282. 5-Alkylacridines. Part II. Dialkylaminoalkylacridines

Abstract

A series of 5-dialkylaminoalkylacridines has been prepared, viz. R*[CH,],*NR', where R = 5-acridinyl, n = 1-4, R' = Me or Et, together with certain corresponding mono-and di-quaternary compounds. Hofmann degradation of 5-acridinylmethyltrimethylammonium iodide gave B-vinylacridine. THE availability of the reactive 5-methylacridine prompted further work on 5-o-dialkylaminoalkylacridines as potential chemotherapeutic agents. 5-Bromomethylacridine with dimethyl-and diethyl-amine gave the corresponding IF-dialkylaminomethylacridines. The dimethylamino-compound so formed with dimethyl sulphate at room temperature furnished 5-acridinylmethyltrimethylammonium monomethosulphate, and this on further treatment with dimethyl sulphate, at go", gave the dimethosulphate. The monoquaternary bromides of 5-dimethylaminomethyl-and 5-diethylaminomethyl-acridine were obtained directly on treatment of 5-bromomethylacridine with t rime t hyl-and t rie t h yl-amine respectively. 5-Methylacridine, formaldehyde, and dimethylamine under normal Mannich conditions gave the known 5-(2-dimethylarninoethyl)a~ridine.~ In a comparable manner, the 5-(2dimethylaminoethyl) analogues of 3-chloro-and 2-chloro-7-methoxy-acridine were prepared.Stepwise quaternisation of the first of these three products was achieved, as above, by treatment with dimethyl sulphate.Hofmann degradation of the monomethiodide or monomethosulphate of the 5-(2-dimethylaminoethy1)acridine gave 5-vinylacridine. A boiling dilute solution of the latter in 2~-hydrochloric acid was transformed into a clear yellow polymer on cooling. Catalytic reduction of 5-vinylacridine gave the known 5-ethyla~ridine.~ Methyl p-5-acridinylpropionate was reduced by lithium aluminium hydride to 3-5'acridanylpropan-1-01, which on oxidation by ferric chloride furnished 3-5'-acridinylpropan-1-01. The latter alcohol with hydrobromic acid gave 3-5'-acridinylpropyl bromide and thence by treatment with dimethylamine 5-(3-dimethylaminopropyl)acridine. The 3-chloroacridine analogues were also prepared. Mono-and di-methosulphates of 5-(3-dimethylaminopropy1)acridine were obtained as in the previous cases. 5-(2-Hydroxyethyl)acridine was converted by thionyl chloride into the chloroethyl compound, converted by the malonic ester synthesis into y-5-acridinylbutyric acid. In a manner comparable with that described above, the derived methyl ester was converted into 5-(4-dimethylaminobutyl)acridine, whose mono-and di-methosulphate were also prepared. EXPERIMENTAL 5-DirnethyZaminorne~hyhylaGridine DihydrochZoride.-5-Bromomethylacridine (3.5 g.) in benzene (150 c.c.) was refluxed while dry dimethylamine was slowly bubbled through it (2 hr.), then washed with water and evaporated. The crystalline residue was redissolved in dry ether, and hydrogen chloride bubbled in to precipitate the crude dihydroclzloride. Recrystallisation of this from hydrochloric acid-acetone gave yellow aggregates (3 g.), m. p. above 180" (decomp.), fusing -250" (Found: C, 62.2; H, 6.0; N, 9.3. C,,H18N,Cl, requires C, 62.2; H, 5.9; N, Similarly, 5...