Patent GB-759174-A (GB)
Title: Improvements in diuretic acting xanthine derivatives
IPC: C07D473/06
Filed: 1953-11-03
Abstract: The invention comprises substituted xanthines of the general formula <FORM:0759174/IV(a)/1> wherein X represents oxygen or sulphur, Alk -OH represents a hydroxyalkyl radical containing 2 to 4 carbon atoms and R1 and R11 represent the same or different lower alkyl or alkenyl radicals which together contain at least 3 carbon atoms, and the preparation thereof by reacting a 1,3-dialkyl-xanthine or -thioxanthine of the general formula <FORM:0759174/IV(a)/2> wherein X, R1 and R11 have the above significance, or an alkali metal salt thereof, with a halogen hydrin of or an inner ether of an alkane diol having 2 to 4 carbon atoms, if necessary with the addition of acid binding agents, or by reacting a 1,3-dialkyl-xanthine or -thioxanthine of the above general formula, or an alkali metal salt thereof, with an ester of a halogen hydrin derived from an alkane diol having 2 to 4 carbon atoms and hydrolyzing the 7-acyloxyalkylxanthine- or -thioxanthine thus obtained to form the 7-hydroxyalkyl radical, or by reducing a 7-oxoalkyl-xanthine or -thioxanthine of the general formula <FORM:0759174/IV(a)/3> wherein m is 1, 2 or 3 and n is 0, 1 or 2 (the sum of m and n being at the most 3) and R1, R11 and X have the above significance, or a 7-carboxyalkyl-xanthine- or -thioxanthine of the general formula <FORM:0759174/IV(a)/4> wherein R represents a hydrocarbon radical, m is 1, 2 or 3 and R1, R11 and X have the above significance, the reducing agent in each case being lithium aluminium hydride or sodium borohydride or, in the case of a xanthine of the above general formula in which X is oxygen, by treating the corresponding compound in which X is sulphur with an inorganic desulphurizing agent, e.g. by heating with a heavy metal oxide such as mercuric oxide or lead oxide.  Suitable halogen hydrins for use in the processes referred to above are ethylene-chlorohydrin and -bromohydrin, 2-chloro-1-propanol, 1-chloro- 2 - propanol, 3 - chloro - 1 - propanol, 1 - chloro- 2 - butanol, 3 - chloro - 2 - butanol, 4 - chloro- 2 - butanol, 4 - chloro - 1 - butanol, 4 - bromo- 1 - butanol, 1 - chloro - 2 - methyl - 2 - propanol, b -chloropropyl acetate, g -chloropropyl acetate and d -bromobutyl acetate.  Suitable inner ethers for use in the process referred to above are ethylene and propylene oxides.  Suitable 1,3-dialkyl-xanthines and -thioxanthines for use in the above processes are 1-methyl-3-ethyl-, 1- ethyl - 3 - methyl -, 1,3 - diethyl -, 1 - methyl- 3 - n - propyl -, 1 - ethyl - 3 - n - propyl, 1- ethyl - 3 - isopropyl -, 1,3 - di - n - propyl -, 1- methyl - 3 - n - butyl -, 1 - ethyl - 3 - n - butyl-, 1,3 - di - n - butyl -, 1,3 - di - isobutyl -, 1- ethyl - 3 - allyl -, 1 - allyl - 3 - ethyl -, and 1,3- diallyl - xanthene, 1 - methyl - 3 - ethyl -, 1,3- diethyl - and 1,3 - di - n - propyl - 2 - thioxanthine.  Substituents which may be present in the 7-position of the xanthine and thioxanthine reactants for the reduction process are the b -oxoethyl, b -oxopropyl, g -oxopropyl, b -oxobutyl, a  - methyl - b  - oxopropyl, g  - oxobutyl, carbethoxymethyl, a -carbethoxyethyl, b -carbethoxyethyl, a -carbomethoxypropyl and g -carboxypropyl groups.  In the examples a number of substituted xanthines of the above general formula are prepared from reactants referred to above.  The preparation of the following intermediate compounds is described.  7 - Oxoalkyl - and 7 - carboxyalkyl - xanthines and -thioxanthines of the general formula referred to above are prepared by reacting the corresponding N7-alkali metal compounds with acetals of the required halogen aldehydes followed by hydrolysis, or with the required halogen ketones or halogen fatty acid esters.  In the examples 1,3-diethyl-7-acetonyl-xanthine is prepared by reacting the sodium salt of 1,3-diethyl-xanthine and monochloroacetone, and 1,3 - diethyl - 7 - (b  - oxo - ethyl) - xanthine is prepared by reacting the sodium salt of 1,3-diethyl-xanthine and chloracetaldehyde diethyl acetal and hydrolysing the resulting acetal with hydrochloric acid.ALSO:A pharmaceutical preparation contains a solid carrier and a substituted xanthine of the general formula:  <FORM:0759174/VI/1> wherein X represents oxygen or sulphur, AlkOH represents a hydroxyalkyl radical containing 2 to 4 carbon atoms and R1 and R11 represent the same or different lower alkyl or alkaryl radicals which together contain at least 3 carbon atoms. Suitable carriers are cornstarch, lactose, stearic acid, talc and magnesium stearate.