Patent GB-862512-A (GB)
Title: Therapeutic compositions of substituted benzodioxanes
IPC: A61K31/00
Filed: 1958-03-27
Abstract: 8-substituted aminobenzodioxanes of general formula: <FORM:0862512/IV (b)/1> wherein R represents hydrogen or a C1-4 alkyl or alkenyl group and R1 is a C2-6 alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl radical, are prepared by a process wherein an O-alkoxycatechol is reacted with ethyl-a , b -dilromopropionate by the method of Koo et alb (J.A.C.S. 77, 5375 (1955) to give a mixture of 5- and 8-alkoxy-2-carboethoxybenzodioxanes which are reacted with alcoholic ammonia to yield a mixture of 5- and 8-alkoxy-2-carboxamidobenzo-dioxanes which may be substantially separated on the basis of their differing solubilities in organic solvents, e.g. ethanol, and the separated 8-alkoxy derivative subsequently purified, e.g. by recrystallisation or chromatography. This is then reconverted into the corresponding 8-alkoxy-2-carboethoxy benzo-dioxane which is reduced with Li Al H4 to the 2-hydroxy-methyl-8-alkoxybenzodioxane which is chlorinated by thionyl chloride to the 2-chloromethyl-8-alkoxybenzodioxane from which the desired amino-benzodioxane is prepared by amination according to Example 1 of U.S.A. Specification 2,056,046. Alternatively, the separated 2-carboethoxy-8-alkoxy - benzodioxane may be reacted with a primary amine to yield the corresponding amide, which may be reduced directly with Li Al H4 to the desired 2-aliphatic-substituted aminomethyl-8-alkoxybenzodioxane.  Acid addition salts of the products are described.  The 8-hydroxy compounds (R=hydrogen in the above formula) may be prepared from the corresponding 8-alkoxy compounds by treatment thereof with an ether-splitting reagent, e.g. hydrobromic or hydriodic acid. Alternatively, the reaction may be carried out on a mixture of the 5- and 8-alkoxy-2-aliphatic-substituted aminomethylbenzodioxanes to yield the 8-hydroxy compound (ether-insoluble acid) and 5-hydroxy compound (ether-soluble oil). By protecting the secondary amino group and alkylating, e.g. with a dialkyl sulphate in the presence of an alkali, the 8-hydroxy compounds may be converted to the corresponding 8-alkoxy or 8-alkenoxy derivatives.  As a further alternative, 8-ethoxy-2-chloromethylbenzodioxane is deethylated, the hydroxy group etherified with a radical other than ethyl, and the product reacted with the amine R1NH2.  The 8-alkoxy-2-substituted benzodioxanes may be resolved into optically active isomers, e.g. by formation of the d-camphor sulphuric acid salts and fractional crystallisation thereof.ALSO:Therapeutic compositions for oral or parenteral use comprise a pharmaceutical carrier and a compound having the general formula <FORM:0862512/VI/1> and pharmaceutically acceptable salts thereof with inorganic and organic acids, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, maleic, acetic, benzoic, succinic, citric, and ascorbic acids; and wherein R is hydrogen or an alkyl or alkenyl radical having 1 to 4 carbon atoms and R1 is an alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl radical having 2 to 6 carbon atoms.  The compositions may be in solid form, for example, a tablet or capsule containing from 5 to 50 mgm. of the active substance, or in liquid forms suitable for intramuscular or subcutaneous injection containing from 5 to 10 mgm. of the active substance per c.c. of solution.  Preferred compounds are those containing an 8-hydroxy, 8-methoxy, or 8-ethoxy grouping, for example, the 2-n-butylaminomethyl - 8 - ethoxy, 2 - allylaminomethyl-8 - ethoxy - 2 - n - butylaminomethyl - 8 - methoxy, 2 - n - butylaminomethyl - 8 - hydroxy, 2 - iso - butyl - aminomethyl - 8 - methoxy, 2-n - amylaminomethyl - 8 - ethoxy, and 2 - (2-methylbutyl) - aminomethyl - 8 - hydroxy benzodioxanes.  Methods of preparing specific compounds of the above general formula are given.  They may be resolved into stereoisomers of which the l form is preferred (see Group IV (b)).