NO143706B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3-ALKYL-7- (OMEGA-1) -OXOXYLXYLXANTINES - Google Patents

Description

From Norwegian patent application no. 742121, oxoalkyldialkylxanthines are known which can be used as vasodilating drugs. Several manufacturing methods are also specified for this substance class.

The known oxoalkyldialkylxanthines have proven to be well suited as pharmaceuticals. However, it would be desirable to produce further xanthine derivatives with therapeutic benefits.

The present invention thus relates to an analogous process for the production of 3-alkyl-7-(u)-1)-oxoalkylxanthines of formula I

where A is the alkylene with 2-6 C atoms and R is an alkyl group with 1-12 C atoms, whereby R must be alkyl with at least 5 C atoms when A is the alkylene with less than 3 C atoms, whereby a ) reacts an alkali metal salt of a 3-alkylxanthine with an oxoalkyl halide of formula II: where A has the above meaning, and Hal means a halogen atom, or b) reacts with a 7-(w-haloalkyl)-3-alkylxanthine of formula III:

where R and Hal have the above meanings and X is an alkylene with 2-5 C atoms, with an alkali acetate diester and subcase

the reaction product is a ketone cleavage.

The aforementioned turnovers are carried out in a manner known per se

manner, usually at a temperature of 50-150°C, preferably 60-120°C, optionally at elevated or reduced pressure, but usually at atmospheric pressure. The individual starting substances can be used in stoichiometric or - for economic reasons - in non-stoichiometric quantities. In working method a), the alkali metal salts can be used in their finished state. However, they are advantageously prepared in the reaction mixture.

Working method b) leads to compounds in which there are at least 3 C atoms between the keto group and the nitrogen atom.

Suitable solvents include compounds which are miscible with water, e.g. methanol, ethanol, propanol, isopropanol or the various butanols, acetone, pyridine, polyhydric alcohols such as ethylene glycol, further ethylene glycol monomethyl or ethyl ether, and likewise formamide and dimethylformamide.

Among the compounds produced according to the invention are 3-methyl-7-(5-oxohexyl)-xanthine and the corresponding (w-l)-oxoheptyl-, oxopentyl- or oxobutyl compounds (the latter provided that the residue R has at least 5 C atoms), further the homologous compounds in which in the 3-position instead of the methyl residue it says e.g. an ethyl, propyl, isopropyl, butyl, iso-butyl, hexyl or decyl residue.

The compounds produced according to the invention excel in relation to the known compounds, e.g. by improving the blood flow in the brain and also - analogously to the known compounds - has a vasodilating effect at the same time as low toxicity. They are well soluble in lipoids and some also in water and can be administered in solid or dissolved dosage form orally and rectally and some of them also in dissolved form parenterally. They can be combined with additional medicines, including vitamins. The Galenic

• processing into the usual forms of application such as solutions, emulsions, tablets, capsules, dragees, suppositories, granules or depot forms takes place in a known manner by using the usual aids for these purposes such as carriers, explosives, binders, coatings, swelling, sliding or lubricating agents, flavourings, sweeteners, agents for achieving a depot effect or

solution providers. Suitable excipients are e.g. lactose, mannitol, talc, milk-egg white, starch, gelatin, cellulose or derivatives thereof, such as methyl cellulose, hydroxyethyl cellulose or suitable swelling or non-swelling copolymers. With the help of astringents, which can be used in smaller or larger quantities, the crumbling of the preparation and thereby also the release of the active substance can be affected.

The compounds produced according to the invention are administered, e.g. in amounts of 0.1 mg to 125 mg/kg body weight, preferably 1 mg-50 mg/kg body weight. The substances can be given in single or multiple doses per day or possibly by infusion.

Appropriately, the drug is available in a dosage

form containing up to 400 mg of active substance.

EXAMPLE 1

In a solution of 5.5 g water, 4.4 g methanol and 0.8 g

(0.02 mol) of sodium hydroxide, 4.16 g (0.02 mol) of 3-n-butylxanthine are introduced, the mixture is heated to 70°C, stirred for one hour and 3.7 g (0.0206 mol) of l-bromo- hexanone-5 at 70°C. This solution is further stirred for 5 hours at 70°C. After cooling to room temperature, the crystals are sucked off.

After washing with 20 ml of water and 20 ml of methanol, the preparation is dried in vacuum from the water jet pump at 70-100°C. Yield: 4.4 g of crude product with a melting point of 122°C (72% of theory, calculated on the butylxanthine used).

Dissolve 4.3 g of crude product in 15 ml of water and 0.86 g of sodium hydroxide at 60°C, add 0.5 g of activated carbon, stir for 15 minutes and filter. The 60°C hot filtrate is adjusted to pH 9.5 with 33% sulfuric acid. It is cooled in an ice bath, the crystals that have fallen out are sucked off, washed with alkali-free water and dried in a vacuum from the water jet pump at 100°C. Yield: 2.6 g of 3-(n-butyl)-7-(5<1->oxohexyl)-xanthine (.42.5% of theory, calculated on the 3-butylxanthine used), melting point: 134°c. By thin-layer chromatography, the product was uniform.

EXAMPLE 2

In a mixture of 275 g water, 220 g methanol and 40 g

(1 mol) sodium hydroxide is introduced with good stirring 166 g (1 mol) 3-methylxanthine, heated to 70°c, stirred approx. 1 hour and then 183 g (1.02 mol) of 1-bromo-hexanone-(5) are added dropwise at 70°C over the course of 1 hour. After approx. after half an hour, a thick, but still stir-able crystal porridge forms. Stirring is continued for 5 hours at 70°C. The pH value thereby decreases slowly and reaches approximately 5-7 towards the end of the reaction. It is cooled to room temperature and the crystals are sucked off. After washing with 500 ml of water and 500 ml of methanol, it is dried in a vacuum from the water jet pump at 70-100°C. You get 210 g of a crude product containing 73% 3-methyl-7-(5-oxohexyl)-xanthine (= 88% of theory, calculated on converted 3-methylxanthine).

Dissolve 205 g of crude product in 100 ml of water and 40 g of sodium hydroxide at 60°C, add 13 g of activated carbon, stir for 15 minutes and filter. The 60°C warm filtrate is adjusted within one hour to pH 9.5 with approx. 97 g of 33% sulfuric acid. Stirring is continued for one hour at 60°C, the crystals that have precipitated are sucked off, washed alkali-free with water and dried in a vacuum from the water jet pump at 100°C.

The yield amounts to 125 g of 3-methyl-7-(5-oxohexyl)-xanthine = 48% of the theory, calculated on the 3-methylxanthine used. Freezing point: 217°C.

From the mother liquor, by acidifying with more sulfuric acid to a pH value of approx. 4 and subsequent purification a further 5% is achieved.

After intraduodenal administration, the compound caused a clear and long-lasting increase in the perfusion of the brain of the drugged cat, which is many times higher than in the case of theophyllineethylenediamine. The compound is also significantly more tolerable when administered intraperitoneally to mice. The LD,-0 value in the mouse is 1000-

1500 mg/kg, while for theophylline-ethylenediamine it is 217 mg/kg.

Example 3

In 750 g of dimethylformamide, 249 g of 3-methylxanthine and 126 g of sodium bicarbonate are suspended and, with stirring, 210 g of 1-chlorohexanone-(5) are added in portions, whereby the reaction mixture is heated to 75°C. After the addition is complete, heat for a further 6 hours to 130-140°C. It is then cooled to room temperature, the crystals are sucked off and washed with isopropanol. The dried precipitate is suspended in 1 liter of water at 90°C, the suspension is brought to pH 9.6 with caustic soda and stirred well. The suspension is allowed to cool and the crystals are sucked off after one day's rest. After washing with water and drying, 325 g of 3-methyl-7-(5'-oxohexylxanthine with a melting point of 219°C are obtained (yield:

82% of the theory).

Example 4

6.0 g (23 mmol) of 3-methyl-7-(3'- bromopropyl)-xanthine, and the mixture is boiled for 2 hours under reflux. The separated crystals are cooled and sucked off. After evaporation of the filtrate, the evaporation residue is first stirred with 100 ml of 5% caustic soda for 2 hours at room temperature, then acidified with 14 ml of 50% sulfuric acid and boiled for 1 hour. After standing for 2 days, the separated 3-methyl-7-(5<1->oxohexyl)-xanthine is filtered off (crude yield: 3.5 g = 58% of theory).

For purification, the crude product is dissolved in a little caustic soda and precipitated with hydrochloric acid, whereby 3-methyl-7-(5<1->oxo-hexyl)-xanthine with melting point 215°C is obtained in 40% yield.

Claims (1)

Analogous process for the preparation of therapeutically active 3-alkyl-7-(cu-1)-oxoalkylxanthines of formula I: where A means the alkylene with 2-6 C atoms and R an alkyl group with 1-12 C atoms, whereby R must be alkyl with at least 5 C atoms when A is the alkylene with less than 3 C atoms, characterized by a) reacting an alkali metal salt of a 3-alkylxanthine with an oxoalkyl halide of formula II: where A has the above meaning, and Hal means a halogen atom, or b) reacting a (w-haloalkyl)-3-alkylxanthine of formula III: where R and Hal have the above meanings and X is an alkylene with 2-5 C atoms, with an alkali acetate diester and subjecting the reaction product to ketone cleavage.