NL8105749A - XANTHINE DERIVATIVES, METHODS FOR PREPARING THEM AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

ÏT.O. 30 681 - 1 - * i '/

Xanthine derivatives, processes for their preparation as well as pharmaceutical preparations containing these derivatives.

The present invention relates to new therapeutically useful xanthine derivatives, to methods of preparation thereof, and to pharmaceutical preparations containing these xanthine derivatives.

It is known that some xanthine derivatives, for example theophylline (i.e. 1,3-dimethylxanthine) have useful therapeutic properties.

Surprisingly, after investigation and experimentation, it has now been found that xanthine derivatives having alkyl substituents on the nitrogen and carbon atoms in the 1 and 8 positions are coupled with a cyclohexenylmethyl, furylmethyl, tetrahydrofurylmethyl or thienylmethyl substituent on the nitrogen atom on the 3-position possess extraordinary pharmaceutical properties, which are suitable for the treatment of respiratory and cardiovascular disease conditions.

The xanthine derivatives of the present invention are therefore 1 3

half those compounds of the general formula 1, wherein R and R

each represents an alkyl group of 1 to 6, preferably up to 4 carbon atoms and R represents a cyclohexenyl, furyl, tetrahydrofuryl-20 or thienyl group, and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing base.

Preferred compounds of the general formula 1 are those compounds wherein R represents a cyclohex-3-enyl, 2-furyl, 2-tetrahydrofuryl or 2-thienyl group and R and Ry as defined above, and more particularly those in which R represents a methyl group. Of particular interest are 1,8-dimethyl-3- (cyclohex-3-enyme thy1) -xanthine, 1,8-dimethyl-3- (2-furylmethyl) -xanthine * 1-methyl-3- (cyclohex-3 -enylmethyl) -8-isopropylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec.butylxanthine, 1,8-dimethyl-3- (2-tetrahydrofurylmethyl) -xanthine, 1-methyl-3 - (2-furylmethyl) -8-ethylxanthine and 1,8-dimethyl-3- (2-thienylmethyl) -xanthine, and more particularly both of the first mentioned compounds.

According to a feature of the present invention, the xanthine derivatives of the general formula 1 are prepared by cyclization 1 2 t * - 2 - of a uracil compound of the general formula 2, wherein R, R and 3 R are as defined above, according to methods known per se, for example by heating with an aqueous solution of sodium or potassium hydroxide, preferably at the boiling point of the reaction mixture. After acidification of the reaction mixture, the xanthine product of the general formula 1 is separated in a manner known per se.

By the term "methods known per se" as used in the specification and claims is meant methods as used heretofore or described in the literature.

The starting 5-acylamido-uracil compounds of the general formula 2 are obtained by reacting a corresponding 1, 2, 5,6-diaminouracil of the general formula 3> wherein R and R are as defined above, with a carboxylic acid of the general formula 3 4 »wherein Ry is as defined above, at a temperature between 100 ° and 180 ° C. An excess of acid should be used, and preferably at least two moles of carboxylic acid are used per mole of 5> 6-diaminouracil.

The 5,6-diaminouracil of the general formula 5 can be prepared from a corresponding 6-aminouracil of the general formula 1 2 5, wherein R and R are as defined above, by reaction with a mixture of sodium nitrite and acetic acid at a temperature between 10 ° C and 50 ° C, whereby the corresponding 5-nitroso derivative is obtained, and reduction of the 5-nitroso compound with sodium dithionite in an aqueous ammonium hydroxide solution at a temperature between 40 ° 0 and 90 ° C to the diamino connection.

The 6-aminouracilli of the general formula (5) can be prepared from the corresponding N, Nf-disubstituted urea by methods known per se, for example, 7. Papesch and E.F. Schroeder, 30 J. Org. Chem., 16, (1951) 1879-90.

The xanthine derivatives of the general formula 1 are also prepared according to another feature of the present invention from a corresponding 5> 6-diaminouracil of the general formula 3 by heating with an excess of the anhydride of the corresponding carboxylic acid of the general formula 4> "preferably at the boiling point of the anhydride. In this case, the 5-aeylamido derivative of the general formula 2 is not separated, since the xanthine derivative of the general formula 1 is obtained directly.

The xanthine products of the general formula 1, obtained by the methods described above, can be purified by methods known per se, for example by recrystallization from an organic solvent, for example methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or ethyl acetate.

The compounds of the general formula 1 have pharmacological properties, which are suitable for the treatment of respiratory diseases and cardiovascular diseases such as bronchial asthma, reversible constipatory respiratory disease and constipative peripheral and cardiovascular disease. Therefore, they relax the bronchial smooth muscle both in vitro and in vivo and inhibit the bronchial tightening induced by histamine, acetylcholine and other smooth muscle stimulants. Furthermore, this direct bronchodilating activity is accompanied by an inhibitory activity against the release of histamine and other autacoids in response to suitable anaphylactic stimuli.

They also relax the smooth muscle of peripheral and coronary blood vessels resulting in vasodilation, an increase in blood flow and a drop in blood pressure, not accompanied by tachycardia.

Central nervous system stimulation effects are minimal as are other xanthine-like actions, such as the induction of diuresis.

Experiments have been performed with some xanthine derivatives of the present invention to compare their pharmacological properties with that of theophylline and 1-methyl-3-furfurylxanthine, a compound (later referred to as compound 1) prepared by E.R.H. Vooldridge and R. Slack, J. Chem. Soc. 19 ^ 2, 1863-1868, both of which are related to the xanthine derivatives of the general formula 1, but do not contain a substituent on the carbon atom at the 8 position.

The compounds of the general formula I tested were 1,8-dimethyl-3- (2-furylmethyl) -xanthine (R * 'and Ή = CH, and R 2 = 2-furyl; denoted as compound 2 in the following tables; 1 -methyl-3- (2-furylmethyl) -8-ethylxanthine (R ^ = CH ,, R ^ = CnH, - and 2 y = 35 R = 2-furyl; compound 3); * 1 t 1,8-dimethyl- 5- (cyclohex-3-enylmethyl) -xanthine (R and R'5 = CH, and 2 3 R = cyclohex-3-enyl; compound 4); 1-methyl-3- (cyclohex-3-enylmethyl) -8 -isopropylxanthine (R a CL, 3 2.2 R = isoC, Hy and R = cyclohex-3-enyl; compound 5); 40 1,8-dimethyl-3- (2-tetrahydrofurylmethyl) -xanthine (R and R ^ = CH, on 3 8105749 IT = 2-tetrahydrofuryl; compound 6);% * - 4 - λ

-J

1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec.butylxanthine (R = CH ,, Q ✓

Ir = -CH (CH 3) CHOCHT and R = tetrahydrofuryl; compound 7) and 3 2 3/13 2 1,8-dimethyl-3- (2-thienylmethyl) -xanthine (R and Ry = CH2 and R = 5 2-thienyl; compound 8).

The results obtained in the experiments with the different compounds are shown in the following tables.

Table A

Compound Antagonism to Vasodilator Toxicity with histamine activity (3) induced (2) broncho-constriction (1)

Theophylline 5 + CT 500 1 4 ++ ^ 1000 2 10 +++> 100 <500 3 9 +++> 100 <.500 4 6 +++> 500 5 6 +++> 500 6 6 +++ y500 '7 »6 +++.> 500 8 6 +++> 100 <500 (1) Number of protected guinea pigs from a group of 10 by 100 mg / kg 10 per os compound against the bronchoconstriction effects of toe enhanced inhalation of nebulized histamine .

(2) Percentage reduction in peripheral resistance in the chloralose-anesthetized cat, + = 26-40; ++ = 41-55; +++ = 56-70r elicited with 3 mg / kg intravenously.

(3) Approximate ID ^ q values (mg / kg per os) in the mouse.

Table B compares the bronchodilating and antianaphylactic properties of the previously specified compounds of general formula 1 with those of theophylline and compound 1.

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The experimental models cited in Table B are described in the following publications: (1) Konzett, H. and Bossier ,. B., Arch. Exp. Path.

Pharmakol., 195, 7174 (1940), 5 (2) Castillo, J.C. and De Beer, E.J., J. Pharmac.

Exp. Ther.,% 0, (1947) 104109, (3) Ovary, Z., Oath. Proc., 24, (1965) 94, (4) Dale, M, M. and Zilletti, L., Br. J. Pharmac., 22, 542-555 (1970).

It will be clear from the results of the experiments that the xanthine derivatives of the general formula 1 with an 8-alkyl substituent are more active on the respiratory tract than the relatives examined xanthine compounds with hydrogen bonded to the 8-position carbon atom . Thus, for example, compounds 15 to 8 (which are compounds of the present invention) are more active against histamine-induced bronchoconstriction than the previously described compound 1 and theophylline. The compounds of the invention are also active in other bronchodilating experiments as well as in pharmacological models for the antiana-phylactic activity and again they are markedly more potent than theophylline, as shown in Table B.

The compounds of general formula 1 are also more active than theophylline as vasodilators (see Table Δ). The vascular activity is not accompanied by a corresponding positive chronotropic effect on the heart, making the new compounds particularly suitable for the treatment of congestive cardiovascular disease. An additional advantage is that the compounds of the general formula 1 have very long half-lives (for example, compounds 2 and 4 have mean half-lives in humans of 52.8 and 13.2 hours, respectively, while the half-life of theophylline is only 3 hours).

Generally, the xanthine derivatives of general formula 1 will be suitable for the treatment of constipative respiratory disease and asthma, on the one hand, and cerebral or cardiovascular insufficiency, on the other.

The xanthine derivatives of the general formula 1 can also form pharmacologically acceptable salts with alkali metal bases or nitrogen-containing organic bases, the salts of which are formed by reacting the compounds of the general formula 1 with an alkali metal hydroxide or a nitrogen-containing organic 8105749 4 - 7 - base using, for example, water, methanol or ethanol as a solvent at a temperature between 40 ° and 100 ° C.

The present invention also includes pharmaceutical compositions which contain, as active ingredient, at least one compound of the general formula 1 or a pharmacologically acceptable salt thereof, as mentioned above, together with a pharmaceutically acceptable carrier or a pharmaceutically acceptable diluent. Preferably, the preparations are prepared in a form suitable for oral, rectal or parenteral administration.

The pharmaceutically acceptable carriers or diluents, which are mixed with the active compound or compounds or salts of such compounds to form the compositions of the present invention are known per se and the suitable actual excipients depend o, a. depending on the intended route of administration of the preparations. Compositions of the present invention are preferably made suitable for administration by the os. In this case, the preparations for oral administration may be in the form of tablets, capsules, cough tablets or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing 20 or more compounds of the invention; such preparations can be prepared by methods known per se.

Diluents which can be used for the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with any coloring or flavoring agents. Tablets or capsules may conveniently contain between 5 and 150 mg, and preferably from 10 to 50 mg, of the active ingredient or the equivalent amount of a pharmacologically acceptable salt thereof. The compounds may also be included in tablets coated with known per se known natural or synthetic polymers to produce sustained release properties or with polymers incorporated in a tablet form to produce the same properties.

The liquid preparations made suitable for oral use can be in the form of solutions or suspensions. The solutions may be aqueous or aqueous alcoholic solutions of a soluble compound or a salt thereof in conjunction with, for example, sucrose or sorbitol to form a syrup. The suspensions can form an insoluble or micro-encapsulated form of an active compound of the invention.

- 8 - together with water or other acceptable solvents together with a suspending agent or flavoring.

Preparations for parenteral injection can be prepared from soluble compounds or salts, which may or may not have been freeze-dried, and which can be dissolved in water or a suitable parenteral injection.

For human therapy, the dosages of the xanthine derivatives depend on the desired effect and the duration of treatment. Dosages for adults are generally between 15 mg and 150 mg per day. In general, the doctor will decide the posology, taking into account the age and weight of the patient to be treated.

Example 1.

To a suspension of 260 g (1.75 mol) of 1-methyl-3- (2-furylmethyl) 15-6-aminouracil and 90 g (1.3 mol) of sodium nitrite in 1870 ml of water, 141.5 ml of acetic acid were temperature of 20 ° C.

The mixture was stirred at this temperature for 24 hours and then the insoluble 1-methyl-3- (2-furylmethyl) -5-nitroso-6-aminouracil obtained was collected by filtration, washed with water and then with diethyl ether and dried (292.g, yield 99> 5%) its melting point was 1,223-225 ° C.

A mixture of 292.5 g (1.169 mol) of this 1-methyl-3- (2-furylmethyl) -5-nitroso-aminouracil in 468 ml of a concentrated aqueous ammonium hydroxide solution was heated to 60 ° C. and J80 g (3.71 mol) of sodium dithionite were added in portions, the color of the mixture changed from violet to light yellow. After cooling, the precipitated solid was collected by filtration, washed with 4 liters of water, recrystallized from methanol and dried, yielding 208 g of 1-methyl-3- (2-furylmethyl) -5,6-diaminouracil (yield 75.3%). mp 168-170 ° C were obtained.

A mixture of 11.8 g (0.05 mol) of this 1-methyl-3- (2-furylmethyl) -5,6-diaminouracil and 18.5 ml (0.25 mol) of propionic acid was refluxed for 2 hours . After cooling, a mixture of diethyl ether and isopropanol was added and crystallized 13 g of 1-methyl-3- (2-furylmethyl) -5 "propionamido-6-aminouracil (yield 89%). Set melting point after recrystallization from methanol was 238-. 240 ° C.

10 g (0.0342 mol) of this compound were treated with 50 ml of a 2N aqueous sodium hydroxide solution and the mixture was refluxed for 30 minutes. After cooling the solution obtained, 8105749 V * - 9, dilute hydrochloric acid was added until an acidic pH was reached and then the mixture was extracted with chloroform. Ί) β organic solution was washed with water, decolorized, dried over sodium sulfate and the solvent was removed to dryness under reduced pressure. The solid residue was treated with diethyl ether and collected by filtration, yielding 7.2 g of 1-methyl-3- (2-furylmethyl) -8-ethylxanthine (yield 76.7%), mp 233-235 ° C (after recrystallization from ethanol) were obtained.

Similarly, 1,8-dimethyl-3- (2-furylmethyl) -xanthine, m.p. were also prepared using the appropriate starting compounds. 280-282 ° C; 1-methyl-3- (2-furylmethyl) -8-sec-butylxanthine, mp. 128-129 ° C and 1-methyl-3- (2-furylmethyl) -8-propylxanthine, mp. 216-218 ° C.

15 Example 2.

A solution of 17.7 g (0.075 mol) of 1-methyl-3- (2-furylmethyl) -5,6-diaminouracil in 150 ml of acetic anhydride was refluxed for 5 hours. After cooling, a solid crystallized, which was collected by filtration and recrystallized from ethanol, whereby 14.2 g of 1,8-dimethyl-3- (2-furylmethyl) -xanthine (yield 72.8%), melting point 280-282 ° C, were obtained,

Example 3 «

A mixture of 10 g (0.04 mol) of 1- (cyclohex-3-enylmethyl) -3-methyl-5,6-diaminouracil and 30 ml of glacial acetic acid was refluxed for 2 hours. The solvent was removed by distillation under reduced pressure and the solid residue was collected with diethyl ether and filtered to yield 11 g of (1- (cyclohex-3-enylmethyl) -3-methyl-5-acetamido-6-aminouracil (94% yield). mp 233-235 ° C.

50 g (0.038 mol) of this compound were treated with 35 ml of a 10% aqueous sodium hydroxide solution and the mixture was refluxed for 30 minutes. After cooling the resulting solution, dilute hydrochloric acid was added until a pH of 5 was reached and the mixture was then extracted with chloroform. The organic solution was washed with water, decolorized, dried over sodium sulfate, and the solvent was removed to dryness under reduced pressure. The solid residue was treated with diethyl ether and collected by filtration, yielding 8.5 g of 1,8-dimethyl-3- (cyclohex-3-enylmethyl) -xanthine (yield 82%), mp 253-255 ° C (after crystallization from isopropanol) 8103749 * * - 10 - were obtained.

Similarly, starting from the appropriate 5,6-diaminouracil and carboxylic acid, the following compounds were also prepared: 1,8-dimethyl-3- (2-thienulmethyl) -xanthine, m.p. 297-299 ° C, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec. butylxan thine, m.p. 112-114 ° C> 1-methyl-3- (2-tetrahydrofurylmethyl) -8-ethylxanthine, mp. 191-193 ° 0.10 1-methyl-3- (2-tetrahydrofurylmethyl) -8-propylxanthine, m.p. 184-18 ° C, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-isopropylxanthine, mp. 177-179 ° C, 1-methyl-3- (cyclohex-3-enylmethyl) -8-sec.butylxanthine, mp. 153-155 ° 0,1-methyl-3- (2-tetrahydrofurylmethyl) -8-tert-butylxanthine, m.p. 195-195 ° C, 1-methyl-3- (cyclohex-3-enylmethyl) -8-isopropylxanthine, mp. 201-203 ° C, 20 1-methyl-3- (cyclohex-3-enylmethyl) -8-propylxanthine, mp. 202-204 ° C, 1-methyl-3- (2-thienylmethyl) -8-sec-butylxanthine, mp. 148-150 ° C, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-butylxanthine, mp. 156-158 ° C, 1-methyl-3- (cyclohex-3-enylmethyl) -8-tert-butylxanthine, mp. 203-205 ° C, 1-propyl-3- (2-tetrahydrofurylmethyl) -8-methylxanthine, mp. 223-225 ° C and 30 1-propyl-3- (cyclohex-3-enylmethyl) -8-methylxanthine, mp. 207-209 ° C.

Example 4 »

A solution of 12 g (0.05 mol) of 1- (2-tetrahydrofurylmethyl) -3-methyl-5> 6-diaminouracil in 100 ml of acetic anhydride was refluxed for 5 hours. After cooling, a gray solid crystallized, which was collected by filtration and recrystallized from ethanol, giving 9.3 § 1,8-dimethyl-3- (2-tetrahydrofurylmethyl) -xanthine (yield 70.4%), melting point 238. -240 ° C were obtained.

8105749 ♦ * - 11 -

Example 5 «

A suspension of 229 S (0.88 mol) 1 µS-dimethyl ^ -S-furyl-methyl) xanthine (prepared as described in Example 2) in 1100 ml of a 10% aqueous solution of sodium hydroxide was refluxed boiled until solution was complete. After cooling, 201 g of the sodium salt of 1,8-dimethyl-3- (2-furylmethyl) xanthine (yield 8196) having a melting point greater than 300 ° G were obtained.

The following examples illustrate pharmaceutical compositions according to the invention.

Yoor picture 6.

100 capsules, each containing 100 mg of 1-methyl-3- (2-furylmethyl-) -8-ethylxanthine, were prepared from the following formulation: 1-methyl-3- (2-furylmethyl) -8-15 ethylxanthine 10 kg lactose monohydrate 8 kg corn starch 2 kg colloidal silicon dioxide 1 kg magnesium stearate 2 kg 20 Method.

The aforementioned ingredients were sieved through a 60-mesh screen, then mixed in a suitable mixer and filled into 100,000 gelatin capsules (230 mg).

Example 7, 1000 suspension bottles (capacity 150 ml), each containing 1500 mg of 1,8-dimethyl-3- (2-furylmethyl) -xanthine, were prepared as follows: 1.8-dimethyl-3- (2-furylmethyl) -xanthine 1500 g microcrystalline cellulose 1500 g 30 sodium carboxymethyl cellulose 900 g 7096's solution of sorbitol in water 33000 g glycerol 4500 g polysorbate 80 400 g sodium methyl p-hydroxybenzoate 240 g 35 sodium propyl p-hydroxybenzoate 60 g polysiloxane anti-foaming agent 150 g sodium saccharin c 300 g [.s.

demineralized water q.s. 150 liters 8105749 - 12 -

Method·*·

To a solution of sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate and sodium saccharin in 30 liters of demineralized water was added a wet ground suspension of sodium carboxy methyl methyl cellulose in glycerol. After stirring for 1 hour, a suspension of the microcrystalline cellulose in 60 liters of demineralized water was added and then the sorbitol solution, polysorbate 80, 1,8-dimethyl-3- (2-furylmethyl) -xanthine, polysiloxane were successively stirred anti-foaming agent and flavoring added · The volume of the mixture was adjusted to 150 liters with demineralized water and the homogeneous suspension was filled into 150 ml bottles using a suitable filling machine.

Example 8.

20,000 solution bottles (150 ml capacity) each containing 3000 mg of 1,8-dimethyl-3 ~ (cyclohex-3-enylmethyl) -xanthine were prepared as follows: 1,8-dimethyl-3- (cyclohex-3- enylmethyl) -xanthine 6 kg 20 ethanol 45 kg 70% solution of s'orbitol in water 1050 kg sodium saccharin 3 kg sodium carboxymethyl cellulose 60 kg flavoring qs

Demineralized water q.s. 3000 liters

Method.

A solution of the sodium carboxymethyl cellulose in 1000 liters of water and 5 kg of ethanol was added to another solution of the 1,8-dimethyl-3- (cyclohex-3-enylmethyl) -xanthine in 40 kg of ethanol and 500 liters of water at a temperature of 50 ° C. Then the sorbitol solution, sodium saccharin and flavoring were added and the volume of the mixture with demineralized water was brought to 3000 liters. After filtration, the solution was filled into 150 ml bottles using a suitable filling machine.

Example 9, 10,000 suppositories each containing 150 mg of 1-methyl-3- (2-tetrahydro-furylmethyl) -8-sec.butylxanthine were prepared as follows: 1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec .

40 butylxanthine 15000 g 8105749 - 13 - theobroma oil 18500 g

The theobroma oil was melted and the active compound was suspended therein. The mixture was then poured into a suitable suppository mold to make 2.0 g superpositories.

Instead of the xanthine derivative specifically mentioned in Examples 5 to 8, any other xanthine derivative within the scope of general formula 1, for example the compounds of that formula cited in Examples 1 to 5, may be used in the described pharmaceutical formulations.

8105749

Claims (10)

1. Xanthine derivatives of the general formula 1, wherein R and R 2 each represent an alkyl group of 1 to 6 carbon atoms and R represents a cyclohexenyl, furyl, tetrahydrofuryl, or thienyl group, and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing organic base. Xanthine derivatives according to claim 1, characterized in that R represents a cyclohexenyl, tetrahydrofuryl or thienyl group and R and R are defined as in claim 10 1, and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing organic base. Xanthine derivatives according to claim 1, characterized in that R represents a cyclohex-3-enyl, 2-furyl, 2-tetrahydro-1 3 'furyl or 2-thienyl group and R and R are defined as in claim 1, and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing organic base. Xanthine derivatives according to claims 1 to 3, characterized in that the alkyl group represented by R and R 20 contains 1 to 4 carbon atoms. Xanthine derivatives according to claims 1 to 4, characterized in that X represents the methyl group. 6. 1,8-dimethyl-3 (cyclohex-3-enylmethyl) -xanthine. 7 · 1,8-dimethyl-3- (2-furylmethyl) -xanthine. 8. 1-Methyl-3- (cyclohex-3-enylmethyl) -8-isopropylxanthine. 9 · 1-methyl-3- (2-tetrahydrofurylmethyl) -8-sec.butylxanthine. 10. 1,8-dimethyl-3- (2-tetrahydrofurylmethyl) -xanthine. 11. 1-methyl-3- (2-furylmethyl) -8-ethylxanthine. 12. 1,8-dimethyl-3- (2-thienylmethyl) -xanthine. Pharmacologically acceptable salts of a compound according to any one of claims 5 to 12 formed with an alkali metal base or a nitrogen-containing organic base. 14 · 1-methyl-3- (2-furylmethyl) -8-sec.butylxanthine, 1-methyl-3- (2-furylmethyl) -8-propylxanthine, 1-methyl-3- (2-tetrahydrofuryl-35 methyl ) -8-ethylxanthine, 1-methyl-3-) 2-tetrahydrofurylmethyl) -8-propylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-isopropyl-xanthine, 1-methyl-3- (cyclohex-3 -enylmethyl) -8-sec.butylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) -8-tert-butylxanthine, 1-methyl-3- (cyclohex-3-enylmethyl) -8-propylxanthine, 1-methyl- 3- (2-thienyl-40-methyl) -8-sec-butylxanthine, 1-methyl-3- (2-tetrahydrofurylmethyl) - 8105749 - 15 - 8-butylxanthine, 1-methyl-3- (cyclohex-3-enylmethyl) -8-tert-butyl-xanthine, 1-propyl-3- (2-tetrahydrofurylmethyl) -8-methylxanthine and 1-propyl-3- (cyclohex-3-enylmethyl) -8-methylxanthine, and pharmacologically acceptable salts of any of these compounds are formed with an alkali metal base or a nitrogen-containing organic base. * A process for the preparation of a xanthine derivative, characterized in that a compound of the formula 1, in which the symbols have the meanings stated in claim 1, is prepared by using a uracil compound of the general formula 2, 12 3 wherein E and E and E are defined as subject to cyclization treatment according to methods known per se. 16. Process according to claim 15, characterized in that the cyclization of the uracil compound is performed by heating with a solution of sodium or potassium hydroxide in water. 17 "Process for the preparation of a xanthine derivative, characterized in that compounds of formula 1, in which the symbols have the meanings stated in claim 1, are prepared by using a 5,6-diaminouracil of the general formula 3" wherein 1 2 E. and E are defined as heated in claim 1 with an excess of an anhydride of a carboxylic acid of the general formula 4 wherein S is defined as in claim 1. Process according to one or more of Claims 15 to 17, 25, characterized in that a xanthine derivative of the general formula thus obtained, as specified in claim 1, is subsequently converted into a pharmacologically acceptable alkali metal salt by a method known per se or a salt with a pharmacologically acceptable nitrogen-containing organic base. Xanthine derivatives of the general formula as specified in claim 1 and pharmacologically acceptable salts thereof with an alkali metal base or a nitrogen-containing organic base when prepared according to the method of any one of claims 15 to 18. Pharmaceutical preparations, characterized by the presence of a xanthine derivative according to one or more of claims 1 to 12 and 14 or a pharmacologically acceptable alkali metal salt thereof or a salt thereof formed with a pharmacologically acceptable nitrogen-containing organic base as an active ingredient together with a pharmaceutically acceptable 8105749 ψ ~ - <- 16 - carrier or diluent. 21. A process for the preparation of pharmaceutical preparations, characterized in that a xanthine derivative of the formula 1, in which the symbols have the meanings stated in claim 1, is brought into a form suitable for such use. 22. Xanthine derivatives of the general formula 1 according to claim 1 and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing organic base, for therapeutic use in the treatment of respiratory and cardiovascular disease conditions such as brochial asthma, reversible occlusive respiratory disease and constipative peripheral and cardiovascular diseases. \ 8105749