GB634211A - Improvements in or relating to quinoline antimalarial compounds - Google Patents

Abstract

6 : 8-Substituted lepidines of the general formula <FORM:0634211/IV (b)/1> wherein R represents an alkyl radical containing from 2 to 8 carbon atoms which may be branched or straight chain, R1 represents hydrogen or an alkyl radical having from 1 to 6 carbon atoms, R2 is an alkyl radical having from 1 to 6 carbon atoms, and R3 is an alkyl radical having from 1 to 4 carbon atoms, are prepared by heating a mixture of o-nitro-p-alkoxy aniline, methyl vinyl ketone, arsenic acid and concentrated sulphuric acid to form a 6-alkoxy-8-nitro-lepidine, reducing said 6-alkoxy-8-nitro-lepidine to a 6-alkoxy-8-amino-lepidine, e.g. with hydrogen in the presence of a hydrogenation catalyst, which is then condensed with an alkylamino-alkyl halide of the general formula <FORM:0634211/IV (b)/2> wherein R, R1 and R2 have the above significance and Ha represents chlorine or bromine, or with its hydrohalide. Methyl ketone may be formed in situ by adding 1 : 3 : 3-trimethoxybutane, b -chloroethylmethyl ketone or 4-methoxylbutanone-2. Compounds of the above general formula in which R3 represents hydrogen may be prepared by dealkylating the 6 : 8-substituted lepidines by heating with acid. In examples, 6-methoxy- and 6-hydroxy-8 - (61 - diethylaminohexylamino) - lepidine, 6 - methoxy- and 6 - hydroxy - 8 - (11 - methyl-41 - isopropylaminobutylamino) - lepidine, 6-methoxy - and 6 - hydroxy - 8 - (51 - isopropylaminoamylamino) - lepidine, 6 - methoxy - and 6 - hydroxy - 8 - (31 - diethylaminopropylamino) - lepidine, 6 - methoxy - and 6-hydroxy - 8 - (41 - ethylaminohexylamino)-lepidine, 6 - methoxy - and 6 - hydroxy - 8-(11 - methyl - 41 - diethylaminobutylamino)-lepidine, and 6 - methoxy - and 6 - hydroxy-8 - (61 - butylaminohexylamino) - lepidine are prepared and their hydrochloride, hydrobromide, phosphate and titrate salts. 6-Diethylaminohexyl bromide hydrobromide is prepared by refluxing diethylaminohexanol and hydrobromic acid. 1 - Methyl - 4 - alkylaminobutyl bromide or chloride and 1 - methyl - 5 - alkylaminoamyl bromide or chloride are prepared by reducing 1 - chloropentanone - 4 or 1 - bromohexanone-5 with aluminium propoxide to form the corresponding carbinol, reacting the product with a primary alkylamine to replace the halogen atom with an alkylamino group, and the resulting alkylamino carbinol is halogenated, preferably with thionyl chloride or bromide to yield the desired compound in the form of its addition salt from which the base is obtained by treatment with alkali, e.g. sodium hydroxide.