2413 had selective antihistaminic activity. Therapeutic index of KB-2413 calculated from the antihistaminic potency on histamine-induced mortality and acute toxicity in guinea pigs was about 110 times greater than that of chlorpheniramine.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolites of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-b enzimidazole difumarate (KG-2413), which has a potent H1-antihistaminic activity, were predicted on the basis of metabolic studies of related compounds and were synthesized to aid in identification of the actual metabolites and for examination of their antihistaminic activity. Among the twelve compounds prepared, nine compounds were actually found as the metabolites of KG-2413 in rat urine. The antihistaminic activities of these metabolites were found to be lower than that of KG-2413.

The quantitative structure-activity relationships (QSAR) of 2-(4-substituted-1-piperazinyl)benzimidazole derivatives for antihistaminic activity were examined. Taking into consideration the specific conformations of some derivatives, a significant correlation was obtained using Verloop's STERIMOL parameters B3 and L of the substituent at the 1-position of the benzimidazole nucleus. The results indicated that the derivatives having a substituent with a small breadth and an appropriate length at the 1-position showed potent activity. From the results, a model of the binding site is proposed. The QSAR of side effects (anticholinergic activity and central nervous system depressive effect) were also examined and the results showed that a sterically small substituent at the 1-position was required to decrease side effects.