FR2498602A1 - NEW THERAPEUTICALLY USEFUL DERIVATIVES OF XANTHINE, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Xanthine derivatives of the general formula in which R<1> and R<3> each denote an alkyl group having 1-6 carbon atoms and R<2> denotes a cyclohexenyl, furyl, tetrahydrofuryl or thienyl group, and pharmacologically tolerable salts thereof with an alkali metal or a nitrogen-containing base, are novel, therapeutically useful compounds. They are particularly useful in the treatment of the respiratory and cardiovascular system. They can be prepared by cyclisation of a suitable 5-alkanoylamido-substituted 4-aminouracil compound or by reaction of a suitable substituted 5,6-diaminouracil with the anhydride of an acid R<3>-COOH.

Description

The present invention relates to novel therapeutically useful derivatives of xanthine, their method of preparation and pharmaceutical compositions containing them.

It is known that certain xanthine derivatives, for example theophylline (or 1,3-dimethylxanthine) exhibit interesting therapeutic properties.
The inventors have discovered, after much research and experiments, that xanthine derivatives having alkyl substituents on nitrogen and carbon atoms respectively in positions 1 and 8, at the same time as a cyclchexylmethyl, furylmethyl, tetrabydrofurylmethyl substituent or thienylmethyl on the nitrogen mowing in position 3 exhibit exceptional pharmacological properties useful for the treatment of respiratory and cardiovascular diseases.

dans laquelle R1 et R3 sont, chacun, un groupe alkyl contenant de 1 à 6 (de préférence 4 au maximum) atomes de carbone et R2 est un groupe cyclohexényl, furyl, tétra- hydrofuryl ou thiényl, ainsi que leurs sels phar-acolo- giquement acceptables foras avec une base organique contenant de l'azote ou un métal alcalin.The xanthine derivatives according to the invention have the following general formula

in which R1 and R3 are each an alkyl group containing from 1 to 6 (preferably at most 4) carbon atoms and R2 is a cyclohexenyl, furyl, tetrahydrofuryl or thienyl group, as well as their phar-acolo- salts. legally acceptable foras with an organic base containing nitrogen or an alkali metal.

Certain preferred derivatives of formula I are those in which R is a cyclohex-3-enyl, 2-furyl, 2-tetrahydrofuryl or 2-thienyl group and R1 and R3 have the definitions given above and, more particularly, those in which R is a methyl group.

Mention may thus be made, as particularly interesting compounds, of 1,8-dimethyl-3- (cyclobex-3-enylmethyl) xanthine, 1,8-dimethyl-3- (2-furylmethyl) -xanthine, 1methyl-3- (cyclohex- 3-enylmethyl) -8-isopropylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec-butylxanthine, 1,8 ~ dimethyl-3 (2-tetrahydrofurylmethyl) -santhine, 1 methyl-3- (2- furylmethyl) -8-ethylxanthine and 1,8-dimethyl 3- (2-thienylmethyl) -xanthine, and more especially the first two compounds.

(dans laquelle R1, R2 et R3 ont les définitions données ci-avant) par des méthodes connues en soi, par exemple par chauffage avec une solution aqueuse d'hydroxyde de sodium ou de potassium, de préférence a la température d'ébullition du mélange réactionnel.The derivatives of formula I according to the invention are prepared by cyclization of a uracyl compound of general formula

(in which R1, R2 and R3 have the definitions given above) by methods known per se, for example by heating with an aqueous solution of sodium or potassium hydroxide, preferably at the boiling point of the mixture reaction.

After acidification of the reaction mixture, the xanthine derivative of formula I is isolated in a manner known per se.

The term "method known in the art used in the present application corresponds to the methods used or described in the literature.

(dans laquelle R et R2 ont les définitions données ciavant) avec un acide carboxylique de formule générale
R - COOH (IV) (dans laquelle R3 a la définition donnée ci-avant) à une température entre 1000 et 180 C. il faut utiliser un exc8s d'acide et de préférence au moins deux moles d'acide carboxylique par mole de 5,6-diamino-uracile. The starting 5-acylamido-uracil compounds of formula II are obtained by reaction of a corresponding 5,6-diaminouracil of general formula

(in which R and R2 have the definitions given above) with a carboxylic acid of general formula
R - COOH (IV) (in which R3 has the definition given above) at a temperature between 1000 and 180 C. it is necessary to use an excess of acid and preferably at least two moles of carboxylic acid per mole of 5 , 6-diamino-uracil.

(dans laquelle R et R2 ont les définitions mentionnées ci-avant), par réaction avec un mélange de nitrite de sodium et d'acide acétique entre 10 C et 800C pour obtenir le dérivé 5-nitroso correspondant, puis par ré- duction du dérivé 5-nitroso en dérivé diamino par le dithionite de sodium en solution aqueuse d'hydroxyde d'ammonium entre 4o0c et 90 C
Les 6-aminouraciles de formule générale V peuvent être préparés à partir d'urée substituée en NeN' par des méthodes connues en soi (V. Papesch et E.F.Schroeder,
J. Org. chem. 16, 1879-90, 1951). The 5,6-diaminouracil of formula III can be prepared from the corresponding 6-aminouracil of general formula

(in which R and R2 have the definitions mentioned above), by reaction with a mixture of sodium nitrite and acetic acid between 10 C and 800C to obtain the corresponding 5-nitroso derivative, then by reduction of the derivative 5-nitroso in diamino derivative by sodium dithionite in aqueous solution of ammonium hydroxide between 4o0c and 90 C
The 6-aminouracils of general formula V can be prepared from urea substituted in NeN 'by methods known per se (V. Papesch and EFSchroeder,
J. Org. chem. 16, 1879-90, 1951).

According to another embodiment, the xanthine derivatives of formula I are also prepared from 5,6-diaminouracil of formula III by heating in the presence of an excess of the carboxylic acid anhydride of formula IV, preferably at the boiling point of this anhydride. In this case, the 5-acylamido derivative of formula II is not isolated, the xanthine derivative of formula I is obtained directly.

The xanthine derivatives of formula I obtained by the above processes can be purified using methods known per se, for example by recrystallization from an organic solvent such as methanol, methanol, isopropanol, tetrahydrofuran, dio xan or ethyl acetate.

The compounds of formula I exhibit pharmacological properties useful in the treatment of respiratory and cardiovascular conditions such as bronchial asthma, reversible obstructive airway conditions and obstructive peripheral and cardiac vascular conditions.

They act by relaxing bronchial smooth muscle both in vitro and in vivo and inhibit bronchoconstriction induced by histamine, acetylcholine and other smooth muscle stimulants.This direct bronchodilator activity is furthermore accompanied by inhibitory activity against the release of histamine and other autacoids in response to appropriate anaphylactic attacks. They also relax smooth muscle in blood, coronary and peripheral vessels causing vasodilation, increased blood flow and a drop in blood pressure unaccompanied by chycardia.

Stimulating effects on the central nervous system are minimal as are other actions such as induction of diuresis
Experiments were carried out with xanthine derivatives according to the present invention in order to compare their pharmacological properties with those of theophylline and 1-methyl-3-furfuryl-xanthine (hereinafter referred to as compound A) prepared by KRH Voodridge and R. Slack - J. Chem. Soc. 1962 - 1863-1868) these two compounds being comparable to the xanthine derivatives of formula I but without a substituent on the carbon atom at 8.

The compounds of formula I examined were
1,8-Dimethyl-3- (2-furylmethyl) -xanthine (R and
R3 = CH3 and R2 = 2-furyl, compounds 2 in ta
bleaux below);
1-methyl-3- (2-furylmethyl) -8-ethylxanthine (R =
CH3, R3 = C2H5 and R2 = 2-furyl, compound 3)
1,8-Dimethyl-3- (cyclohex-3-enylmethyl) -xanthine
(R1 and R3 = CH3 and R2 = cyclohex-3-enyl, compound 4)
1-methyl-3- (cyclohex-3-enylmethyl) -8-isopropyl
xanthine (R = CH3, R = isoC3H7 and R = cyclohex-3
enyl, compound 5); ;
1,8-Dimethyl-3- (2-tetrahydrofurylmethyl) -xanthine
(R1 and R3 = CH3 and R2 = 2-tetradrofuryl, compound 6)
1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec-butyl
xanthine (R = CH3, R3 = -CH (CH3) CH2CH3 and R2 = tee
trahydrofuryl, compound 7), and
1,8-Dimethyl-3- (2-thienylmethyl) xanthine (R and
R3 = CH3 and R2 = 2-thienyl, compound 8).

The results obtained are collated in the following table
TABLE I

<tb><SEP> Antagonism <SEP> Activity <SEP> Toxicity
<tb><SEP> Compound <SEP> against <SEP> the <SEP> bron- <SEP> vasgdila- <SEP> (3)
<tb><SEP> cho-constric- <SEP> tatrice
<tb><SEP> induced <SEP><SEP> (2)
<tb><SEP> by <SEP> the hista- <SEP>
<tb><SEP> groin <SEP> (1) <SEP>
<tb> Theophylline <SEP> 5 <SEP> + <SEP>#<SEP><SEP> 500
<tb><SEP> 1 <SEP> 4 <SEP> ++ <SEP>#<SEP> 1000
<tb><SEP> 2 <SEP> 10 <SEP> +++ <SEP>> 100 <500
<tb><SEP> 3 <SEP> 9 <SEP> +++ <SEP>> 100C500
<tb><SEP> 4 <SEP> 6 <SEP> +++ <SEP>> 500
<tb><SEP> 5 <SEP> 6 <SEP> +++ <SEP>> 500 <SEP>
<tb><SEP> 6 <SEP> 6 <SEP> +++ <SEP>> 500
<tb><SEP> 7 <SEP> 6 <SEP> +++ <SEP>> soo <SEP>
<tb><SEP> 8 <SEP> 6 <SEP> +++ <SEP>> 100 <500
<tb> (t) Number of guinea pigs (groups of 10) per 100 mg-kg-
oral compound protected against the effects
forced inhalation broncho-constrictors dhista-
nebulized mine.

(2) Percent reduction in peripheral resistance
in cats anesthetized with chloralosis; + = 26-40,
++ = 41-55, +++ = 56-70: induced by 3 mg kg 1
intravenous route.

(3) Approximate LD50 values in mice (mg kg -1
oral).

Table 2 makes it possible to compare the bronchodilator and antianaphylactic properties of the previously mentioned compounds of formula I with those of theophylline and of compound I.

TABLE 2

Model <SEP> Species <SEP> Theophylline <SEP> Compoaés
<tb> experimental <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6 <SEP> 7 <SEP> 8
<tb> (1) Konzett <SEP> Guinea pig <SEP> 6-5 <SEP> 5 <SEP> 2 <SEP> 4 <SEP> 0.7 <SEP> 2 <SEP> 5.5 <SEP> 2 <MS> 1.7
<tb><SEP> and <SEP> Rossier
<tb> (2) <SEP> String <SEP> Guinea pig <SEP> 10 <SEP> 7 <SEP> 2 <SEP> 4 <SEP> 1 <SEP> 6 <SEP> 7 <SEP> 2 <SEP> 3
<tb><SEP> tracheic
<tb><SEP> isolated
<tb><SEP> (iu-vitro)
<tb> (3) <SEP> Anophyla- <SEP> Rat <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> ++
<tb><SEP> xie <SEP> cuta
<SEP> born <SEP> not
<SEP> sive
<tb> (4) <SEP> Reaction <SEP> Guinea pig <SEP> 5x10-4 <SEP> 3x10-4 <SEP> 1x10-4 <SEP> 3x10-4 <SEP> 3x10-5 <SEP> 3x10-4 <SEP> 3x10-5 <SEP> 3x10-4 <SEP> 3x10-5
<tb><SEP> Schuitz-Dale
<tb><SEP> in
<tb><SEP> ileum
<tb><SEP> isolated
<tb> (1) Approximate ED50 (mg kg- in-vitro) against histamine-induced bronchoconstriction
intravenous (minimum 3 experiments) (2) approximate ED50 (g ml- of a body fluid bath) for smooth muscle relaxation
trachelk (minimum 3 experiments) (3) Actrvity at 100 mg kg0 orally against the PCA reaction induced by prewashed serum
in rats sensitized to ovalbumin (group of 12) (4) Molar concentration for inhibition of both induced contraction and his
tamine released from the ileum isolated from sensitized guinea pigs (evalbumin) in response to
antigen attack (minimum 3 experiments).

The experimental models referred to in Table 2 are described in the following publications.
(1) Konzett, H. and Rossler, R. Arch. Exp. Path.

Pharmakol. t95, 71-74 (1940)
(2) Castillon, JC and De Beer, EJJ Pharmac.

Exp. Ther. 90, 104-109 (1947)
(3) Ovary, Z, Fed. Proc. 24, 94 (1965)
(4> Dale, MM and Zilletti, L. Br. J. Pharmac. 39,
542-555 (1970)
The results of these experiments show that the xanthine derivatives of general formula I with an 8-alkyl substituent are more active towards the respiratory system than similar xanthine compounds with a hydrogen atom in the 8-position. C Thus, for example, compounds 2 to 8 (according to the invention) are more active against brouchoconstriction induced by histamine than compound 1 and theophylline.

The compounds according to the invention are also effective in other bronchodilator tests as well as in pharmacological models for antianaphylactic activity and, again, they are clearly more active than theophylline as shown in Table 2.

The compounds of general formula 1 are also more active than theophylline as vasodilators (see Table I). This vascular activity is not accompanied by a corresponding positive chronotropic effect on the heart, which makes the new compounds particularly useful for the treatment of obstructive cardiovascular diseases. A further advantage is that the compounds of general formula I have very long half-lives (e.g. compounds 2 and 4 have average half-lives of 52.8 to 13.2 hours respectively whereas the half-life of phylline tea is not is only three hours
In general, the xanthine derivatives of formula I will be useful for the treatment of obstructive respiratory diseases and asthma as well as in cases of cerebral or cardiac vascular insufficiency.

Xanthine derivatives of formula I can also form pharmacologically acceptable salts with alkali metal bases or organic bases containing nitrogen, these salts being formed by reaction of compounds of formula I with an alkali metal hydroxide or a base. organic nitrogen containing, for example as a solvent of water, methanol or ethanol, at a temperature between 40 and 1000C.

The present invention also relates to pharmaceutical compositions containing1 as active ingredient at least one compound of formula I, or one of its pharmacologically acceptable salts, associated with a pharmaceutically acceptable carrier or diluent. The compositions are preferably packaged for oral, rectal or parenteral administration.

The pharmaceutically acceptable carriers or diluents which are mixed with the active compounds or their salts to form the compositions according to the invention are well known per se and the excipients used depend, inter alia, on the method provided for the administration of the compositions. These compositions are more particularly suitable for oral administration.

In this case, they can take the form of tablets, capsules, pastilles, effervescent granules or of liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds according to the invention; these preparations can be made by methods well known in the prior art.

The diluents which can be used in the preparation of the compositions according to the invention comprise the solid or liquid diluents compatible with the active ingredient, together with the optional coloring or flavoring products. The tablets or capsules can advantageously contain between 5 and 150 mg and preferably between 10 and 50 mg of active ingredient or the equivalent amount of its pharmaceutically acceptable salt.

The compounds according to the invention can also be incorporated into pastilles coated with suitable natural or synthetic polymers known to obtain delayed release characteristics, or else incorporated into these polymers in the form of tablets to obtain the same characteristics.
Liquid compositions suitable for oral use can be in the form of solutions or suspensions.

The solutions can be aqueous or hydroalcoholic solutions of a soluble compound or its salt, combined, for example, with sucrose or sorbitol to form a syrup. The suspensions may comprise the insoluble or micro-encapsulated forms of an active component according to the invention, associated with water or with any other acceptable solvent at the same time as a suspending agent or a flavoring agent.

Compositions for parenteral injections may be prepared from soluble compounds or salts which may or may not be freeze-dried, and which may be dissolved in water or any fluid suitable for parenteral injection.

In human therapy, the doses of the xanthine derivatives according to the invention depend on the desired effect and on the duration of the treatment; adult doses generally range from 15 mg to 150 mg / day. The doctor will decide on the dosage taking into account the age and weight of the patient to be treated.

The following examples illustrate the preparation of the xanthine derivatives according to the invention.

Example 1
Slowly added to a suspension of 1-methyl-3 (2-furylmethyl) -6-aminouracil (260 g, 1.175 mole) and sodium nitrite (90 g, 1.3 mole) in water (1870 ml). ) acetic acid (141.5 ml) at a temperature of 200C.

The mixture is stirred for 24 hours at this temperature, then the insoluble 1-methyl-3- (2-furylmethyl) -5-ni-troso-6-aminouracil obtained by filtration, washed with water and then with l. ethyl ether and dried (292.5 g; yield 99.3%) The melting point of this compound is 223-2250C.

A mixture of this i-methyl-3- (2-furylmethyl) -5-nitroso-6-aminonracil (292.5 g, 1.169 moles) and an aqueous solution of concentrated ammonium hydroxide (4680 ml) is heated to 600c and then gradually added sodium dithionite (780 g, 3.71 mol). The color of the mixture changes from purple to pale yellow. After cooling, the solid product which precipitates is collected by filtration, washed with water (4 liters), recrystallized from methanol and dried to give 1-methyl-3- (2-furylmethyl). , 6-diaminouracil (208 g, 75.3% yield) pt. f. 168-170C.

A mixture of this 1-methyl-3- (2-furylmethyl) -5,6-diaminouracil (11.8 g, 0.05 mol) and propionic acid (18, 5 ml, 0.25 mole).

After cooling, a mixture of ethyl ether and isopropanol is added and 1-methyl-3- (2-furyl-methyl) -5-propionamido-6-aminouracil crystallizes (13 g, yield 89%). Scu melting point, after recrystallization from methanol is 238-2400C.

This compound (10 g, 0.0342 mole) is treated with 2N aqueous sodium hydroxide solution (50 ml) and the mixture is boiled under reflux for half an hour. After cooling the solution obtained, dilute hydrochloric acid is added until an acidic pH is obtained and the mixture is then extracted with chloroform.

The organic solution is washed with water, decolorized, dried (Na2SO4) then the solvent evaporated in vacuo to dryness.

The solid residue is treated with ethyl ether and then collected by filtration. 1-methyl-3- (2-furyl-methyl) -8-ethylxanthine (7.2 g; yield 76.7%) pt.

mp 233-2350C (after recrystallization from ethanol.

The following products are prepared in a similar manner, using suitable starting materials.
- 1,8-dimethyl-3- (2-furylmethyl) -xanthine, pt. f.

280-282 C;
- 1-methyl-3- (2-furylmethyl) -8-sec-butylxanthine,
pt. f. 128-129 C, and
- 1-methtyl-3- (2-furylmethyl) -8-propylxanthine, pt.

f. 216-2180C.

Example 2
A solution of 1-methyl-3- (2-furylmethyl) -5,6-diaminouracil (17.7 g, 0.075 mole) in acetic anhydride (150 ml) is boiled under reflux for 5 hours.

After cooling, a crystallized solid product is collected by filtration and recrystallized from ethanol to give 1,8-dimethyl-3- (2-furyl-methyl) xanthine (14.2 g, yield 72%. ). Pt. F 280-2820C.

Example 3
A mixture of 1- (cyclohex-3-enylmethyl) -3-methyl-5,6-diaminouracil (10 g, 0.04 mol) and glacial acetic acid (30 ml) is boiled under reflux for 2 hours. The solvent is removed by distillation in vacuo and the solid residue is combined with ethyl ether. Filtered to obtain 1 (cyclohex-3-enylmethyl) - 3-methyl-5-acetamido-6-aminouracil (11 g, 94% yield).

Pt. F. 233-2350C.

This compound (11 g, 0.038 mol) is treated with 10% aqueous sodium hydroxide solution (35 mL) and the mixture is boiled under reflux for half an hour. After cooling the solution obtained, dilute hydrochloric acid is added until a pH of 5 is obtained and the mixture is extracted with chloroform. The organic solution is washed with water, decolorized, dried (Na2SO4) and the solvent evaporated under vacuum to dryness.

The solid residue is treated with ethyl ether and collected by filtration. 1,8-dimethyl-3- (cyclohex 3-enylmethyl) -xanthine (8.5 g, yield 82%)) Pt. F.

253-2550C (after recrystallization from isopropanol).

The following compounds are prepared in the same way, starting from 5,6 diaminouracils and suitable carboxylic acids
1,8-Dimethyl-3- (2-thienylmethyl) xanthine, pt. f.

297-299 C
I-methyl-3- (2-tetrahydrofurylmethyl) -8-sec-butyl-
xanthine, pt. f. 112-114 C
1-methyl-3- (2-tetrahydrofurylmethyl) -8-ethylxan
thine, pt. f. 191-193 C
1-methyl-3- (2-tetrahydrofurylmethyl) -8-propyl
xanthine, pt. f. 184-186eC
1-methyl-3- (2-tetrahydrofurylmethyl) -8-isopropyl
xanthine, pt. f. 177-1790C
I-methyl-3- (cyclohex-3-enylmethyl) -8-sec-butylxan
thine, pt. r. 153-155 C
1-methyl-3- (2-tetrahydrofurylmethyl) -8-t-butyl
xanthine, pt. f. 193-1950C
1-methyl-3- (cyclohex-3-enylmethyl) -8-isopropylxan
thine, pt. f. 201-2030C
1-methyl-3- (cyclohex-3-enylmethyl) -8-propylxantbine,
pt. f. 2O2-2040C
1-methyl-3- (2-thienylmethyl) -8-sec-butylxanthine,
pt f. 148-150 C
1-methyl-3- (2-tetrahydrofurylmethyl) -8-butylxan
thine, pt. f. 156-1580C
1-methyl-3- (cyclohex-3-enylmethyl) -8-t-butylxan
thine, pt. f. 203-2050C
I-propyl-3- (2-tetrahydrofurylmethyl) 8-methylxan
thine, pt. f. 223-2250C, and
1-propyl-3- (cyclohex-3-enylmethyl) -8-methylxan
thine, pt. f. 207-2090C.

Example 4
A solution of 1- (2-tetrahydrofurylmethyl) -3-methyl-5,6-dia minouracil (12 g, 0.05 mol) in acetic anhydride (100 ml) is boiled under reflux for 5 hours. . After cooling, a crystal gray solid reads; collected by filtration and recrystallized from methanol to afford 1,8-dimethyl-3-tetrahydrofurylmethyl) -xanthine (9.3 g, yield 70.4, ')
Pt. F. 238-2400C.

Example 5
A suspension of 1,8-dimethyl-3- (2-furylmethyl) - xanthine (229 g, 0.88 mol) (prepared as described in Example 2) (prepared as described in Example 2) is boiled under reflux until complete dissolution in a solution. 10% sodium hydroxide aqueous (1100 mL). Upon cooling, the sodium salt of 1,0-dimethyl-3- (2-furylmethyl) -xanthine is obtained. (201 g, 81% yield). Pt.> 3000C.

The following examples illustrate pharmaceutical compositions according to the invention.

Example 6
100,000 capsules each containing 100 mg of 1-methyl-3- (2-furylmethyl) -8-ethylxanthine are prepared from the following formulation
1-methyl-3- (2-furylmethyl) -8
ethylxanthine 10 kg
lactose monohydrate 8 kg
wheat starch 2 kg
colloidal dioxide silicone 1 kg
magnesium stearate 2 kg
Process
The above ingredients are passed through a sieve with a mesh size of 250 mm, then mixed in a suitable mixer and placed in 100,000 gelatin capsules (230 mg).

Example 7
1000 vials (150 ml capacity) each containing 1,500 mg of 1,8-dimethyl-3- (2 (furyl-methyl) - xanthine are prepared as follows
1,8-dimethyl-1-3- (2-furylmethyl) xanthine 1.500 g
microcrystalline cellulose 1.500 g
sodium carboxymethylcellulose 900 g
sorbitol in 70% aqueous solution 33,000 g
glycerin 4.500 g
polysorbate 80 400 g
sodium methyl hydroxybenzoate 240 g
sodium propyl p-hydroxybenzoate 60 g
anti-foam silicone 150 g
sodium saccharin 300 g
flavoring qs

demineralized water qs for 150 liters
Process
A solution of sodium methyl-p-hydroxybenzoate, sodium propyl p-hydroxybenzoate and sodium saccharin in 30 l of demineralized water is added to a wet ground suspension of sodium carboxy methyl cellulose in glycerin. After stirring for one hour, a suspension of microcrystalline cellulose in 60 1 of demineralized water is added, then the sorbitol solution, polysorbate 80, 1,8dimethyl-3-2-furyl-methyl - are added successively, with stirring, xanthine, silicone defoamer and flavoring. The volume of the mixture is brought to 150 1 with demineralized water and the homogeneous suspension is placed in 150 ml flasks, using a suitable filling machine.

Example 8
20,000 vials (150 ml) each containing 300 mg of 1,8-dimethyl-3- (cyclohex-3-enylmethyl) -xanthine 1, 8-dimethyl -3- (cyclohex-3-enylmethyl) are prepared as follows.
xanthine 6 kg
lthanOl 45 kg
70% aqueous sorbitol solution 1.050 kg
Sodium saccharin 3 kg
Sodium carboxymethylcellulose 60 kg
Flavoring qs

Demineralized water qs for 3000 liters
Process
A solution of sodium carboxymethylcellulose in 1000 liters of water and 5 kg of ethanol is added to another solution of 1,8-dimethyl-3- (cyclohex-3-enylmethyl) -xanthine in 40 kg of ethanol and 500 liters of water at a temperature of 50 ° C. The sorbitol solution, sodium saccharin and flavoring agent are then added and the volume of the mixture is brought to 3000 liters with demineralized water. After filtration, the solution is placed in 150 ml flasks by means of a suitable filling machine.

Example 9
10,000 suppositories each containing 150 mg of 1-methyl-3- (2-tetrahydrofuryl-methyl) -8-sec-butyl-xanthine are prepared as follows.
1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec
butylxanthine 1.500 g
theobroma oil 18.500 g
The theobroma oil is melted and the active compound suspended therein. The mixture is then poured into molds for suppositories suitable for making suppositories of 2.0 g.

Instead of the xanthine derivatives specifically mentioned in Examples 5 to 8, it is possible to use, in the pharmaceutical formulations described, any other xanthine derivative falling within the definition of general formula 1, for example the compounds of this formula to which refer. examples 1 to 3.

Claims (19)

- CLAIMS 1 - Xanthine derivatives, characterized in that they have the following general formula

wherein R1 and R3 are each an alkyl group containing from 1 to 6 carbon atoms and R2 is a cyclohexenyl, furyl, tetrahydrofuryl or thienyl group, as well as their pharmacologically acceptable salts formed with an organic base containing nitrogen or an alkali metal. 2 - Derivatives according to claim 1, characterized in that R2 is a cyclohex-3-enyl, 2-furyl, 2-tetrahydrofuryl or 2-thimnyl group and R1 and R3 have the definitions given above as well as their pharmacologically acceptable salts formed with an organic base containing nitrogen or an alkali metal. 3 - Xanthine derivatives according to claims 1 and 2, characterized in that the alkyl group corresponding to R 1 and to R 3 is a group containing from i to 4 carbon atoms. 4 - A derivative according to any one of claims 1 to 3, characterized in that R is a methyl group 5 - A derivative according to claim 4, characterized in that it is 1,8-dimethyl-3- (cyclohex-3-enylmethyl) - xanthine. 6 - A derivative according to claim 4, characterized in that it is 1,8-dimethyl-3-2-furylmethyl) xanthine. 7 - A derivative according to claim 4, characterized in that it is 1-methyl-3- (cyclohex-3-enylmethyl) -8- isopropylxanthine. 8 - A derivative according to claim 4, characterized in that it is 1-methyl-3- (2-tetrahydrofurylmethyl sec-butylxanthine. 9 - Derivatives according to claim i, characterized ao that it is 1,8-dimethyl-3- (2-tetrahydrofurylsethyl) xanthine. 10 - A derivative according to claim 4, characterized in that it is 1-methyl-3- (2-furylmethyl) -8-ethylxanthine. 11 - A derivative according to claim 4, characterized in that it $ is 1.8-dimethyl-3- (2-thienylmethyl) xanthine. 12 - Pharmacologically acceptable salts of xanthine derivatives according to any one of claims ~ to 11. 13 - A derivative according to any one of claims ia 4, characterized in that it is chosen from 1-methyl- 3- (2-furylmethyl) -8-sec butyl-xanthine, 1-methyl-3- ( 2- furylmethyl) -8-propylxanthine, 1-methyl-3- (2-tetrahydro furylmethyl) -8-ethylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-propylxanthine, 1-methyl-3 - (2-tetrahydrofurylmethyl) -8-isopropylxanthine, 1-methyl-3- (cyclohex3-enylmethyl) -8-sec-butylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl-8-t-butylxanthine, 1 -methyl-3- (cyclohex-3-enylmethyl) -8-propylxanthine, 1-methyl-3- (2-thienylmethyl) -8-sec-butylxanthine, 1-methyl-3- (2-tetrahyldrofurylmethyl) -8 -butylxanthine, 1-methyl-3- (cyclohex3-enylmethyl) -8-t-butylxanthine, 1-propyl-3- (2-tetrahydrofurylmethyl) -8-methylxanthine at 1-propyl-3- (cyclohex-3 -enylmethyl) -8-methylxanthine, as well as the pharmacologically acceptable salts of these compounds. 14 - Process for the preparation of xanthine derivatives according to any one of claims i to 13, charac terized in that it consists in cyclizing a compound ura formula cycle

in which X is a hydrogen atom or the radical COR3 and R, R and R have the definitions given in claim 1. 15 - Process according to claim 14, characterized in that the cyclization of a uracyl compound of formula

is carried out by heating with an aqueous solution of sodium or potassium hydroxide. 16 - Process for preparing a xanthine derivative according to claim 14, characterized in that it consists in heating a 5,6-diaminouracil of formula

in which R and R have the above definitions with an excess of anhydride of a carboxylic acid of formula R3 - COOH in which R3 has the definition above 17 - Process according to any one of claims 14 to 16, characterized in that it is followed by a step of transformation, by a known method, of the xanthine derivative into its pharmacologically acceptable salt. 18 - Pharmaceutical compositions containing, as active ingredient, a xanthine derivative according to any one of the preceding claims or one of its pharmacologically acceptable salts, associated with a carrier or with a pharmacologically acceptable diluent. 19 - Pharmaceutical compositions according to claim 18, characterized in that the active ingredient is chosen from 1-methyl-3- (2-furylmethyl) -8-ethyl-xanthine, 1,8-dimethyl-3- (2 -furylmethyl) xanthine, 1, 8-dimethyl-3- (cyclohex-3-enylmethyl) -xanthine and i-methyl-3- (2-tetrahydrofurylmethyl) -8-sec-butylxantine