The introduction of halogen into the thiophene group of N, N-dimethyl-N'-(2-pyridyl)-'-(2-thenyl)ethylenediamine has been effective in some instances in enhancing the antihistamine activity of that compound (1, 2). Also, high antihistamine activity has been reported for N,N-dimethyl-N'-(4-methoxybenzyl)-N'-(2-pyridyl)ethylenediamine (Neoantergan) (3,4) as well as for the parent compound, N,N-dimethyl-N'-benzyl-N'-(2-pyridyl)ethylenediamine (Pyribenzamine) (4). In view of these results, it seemed of interest to determine the effect of halogenation on the antihistamine activity of N,N-dimethyl-N'-benzyl-N'-(2-pyridyl)ethylenediamine. The compounds prepared are listed in Table I along with their relative antihistamine activities.Compounds I to VI were prepared by the condensation of N ,N-dimethyl-N'-(2-pyridyl)ethylenediamine (DPE) with the appropriate halogenated benzyl halide in the presence of alkali amide or hydride. The yields in general were about 40-60%. In most cases no further attempt was made to improve these yields, since the primary object was to obtain sufficient material for preliminary pharmacological testing.Direct bromination of N,N-dimethyl-N'-benzyl-N'-(2-pyridyl)ethylenediamine resulted in substitution in the 5-position of the pyridine ring to yield N ,N-dimethyl-N'-benzyl-N'-(5-bromo-2-pyridyl)ethylenediamine (VIII). The orientation of the substituent was proved by the alternate synthesis of the compound, starting from N, N-dimethyl-N'-(5-bromo-2-pyridyl)ethylenediamine(2). In like manner, direct bromination of N,N-dimethyl-N'-(3-bromobenzyl)-N'-(2-pyridyl)ethylenediamine (V) gave a compound which is assigned the structure of N, N-dimethyl-N'-(3-bromobenzyl)-N'-(5-bromo-2-pyridyl)ethylenediamine (IX). The structure of N,N-dimethyl-N'-benzyl-N'-(5-chloro-2-pyridyl)ethylenediamine (VII) is based on its synthesis from 5-chloro-2-(N-benzyl)aminopyridine and dimethylaminoethyl chloride. The intermediate 5-chloro-2-(N-benzyl) aminopyridine was prepared from 2-amino-5-chloropyridine and benzaldehyde in formic acid by the procedure of Tschitschibabin (5).The antihistamine activities listed in Table I were obtained in guinea pigs by the histamine-aerosol technique (6), and are expressed as relative to Pyribenzamine, which has an assigned value of one. The highest activity is found in those derivatives halogenated in the 4-position of the benzyl group, and this
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