Twelve compounds derived from histamine have been prepared. In these the primary amine hydrogen atoms of histamine are replaced by methyl groups and the imidazole nucleus is substituted in the two position by a range of aliphatic and aromatic residues. Most members of the series have histamine-like pharmacological properties ; two compounds have antihistamine activity.OF the large number of compounds synthesised for possible histamine-like or antihistamine activity few have contained the imidazole nucleus and of these only a small number can be considered to be derivatives of histamine (see, e.g. Protiva, 1955). In view of the competitive antagonism to histamine shown by many antihistamine drugs it seemed that compounds closely related to histamine might possess antihistamine activity. Because many successful antihistamine compounds have an aliphatic chain terminated by a dimethylamino-group, NN-dimethylhistamine was chosen as the parent of a series.
EXPERIMENTAL METHODSThe parent compound has been synthesised conveniently by Huebner (1951) using the Weidenhagen reaction (Weidenhagen and Herrmann, 1935), a method capable of general application to histamine derivatives substituted in the two position of the imidazole nucleus. In this method but-2-yne-l,4-diol (I) in ethyl acetate solution is isomerised to hydroxymethyl vinyl ketone (11) using a mercuric oxide-trichloroacetic acid-boron trifluoride catalyst (Reppe, 1949). The ketone with dimethylamine solution gives the Mannich-type base (111) which is not isolated but treated with an aldehyde and cupric acetate : ammonia solution on a heated water-bath. In the original Weidenhagen method the resulting precipitate of cuprous imidazole (IV) is separated by filtration, decomposed with hydrogen sulphide and the liberated imidazole derivative (V) obtained by suitable means. We found that improved yields are obtained when the whole of the reaction mixture is treated with hydrogen sulphide to precipitate all the copper as sulphide. This is because the cuprous imidazole compounds of this series are appreciably soluble in ammonia solution. The filtrate is then acidified, evaporated to low bulk, treated with 50 per cent potassium hydroxide solution and the liberated imidazole extracted with n-butanol. The hydrochloride is obtained either by acidification or better by first distilling the base in vacuum and then converting to the salt. 620 *
The product of a Mannich reaction on butane-2.3-dione depended upon the secondary base employed. With dimethylamine the product was 2.4-bisdimethylaminomethyl-2-methylfuran-3(2H) -one (11). With morpholine or N-methylpiperazine, a bis Mannich base derived from 2.5-dimethylbenzene-1.4-diol was obtained while pyrrolidine was the only base investigated which gave the expected open chain bis Mannich derivative. P. H. B. Ingle, Ph.D. Thesis, University of Bradford, 1970.
The reduction of some aminoacridines has been investigated by controlled potential coulometry. The number of electrons involved in the first reduction stage has been determined by a graphical treatment of the current‐time values obtained using a divided electrolysis cell. With the exception of 5‐aminoacridine the results confirm the values obtained indirectly by Kaye5.
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