DE926788C - Process for the preparation of 1, 3-dialkylated 7-oxyalkyl-xanthine capsules - Google Patents

Description

Process for the preparation of 1,3-dialkylated 7-oxyalkylxanthine derivatives In the German patent igi io6, it was suggested that they could be used as diuretics Xanthines, such as theophylline, methylxanthine and theobromine, in their N-oxyalkyl derivatives, z. B. to transfer the 7-oxyethyl-theophylline. The latter connection is consequential their easy solubility and lack of irritation are also suitable for injection purposes and according to recent animal experiments and clinical studies in the diuretic Effectiveness may not be superior to the theophylline on which it is based, but exceed this considerably in terms of tolerability.

7- (P), γ-dioxy-propyl) -theophylline was used in US Pat. No. 575,344 Proposed as a diuretic that has better solubility and tolerability than Theophylline is said to have.

It has now been found that the i, 3-dialkyl-7-oxyalkyl-xanthines of the general formula wherein alk-O H is an oxyalkyl radical with 2 to 4 carbon atoms and R 'and R "mean the same or different low molecular weight alkyl or alkenyl radicals with at least 3 carbon atoms together, with likewise good compatibility one in comparison to theophylline, 7-oxyethyltheophylline and 7- ( ß, y-Dioxy-propyl) -theophylline have a significantly stronger diuretic effectiveness.

The new compounds can be prepared by using i, 3-dialkyl-xanthines of the general formula where R 'and R "have the meaning given above, optionally with the addition of dehydrating or acid-binding agents or in the form of their salts, with alkanediols having 2 to 4 carbon atoms or their reactive derivatives, such as the halohydrins or the internal ethers (alkylene oxides), implements.

The i, 3-dialkyl-xanthines are used for reaction with halohydrins expediently in the form of their alkali salts, which are readily soluble in water. You can i, 3-dialkyl-xanthines e.g. B. dissolve directly in dilute sodium hydroxide solution, the halohydrin add and heat the reaction solution in the autoclave. When using relative higher i, 3-dialkyl xanthines or water-immiscible halohydrins can be used to reduce the liquid volume of the caustic soda z. B. still methanol or add ethanol.

Used for reaction with alkylene oxides as well as with the alkanediols one the free i, 3-dialkyl-xanthines. One can do the reactions in inert organic Make solvents.

There is a special embodiment of the above method in that instead of free halohydrins, their easily cleavable esters, z. B. acetic acid ester, used for reaction with the i, 3-dialhyl xanthines and the i, 3-dialkyl-7-acyloxyalkyl-xanthines initially obtained to the corresponding i, 3-Dialkyl-7-oxyalkyl-xanthines hydrolyzed, for example using the calculated amount of lye in aqueous or alcoholic solution.

As i, 3-dialkyl-xanthines of the general formula given above i-methyl-3-ethylxanthine, i-ethyl-3-methyl-xanthine, i, 3-diethylxanthine, i-methyl-3-n-propyl-xanthine, i-ethyl-3-n-propyl-xanthine, i-ethyl-3-isopropyl-xanthine, i, 3-di-n-propyl-xanthine, i-methyl-3-n-butyl-xanthine, i-ethyl-3-n-butyl-xanthine, i, 3-di-n-butylxanthine, i, 3-Di-isobutyl-xanthine, i-ethyl-3-allyl-xanthine, i-allyl-3-ethyl-xanthine, i, 3-di-allyl-xanthine called.

As halohydrins of alkanediols, for. B. ethylene chlorohydrin and -bromohydrin, 2-chloro-propanol, i-chloro-2-propanol, 3-chloro-i-propanol, i-chlorine -2-butanol, 3-chloro-2-butanol, 4-chloro-2-butanol, 4-chloro-i-bu, tamol, 4-bromo-i-butanol and i-chloro-2-methyl-2-propanol (chloro-tert-butanol) can be used. As alkylene oxides be ethylene oxide and propylene oxide, as esters of halohydrins ß-chloro-propyl acetate, called y-chloropropyl acetate and 8-bromo-butyl acetate.

Instead of the hydrogen atom in position 7 directly through an oxyalkyl radical to replace, one can first introduce a remainder at this point, which contains a group which can be reduced to the oxy group, and then the group in question convert to the oxy group. Such reducible groups are the keto group, the Aldehyde group, which is preferably in the form of a subsequently hydrolyzed Acetals is introduced, and the carboxylic acid ester group.

Another process for the preparation of the new compounds consists in that one i, 3-dialkyl-7-oxoalkyl-xanthine of the general formula where m is a number from i to 3 and n is a number from o to 2, m and n together, however, are at most 3 and R 'and R "have the meaning given above, treated with reducing agents.

According to a further process related to the preceding, the new compounds are prepared by adding an ester of an i, 3-Dia1ky1-7-carboxyalkyl-xanthine, which has the general formula corresponds, in which R represents a hydrocarbon radical and R ', R "and na have the meanings given above, treated with reducing agents.

Both the reductions of the i, 3-dialkyl-7-oxoalkyl-xanthines of the general Formula (III) as well as the reductions of the esters of i, 3-dialkyl-7-carboxyalkyl-xanthems can be mixed -satisfactory to good yield by means of lithium aluminum hydride for example in ether.

As starting materials for the two processes defined above come, for example, those in position 7 through a β-oxo-ethyil @ - (formylmethyl), ß-oxo-propyl- (acetonyl) y y-oxo-propyl-, ß-oxobutyl -, a-methyl-ß-oxo-propyl-, y-oxo-butyl-, carbethoxy-methyl-, a-carbethoxy-ethyl-, ß-carbethoxy-ethyl, a-carbomethoxy-propyl- or y-carbethoxy-propyl group-substituted derivatives of the previously mentioned 1, 3-dialkyl-xanthines into consideration. For example, you can implement the Alkali compounds of the i, 3-dialkylxanthines mentioned with acetals of the corresponding Halogenaldehydes and subsequent hydrolysis or with the corresponding halogen ketones or easily prepared with the appropriate halogen fatty acid esters.

Finally, 7-oxyalkyl-thioxanthine derivatives of the general formula obtained in an analogous manner can also be used in which alk-O H, R 'and R "have the meaning given above, converted into the corresponding 7-oxyalkylxanthine derivatives by treatment with the customary desulphurizing agents, for example by heating with heavy metal oxides, such as mercury or lead oxide.

The new 1,3-dialkyl-7-oxyalkyl-xanthines are mostly crystallized Substances which dissolve in water to about i 1 / u; the water solubility increases increasing size of the alkyl radicals in the i- and 3-positions.

The following examples are intended to illustrate the preparation of the new compounds explain in more detail. Unless otherwise stated, parts mean parts by weight; these are related to parts by volume as grams to cubic centimeters. Example s 41.6 Parts 1, 3-diethyl: xanthine become parts by volume of n-sodium hydroxide solution while being heated in Zoo dissolved, then treated with 17 parts of ethylene chlorohydrin and 180 parts by volume of water and heated in a stirred autoclave to 130 to 14o ° for 5 hours. After cooling down, the The reaction solution was purified by filtration and made neutral with sodium carbonate. Then it is concentrated in vacuo to about a third of its volume and cooled. The main amount of the reaction product separates out; after filtering the same can be used to narrow the filtrate still further, with a slight amount Amount is eliminated. After recrystallization from ethanol, the 1,3-diethyl-7- (ß-oxy-ethyl) -xanthine melts at 131 to 133 °. Beispie12 19.4 parts of i-methyl-3-ethyl-xanthine are in 100 parts by volume: len Dissolved n @ sodium hydroxide solution, added 14 parts of ethylene chlorohydrin, and the mixture is heated in the autoclave to 12o to 13o ° for 5 hours. The obtained reaction solution becomes Purified by filtration, neutralized with sodium carbonate and then if necessary, filtered again. The filtrate is evaporated to dryness in vacuo, the residue is boiled in 150 parts by volume of absolute ethanol with the addition of animal charcoal and filtered hot. On cooling, the i-methyl-3-ethyl-7- (ß-oxy-ethyl) -xanthine separates from a melting point of 127.5 to 130 °. Example 22.2 parts of i-ethyl-3-n-propyl-xanthine are dissolved in 100 parts by volume of n-sodium hydroxide solution and mixed with 12 parts of ethylene chlorohydrin and 50 parts by volume of water in an autoclave heated to 13o to 14o ° for 5 hours. After work-up, As indicated in Example i, the i-ethyl-3-n-propyl-7- (β-oxy-ethyl) -xanthine is obtained from melting point 12o.5 to 122 '.

Example 4 26.4 parts of i, 3-bi-n-buty l-xanthine in 100 parts by volume n-sodium hydroxide solution and 20 parts by volume of ethanol dissolved with heating, 8.5 parts of ethylene chlorohydrin and 100 parts by volume of water are added, and the mixture is in the autoclave for 5 hours heated to 13o to 14o °. Work-up takes place as in Example 2; for recrystallization .

acetone is used. 1,3-Din-butYl-7- (ß-axy-ethyl) -xanthine is obtained in the form of white crystals with a melting point of 89 to.91 °. Example 2o, 8 parts of 1,3-diethylxanthine are suspended in 80 parts by volume of water and 5 parts of ethylene oxide are added. The mixture is then heated to 130 to 14o ° in the autoclave for 4 hours and worked up as indicated in Example i, the same product being obtained. Example 6 20.8 parts of 1,3-di-ethyl-xanthine and 7 parts of propylene oxide are heated in 40 parts by volume of water in an autoclave to 130 ° to 14 ° for 3 hours. The water is then evaporated in vacuo, the residue is triturated with 2N sodium hydroxide solution in order to dissolve out unchanged starting substance, suction filtered, washed neutral with water and recrystallized from ethyl acetate. The 1,3-Diäfyl-7- (ß-oxy-propyl) -xanthine with a melting point of 132 to 134.5 ° is obtained in good yield. Example ? 25.8 parts of i, 3-Dn @ propyl-xanthiin-N.atri @ um and 19.5 parts of b-bromo-butyl acetate are refluxed in 100 parts by volume of tetrahydronaphthalene for 2 hours. It is then filtered and the solvent is evaporated off in vacuo. The residue is refluxed for 1 hour in a sodium alcoholate solution composed of 100 parts by volume of ethyl alcohol and 2.3 parts of sodium and then neutralized with 2N hydrochloric acid. The alcohol is finally distilled off in vacuo, the residue is freed from the inorganic salts and distilled in vacuo. The 1,3-di-n-propYl-7- (8-oxy-butyl) is suction filtered, the xylene is evaporated off in vacuo and the residue is triturated with 2N sodium hydroxide solution to add unreacted i, 3-diethylxanthine remove. The crude acetal, filtered off with suction and washed with water, is suspended in dilute hydrochloric acid and heated on a water bath for 1 hour while stirring; the i, 3-diethyl-7- (ß-oxo-ethyl) -xanthine formed is taken up in ether, the ether solution is dried thoroughly with freshly calcined magnesium sulfate and reduced with 2.5 parts of lithium aluminum hydride, as indicated in Example 8, whereby the i, 3-diethyl-7- (ß-oxy-ethyl) -xanthine described in Example i is obtained. EXAMPLE ii 2.68 parts of 1,3-diethyl-7- (β-oxy-ethyl) -2-thioxanthene: im (F. i31 to .133 °) are mixed in 120 parts by volume of tetrahydronaphthalene with 11 parts of mercury oxide (11g0, orange ) Heated under reflux for 3 hours, the color of the mercury oxide gradually becoming dull and finally dark. One slips hot from the mercury sulphide and oxide. The 1,3-diethyl-7- (ß-oxy-ethyl) -xanthine crystallizes from the filtrate and, after recrystallization from alcohol, melts at 131.5 to 133 °. A mixed melting point with a sample prepared according to Example i does not result in any depression, while the mixture of the product obtained with the starting material results in a significant depression of the melting point.

Claims (6)

PATENT CLAIMS: i. Process for the preparation of i, 3-dialkylated 7-oxyalky-1-xanthine derivatives, characterized in that i, 3-dialkyl-xanthines of the general formula wherein R 'and R "mean the same or different low molecular weight alkyl or alkenyl radicals with a total of at least 3 carbon atoms, optionally with the addition of dehydrating or acid-binding agents or in the form of their salts with alkanediols having: 2 to 4 carbon atoms or their reactive derivatives, such as the Halohydrins or the internal ethers, so that compounds of the general formula xanthine goes under 0.33 mm pressure at 2o2 to 2o5 °, under 0.15 mm pressure at 193 to .z95 ° and is a light yellow oil that alilmählioh In an analogous manner, using 1,3-diethyl-xanfhin sodium instead of 1,3-di-n-propyl-xantnine sodium, 1,3-diethyl-7 - ($ - oxy- butyl) -xanthine from Kpo, "r95 to i98 °, which forms a hydrate with a melting point of 74 °. The following compounds, for example, can also be prepared using the processes described in the above examples: 1. i-Ethyl-3-i @ sopropyl-7- (β oxy-ethyl) -xa-nfhin, melting point 76 to 80 °, 2 1,3-Di-isobutyl-7- (ß-oxy-ethyl) -xanthine, m.s. ) - xanthine, melting point 113 to 116 °, 4. i-allyl-3-ethyl-7- (β-oxy-ethyl) -xanthine, melting point 94 to 96.5o, 5.1, 3-diallyl-7 - (ß-oxy-ethyl) -xanthine, F. 122 to 124o, 6.1, 3-Di-n-propyl-7- (ß-oxy-propyl) -xanthine, F. 89.5 to 91 °, 7. 1,3-Di-n-bwtyl-7- (β-oxy-propyl) -xanthine, mp 67 to 71 °, B. 1,3-diethyl-7- (γ-oxy-propyl) -xanthine , F. 86.5 to 88.50 , 9.1, 3-Di-n-propyl-7- (y-oxy-propyl) -xanthine, M. 8o to 82 °, 10. 1, 3-diethyl 7- (β-oxy-isobutyl) -xanthine, m.p. 118.5 to 120 °, ii. 1,3-Dn-propyl-7- (β-oxy-isobutyl) -xanthine, m.p. 10.7 to 10.9.5 °. EXAMPLE 8 29.4 parts of i, 3-diethyl-7-carbethoxymethyl-xanthine with a melting point of 113.5 ° to 115 ° are refluxed for 7 hours in i8oo parts by volume of absolute ether with 2.5 parts of lithium aluminum hydride, the ether is distilled off and the residue stirred with ammonium chloride solution; then slipped off, the filter residue extracted with hot alcohol and the i "3-diethyl-7-ß-oxy-ethyl-xanthine obtained by concentrating the alcoholic solution. Example 9 26.4 parts of i, 3-diethyl-7-acetonyl-xanthine from a melting point of 133 to 135 '(from 1,3-diethylxanthine-sodium and monochloroacetone or from 1,3-diethylxanthine-7-acetic acid by boiling with aetanhydride pyridine), in 800 parts by volume of absolute ether with 6 parts of lithium aluminum hydride, 21 After evaporating the ether and working up as in Example 8, 1,3-diethyl-7- (β-.oxy-propyl) -xanthine is obtained. Example 10 23, 1 part 1,3-diethyl-xanthine Sodium is refluxed for 4 hours in 150 parts by volume of absolute xylene with 15 parts of chloroacetal (chloroacetaldehyde diethylacetal) wherein alk-OH denotes an oxyalkyl radical with 2 to .4 carbon atoms and R 'and R "have the meaning given above, are formed. 2. The method according to claim i, characterized in that Alkalisal.ze of i, 3-dialkyl-xanthines of the general formula wherein R 'and R "have the meaning given in claim i, are reacted with halohydrins of alkanediols having 2 to 4 carbon atoms. 3rd embodiment of the method according to claim i, characterized in that instead of the free halohydrins their easily cleavable esters are used for reaction with the i, 3-dialkylxanthines and the i, 3-dialkyl-7-acyloxyalkyl-xanthines initially obtained to the corresponding i, 3-Dialkyl-7-oxyalkylxanthines hydrolyzed. 4. Modification of the method according to claim i, characterized in that a 1, 3-dialkyl-7-oxoalkyl-xanthine of the general formula where na is a number from i to 3 and n is a number from o to 2, m and 7t together but not more than 3 and R 'and R "have the meaning given in claim i, treated with reducing agents. Modification of the process according to claim i, characterized in that an ester of an i, 3-D.ialkYl-7-carboxya, 1kylxanthine, which of the general formula corresponds, in which R is a hydrocarbon radical and in a number from i to 3 and R 'and R "have the meaning given in claim i, treated with reducing agents. 6. Modification of the method according to claim i, characterized in that 7-oxyalkyl-fhio-xant'hinderivate of the general formula wherein alk-O H, R 'and R "have the meaning given in claim i, converted into the corresponding 7-oxyalkyl-xanthine derivatives by treatment with the customary desulphurizing agents. Cited publications: German patent specifications No. igi io6, 193 799; French patent specification No. 569,463; USA.-Pat. Nos. 2,517,410, 2,575,344; Archiv der Pharmazie, Vol. 268 [193o], pp. 568ff.