LU83849A1 - PROCESS FOR THE PREPARATION OF XANTHINE DERIVATIVES - Google Patents

Description

- 1 - ί ! ! * DESCRIPTION "XANTHINE. DERIVATIVE S11 V ‘ *

This invention relates to new therapeutically useful xanthine derivatives, to processes for their * préparation and pharmaceutical compositions containing them.

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

It has now unexpectedly been found after research and expérimentation that xanthine derivatives 10 with alkyl substituents on the nitrogen and carbon atoms in the 1- and 8-positions respectively coupled with a cyclohexenylmethyl, furylmethyl, tetrahydrofurylmethyl or thienylmethyl substituent on the 3-position nitrogen atom possess outstanding pharmacological properties 15 useful in the treatment of respiratory and cardiovascular conditions.

The xanthine derivatives of the present invention are accordingly those compounds of the general formula: r\ i ! ; ί - 2 -Ο Η < X ί ,*3 τ ·

LoXJÎ ; 0 ΛΓ CH0 1 22

. - * R

13 . .

wherein R and R each represent an alkyl group contaming 2

frcsm 1 to 6 (preferably at most 4) carbon atoms, and R

représente a cyclohexenyl« furylt tetrabydrofuryl or 5 thienyl group, and pharmacologically acceptable salts thereof formed with an alkali métal or a nitrogen- containing organic base.

Preferred compounds of general formula I are 2 those wherein R represents a cyclohex-3-enyli 2-furyl* 1 3

10 2-tetrahydrofuryl or 2-thienyl group, and R and R

are as hereinbefore defined and, more particularly, those i wherein R"1" represents a methyl group. Of outstanding * interest are 1,8-dimethyl-3-(cyclohex-3-enyImethyl)- xanthine, 1,8-dimethyl-3-(2-furylmethyl)-xanthine, 15 l-methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine, l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine, 1.8- dimethyl-3-(2-tetrahydrofurylmethyl)-xanthine, l-methyl-3-(2-furylmethyl)-8-ethylxanthine and 1.8- dime thyl- 3- ( 2-thienylmethyl ) -xanthine 20 and, more especially, the two first-mentioned compounds.

l· i r . * - 3 -

According to a feature of the present invention» the xanthine derivatives of general formula I are prepared by cyclizing a uracil compound of the general formula: ‘ i 0 o

R II NHCO-R

.¾ CH~ I z Â2 12 3 (wherein R » R and R are as hereinbefore defined) by application of methods known per se» for example by heating with an aqueous solution of sodium or potassium hydroxide, preferably at the boiling point of the 10 reaction mixture. After acidification of the reaction mixture the xanthine product of the general formula I is isolated in manner known per se.

By the term "methods known per se" as used in this spécification and accompanying daims is meant .

•e 15 methods heretofore used or described in the literature.

The 5-acylamido-uracil starting materials of général formula II are obtained by reaction of a corresponding 5»6-diaminouracil of the general formula: h * # - 4 - ”>2 J-X .

Y ^ NH2 CH~ k22 * * 1 2 (wherein R and R are as hereinbefore defined) with a carboxylic acid of the general formula:

R3 - COOH IV

3 5 (wherein R is as hereinbefore defined) at a température between 100° and 180°C. An excess of acid must be used, and preferably at least two moles of carboxylic acid are employed per mole of 5f6-diaminouracil.

The 5t6-diaminouracils of general formula III 10 can be prepared from a corresponding 6-aminouracil of the general formula: 0 | NH2 CH, <2

R

f - 5 - 1 2 (wherein R and R are as hereinbefore defined) by reaction with a mixture of sodium nitrite and acetic acid at a température between 10°C and 80°C to give the corresponding 5-nitroso derivative, and réduction of the ;

5 5-nitroso compound with sodium dithionite in ammonium , ^ hydroxide aqueous solution at a température between 40°C

and 90°C to the diamino compound.

The 6-aminouracils of general formula V cart be prepared from the corresponding N,N*-disubstituted-urea 10 by methods known per se, e.g. V. Papesch and E.F. Schroeder, J. Org. Chem., 16, 1879-90, (1951).

The xanthine derivatives of general formula I are also prepared, according to a further feature of the present invention, from a corresponding 5,6-diaminouracil 15 of general formula III by heating with an excess of the anhydride of the corresponding carboxylic acid of general formula IV, preferably at the boiling point of that anhydride. In this case the 5-acylamido derivative of general formula II is not isolated as the xanthine 20 derivative of general formula I is obtained directly.

The xanthine products of general formula I obtained by the aforedescribed processes can be purified by application of methods known per se, for example by recrystallization from an organic solvent, e.g.

25 methanol, éthanol, isopropanol, tetrahydrofuran, dioxan or ethyl acetate.

h f - 6 -

The compounds of general formula I exhibit pharmacological properties useful in the treatment of respiratory and cardiovascular conditions such as bronchial asthma, reversible obstructive respiratory disease, and 5 obstructive peripheral and cardiac vascular disease. * * Thus they relax bronchial smooth muscle both :m vitro and in vivo and inhibit the bronchoconstriction induced by histamine, acétylcholine and other smooth muscle stimulants. Furthermore, this direct 10 bronchodilator activity is accompanied by inhibitory activity against the libération of histamine and other i autacoids in response to appropriate anaphylactic challenges. They also relax the smooth muscle of peripheral and coronary blood vessels resulting in vasodilation, an 15 increase in blood flow and a fall in blood pressure unaccompanied by tachycardia.

Stimulant effects on the central nervous System are minimal as are other xanthine-like actions such as the induction of diuresis.

20 Experiments hâve been carried out with some xanthine derivatives of the present invention in order to compare their pharmacological properties with those of theophylline and l-methyl-3-furfuryl-xanthine, a compound (referred to later herein as Compound i) prepared 25 by K.R.H. Wooldridge and R. Slack, J. Chem. Soc. 1962, 1863-1868, both compounds being related to the xanthine derivatives of general formula I but having no l· - 7 - substituent on the 8-position carbon atom.

The compounds of general formula I tested were · l*8-diinethyl-3-(2-furylmethyl)-xanthine (R"*· and R3 = CH3 and R = 2-furylî referred to in the following ‘ s 5 Tables as Compound 2): l-methyl-3-(2-furylmethyl)-8-ethylxanthine (R^ = CH^» 3 2 ‘ R = an^ R = 2-furyl; Compound 3); t 1,8-dimethyl-3-(cyclohex-3-enylmethyl)-xanthine 13 2 (R and R = CH^ and R = cyclohex-3-enyl; Compound 4); 10 l-methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine 13 2 (R = CH3* R = isoC3H7 and R = cyclohex-3-enyl;

Compound 5): 1i8-dimethyl-3-(2-tetrahydrofurylmethyl)-xanthine 13 2 (R and R = CH3 and R = 2-tetrahydrofuryl; Compound 6)î 15 l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine (R1 = CH3, R3 = -CH(CH3)CH2CH3 and R2 = tetrahydrofuryl; Compound 7)* and 1 *5 l«8-dimethyl-3-(2-thienylmethyl)-xanthine (R and R"' = CH3 2 and R = 2-thienyl; Compound 8).

20 The results obtained in the experiments with the various compounds are given in the following Tables.

(s\ - 8 - TABLE 1

Compound Antagonism Vasodilator Toxicity^’^ to histamine Activity(2) induced ; • 5 broncho- /, v constriction' .

Theophylline 5 + - 500 1 4 ++ s 1000 2 10 +++ >100<500 10 3 9 +++ >100<500 4 6 +++ >500 5 6 +++ >500 6 6 +++ >500 7 6 +++ >500 15 8 6 +++ >100 <500 (1) No. of guinea-pigs protected (group of 10) by 100 mg kg-1 p.os. of compound against the broncho-constrictor effects of enforced inhalation of nebulized histamine.

20 (2) Percentage réduction in peripheral résistance in the chloralose anaesthetised cat» + = 26-40; ++ = 41-55; +++ = 56-70: induced by 3 mg kg~·*· i.v.

(3) Approximate LDj-q values (mg kg-^ p.os.) in the mouse.

Table 2 gives a comparison of the bronchodilator 25 and antianaphylactic properties of the aforementioned specific compounds of general formula I with those of theophylline and Compound 1.

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

Pharmakol., 195, 71-74 (1940), 5 (2) Castillo, J.C. and De Beer, E.J., J. Pharmac.

Exp. Ther., 90, 104-109 (1947), . (3) Ovary, Z-, Ped. Proc., 24, 94 (1965), (4) Dale, M.M. and Zilletti, L., Br. J. Pharmac., < 39, 542-555 (1970).

10 It will be appreciated from the results of the experiments that the xanthine derivatives of general formula I with an 8-alkyl substituent are more active on the respiratory tract than the related xanthine compounds tested having hydrogen attached to the carbon atom in 15 position 8. Thus, for example, Compounds 2 to 8 (which are compounds of the invention) are more active against histamine-induced bronchoconstriction than the previously described Compound 1 and theophylline. The compounds of the invention are also effective in other bronchodilator 20 tests as well as in pharmacological models for antianaphylactic activity and again they are clearly more potent than theophylline as shown in Table 2.

The compounds of general formula I are also more active than theophylline as vasodilators (see 25 Table 1). This vascular activity is not accompanied by a corresponding positive chronotropic effect on the /1 - 11 - * \ heart, which makes the new compounds especially useful for treatment of obstructive cardiovascular. disease.

An additional advantage is that the compounds of general formula I hâve very long half-lives (e.g. > 5 Compounds 2 and 4 hâve mean half-lives in man of 52.8 and 13.2 hours respectively whereas the half-life of theophylline is only 3 hours).

In general the xanthine derivatives of général formula I will be useful for the treatment of obstructive 10 respiratory disease and asthma on the one hand« and cerebral or cardiac vascular insufficiency on the other.

The xanthine derivatives of general formula I may also form pharmacologically-acceptable salts with alkali metals or nitrogen-containing organic bases whose 15 salts are formed by reaction of the compounds of general formula I with an alkali métal hydroxide or a nitrogen-containing organic base using/ for example, water, methanol or éthanol as a solvent at a température between 40° and 100°C.

20 Also included within the scope of the present invention are pharmaceutical compositions which comprise, as active ingrédient, at least one compound of general formula I, or a pharmacologically-acceptable sait thereof as hereinbefore mentioned, in association with a 25 pharmaceutically-acceptable carrier or diluent. Preferably the compositions are made up in a form suitable for oral, h - 12 - \ rectal or parenteral administration.

The pharmaceutically-acceptable carriers or diluents which are admixed with the active compound or compounds or salts of such compounds to form the i i 5 compositions of this invention are well known per se and the actual excipients used dépend inter alia on the . § intended method of administration of the compositions.

Compositions of this invention are preferably adapted' for administration per os. In this case, the compositions 10 for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid préparations such as élixirs, syrups or suspensions, ail containing one or more compounds of the invention} such préparations may be made by methods well known in the art.

15 The diluents which may be used in the préparation of the compositions include those liquid and solid diluents which are compatible with the active ingrédient, together with colouring or flavouring agents if desired. Tablets or capsules may conveniently contain between 5 and 150 mg 20 and preferably from 10 to 50 mg of active ingrédient or the équivalent amount of a pharmacologically-acceptable sait thereof. The compounds may also be incorporated into pellets coated with appropriate natural or synthetic polymers known in the art to produce sustained release 25 characteristics or incorporated with polymers into tablet form to produce the same characteristics.

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- 13 -

The liquid compositions adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous or aqueous-alcoholic solutions , of a soluble compound or sait thereof in association ·* 5 with,;for example/ sucrose or sorbitol to form a syrup.

The suspensions may comprise an insoluble or micro-encapsulated form of an active compound of the r invention in association with water and other acceptable solvents together with a suspending agent or flavouring 10 agent.

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

15 In human therapy, the doses of the xanthine derivatives dépend on the desired effect and duration of the treatmentj adult doses are generally between 15 mg and 150 mg per day. In general the physician will décidé the posology taking into account the âge and weight 20 , intrinsic to the patient being treated.

h ' 9 t - 14 -

The following Examples illustrate the préparation of xanthine derivatives of the present invention.

EXAMPLE 1

To a suspension of l-methyl-3-(2-furylmethyl)-6- i 5 aminouracil (260 g; 1.175 moles) and sodium nitrite (90 g; 1.3 moles) in water (1870 ml), acetic acid (141.5 ml) was slowly added at a température of 20°C.

The mixture was stirred for 24 hours at this température and then the resulting insoluble l-methyl-3-(2-10 furylmethyl)-5-nitroso-6-aminouracil was collected by filtration, washed with water, then with diethyl ether and dried (292.5 g; yield 99.3%)7 its melting point was 223-225°C.

A mixture of this l-methyl-3-(2-furylmethyl)-5-15 nitroso-6-aminouracil (292.5 g; 1.169 moles) in concentrated ammonium hydroxide aqueous solution (4680 ml) was heated to 60°C and sodium dithionite (780 g; 3.71 moles) . added portionwise 7 the colour of the mixture changed from violet to pale yellow. After cooling, the precipitated 20 solid was collected by filtration, washed with water (4 litres), recrystallised from methanol, and dried to give l-methyl-3-(2-furylmethyl)-5,6-diaminouracil (208 g7 yield 75.3%), m.p. 168-170°c.

A mixture of this l-methyl-3- ( 2-f urylmethyl ) -25 5,6-diaminouracil (11.8 g? 0.05 moles) and propionic acid (18.5 ml7 0.25 moles) was boiled under reflux for 2 hours.

h ~ 15 - f

After cooling, a mixture of diethyl ether and isopropanol was added and l-methyl-3-(2-furylmethyl)-5-propionamido- 6-aminouracil crystallized (13 g; yield 89%). Its melting point after recrystallization from methanol was · 5 238-240°C.

* This compound (10 g? 0.0342 moles) was treated with a 2N sodium hydroxi de aqueous solution (50 ml) and the mixture boiled under reflux for half an hour. After cooling the resulting solution! dilute hydrochloric acid 10 was added until an acidic pH was attained and then the mixture was extracted with Chloroform. The organic solution was washed with watert decolorized* dried (Na2S0^) and the solvent removed in vacuo to dryness.

The solid residue was treated with diethyl ether and 15 collected by filtration to give l-methyl-3-(2-furylmethyl )- 8-ethylxanthine (7.2 g: yield TS.1%), m.p. 233-235°C (after recrystallization from éthanol).

Also prepared in a similar manner using the appropriate starting materials were 20 l|8-dimethyl-3-(2-furylmethyl)-xanthine! m.p.

280-282°C; l-methyl-3-( 2-furylmethyl )-8-sec-butylxanthine ! m.p. 128-129°Ct and l-methyl-3- ( 2-furylmethyl )-8-propylxanthine, m.p.

25 216-218°C.

h - 16 - * EXAMPLE 2 A solution of l-methyl-3-(2-furylmethyl)-5i6-diaminouracil (17.7 g; 0.075 moles) in acetic anhydride (150 ml) was boiled under reflux for 5 ' » 5 hours. After coolingi a solid crystallized which was collected by filtration and recrystallized from éthanol to give 1,8-dimethyl-3-(2-furylmethyl)-xanthine (14.2 g: yield 72.8%), m.p. 280-282°C.

EXAMPLE 3 10 A mixture of l-(cyclohex-3-enylmethyl)-3- methyl-5,6-diaminouracil (10 g; 0.04 mole) and glacial acetic acid (30 ml) was boiled under reflux for 2 hours.

The solvent was removed by distillation in vacuo and the solid residue was collected with diethyl ether 15 and filtered to give l-(cyclohex-3-enylmethyl)-3-methyl- 5-acetamido-6-aminouracil (11 gj yield 94%), m.p.

233-235°C.

This compound (11 g; 0.038 moles) was treated with a 10% sodium hydroxide aqueous solution (35 ml) 20 and the mixture boiled under reflux for half an hour.

After cooling the resuiting solution, dilute hydrochloric acid was added until pH 5 was reached, and the mixture was then extracted with Chloroform. The organic solution was washed with water, decolorized, dried (Na2S0^) and the 25 solvent removed in vacuo to dryness. The solid residue /λ / LS * f - 17 - was treated with diethyl ether and collected by filtration to give 1 *8-dimethyl-3- (cyclohex-3-enylmethyl)-xanthine (8.5 g; yield 82%)* m.p. 253°-255°C (after recrystallization from isopropanol). ; 5 Also prepared in a similar manner starting from the appropriate 5 * 6-diaminouracil and carboxylic acid were l*8-dimethyl-3-(2-tbienylmethyl)-xanthine* m.p. 297-299°Cî l-methyl-3- ( 2-tetrahydrof urylmethyl ) -8-sec-butylxanthine * 10 m.p. 112-114°C: l-methyl-3-(2-tetrahydrofurylmethyl)-8-ethylxanthine * m.p. 191-1930C: l-methyl-3-(2-tetrahydrofurylmethyl)-8-propylxanthine, m.p. 184-186°C; 15 l-methyl-3-(2-tetrahydrofurylmethyl)-8-isopropylxanthine, m.p. 177-179°C; l-methyl-3-(cyclohex-3-enylmethyl)-8-sec-butylxanthine * m.p. 153-155°Cï l-methyl-3-(2-tetrahydrofurylmethyl)-8-t-butylxanthine * 20 m.p. 193-195°Cï l-methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine * m.p. 201-203°Cî l-methyl-3-(cyclohex-3-enylmethyl)-8-propylxanthine * m.p. 202-204°Cî 2 5 l-methyl-3-(2-thienylmethyl)-8-sec-butylxanthine * m.p. 148-150°C; l-methyl-3-(2-tetrahydrofurylmethyl)-8-butylxanthine, /1 m.p. 156-158°C; * * ”, - 18 - l-methyl-3-(cyclohex-3-enylmethyl)-8-t-butylxanthine, m.p. 203-205°C; l-propyl-3-(2-tetrahydrofurylmethyl)-8-methylxanthine, m.p. 223-225°C, and 5 l-propyl-3-(cyclohex-3-enylmethyl)-8-methylxanthine, » m.p. 207-209°C.

EXAMPLE 4 A solution of 1-(2-tetrahydrofurylmethyl)-3-methyl-5z6-diaminouracil (12 g; 0.05 moles) in acetic 10 anhydride (100 ml) was boiled under reflux for 5 hours.

After cooling, a grey solid crystallized which was collected by filtration and recrystallized from éthanol to give 1,8-dimethyl-3-(2-tetrahydrofurylmethyl )-xanthine (9.3 g; yield 70.4%)/ m.p. 238-240°C.

15 EXAMPLE 5 A suspension of l/8-dimethyl-3-(2-furylmethyl)-xanthine (229 g; 0.88 moles) (prepared as described in Example 2) in 10% sodium hydroxide aqueous solution (1100 ml) was boiled under reflux until dissolution was complété. On 20 cooling, the sodium sait of 1,8-dimethyl-3-(2-furylmethyl)-xanthine (201 g: yield 81%) was obtained, m.p. >300°C.

The following Examples illustrate pharmaceutical compositions according the invention.

EXAMPLE 6 25 100,000 capsules each containing 100 mg of l-methyl-3-(2-furylmethyl)-8-ethylxanthine were prepared . i .

- 19 - from the following formulation: 1-methyl-3—(2-furylmethyl)-8- ethylxanthine 10 kg % lactose monohydrate 8 kg 5 corn starch 2 kg '* colloidal Silicon dioxide 1 kg ’ magnésium stéarate 2 kg

Procedure i

The above ingrédients were sieved through 10 a 60-mesh sieve, then mixed in a suitable mixer and filled into 1001000 gélatine capsules (230 mg).

EXAMPLE 7 1000 bottles of suspension (capacity 150 ml) each containing 1500 mg of 1/8-dimethyl-3-(2-furylmethyl)-15 xanthine were prepared as follows: li8-dimeth 1-3-(2-furylmethyl)-xanthine 1/500 g microcrystalline cellulose 1,500 g sodium carboxymethylcellulose 900 g 70% sorbitol aqueous solution 33/000 g 20 glycérine 4/500 g polysorbate 80 400 g sodium methyl p-hydroxybenzoate 240 g sodium propyl p-hydroxybenzoate 60 g anti-foam silicone 150 g 25 sodium Saccharin 300 g flavouring q- s.

demineralised water q.s. 150 litres

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- 20 -

Procedure Το a solution of the sodium methyl p-hydroxy-benzoate, sodium propyl p-hydroxybenzoate and sodium Saccharin in 30 litres of demineralised water, a wet-5 milled suspension of the sodium carboxymethylcellulose .» in glycérine was added. After stirring for 1 hour, i a suspension of the microcrystalline cellulose in 60 litres of demineralised water was added and then the sorbitol solution, polysorbate 80, l,8-dimethyl-3-(2-10 furylmethyl)-xanthine, anti-foam silicone and flavouring were successively added with stirring. The volume of the mixture was adjusted to 150 litres with demineralised water and the homogeneous suspension was filled into 150 ml bottles using an appropriate filling machine.

15 EXAMPLE 8 20,000 bottles of solution (capacity 150 ml) each containing 300 mg of 1,8-dimethyl-3-(cyclohex-3-enylmethyl)-xanthine were prepared as follows: 1,8-dimethyl-3-(cyclohex-3-enylmethyl)-20 xanthine 6 kg éthanol 45 kg •70% sorbitol aqueous solution 1,050 kg sodium Saccharin 3 kg sodium carboxymethylcellulose 60 kg 25 flavouring q.s.

demineralised water q.s. 3000 litres /1 - 21 - ' f ♦

Procedure A solution of the sodium carboxymethylcellulose in 1000 litres of water and 5 kg of éthanol was added to another solution of the 1#8-dimethyl-3-(cyclohex-3-5 enylmethyl)-xanthine in 40 kg of éthanol and 500 litres » of water at a température of 50°C. Then the sorbitol * solution# sodium saccharin and flavouring were added and the volume of the mixture was adjusted to 3000 litres with demineralised water. After filtration# the solution 10 was filled into 150 ml bottles using an appropriate filling machine.

EXAMPLE 9 10/000 suppositories each containing 150 mg of l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butyl-15 xanthine were prepared as follows: l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine 1#500 g theobroma oil 18#500 g

The theobroma oil was melted and the active 20 compound suspended in it. The mixture was then poured into appropriate suppository mould to make 2.0 g suppositories.

Instead of the xanthine derivatives specifically mentioned in Examples 5 to 8, there may be used in the 25 pharmaceutical formulations described any other xanthine derivative within the scope of general formula I# for example those compounds of that formula referred to in Examples 1 to 3.

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Claims (14)

1. Xanthine derivatives of the general formula: JL H R3 VVr CH k2 1 3 wherem R and R each represent an alkyl group contaming 2 from 1 to 6 carbon atoms, and R represents a cyclohexenyl, furyli tetrahydrofuryl or thienyl group, and pharmacologically-acceptable salts thereof formed with an alkali métal or a nitrogen-containing organic base.

2. Xanthine derivatives according to Claim 1 2 wherem R represents a cyclohexenyl, tetrahydrofuryl or 1 3 * thienyl group, and R and R are as defined in Claim 1, , and pharmacologically-acceptable salts thereof formed with an alkali métal or a nitrogen-containing organic base.

3. Xanthine derivatives according to 2 Claim 1 wherein R represents a cyclohex-3-enyl, 2-furyl, 2-tetrahydrofuryl or 2-thienyl group and R^ 3 and R are as defmed in Claim 1, and pharmacologically- f * t * - 23 - acceptable salts thereof formed with an alkali métal or a nitrogen-containing organic base.

4. Xanthine derivatives according to claim 1/ 2 or 3 wherein the alkyl group represented by R"*" and '* contains from 1 to 4 carbon atoms.

5. Xanthine derivatives according to claim 1# 2, 3 or 4 wherein R**" represents the methyl group. 6. 118-Dimethyl-3- ( cyclohex-3-enylmethyl ) - xanthine. 7. 1 / 8-Dime thyl-3- ( 2-f urylmethyl ) -xanthine. 8. l-Methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine. 9. l-Methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine. 10. li8-Dimethyl-3-(2-tetrahydrofurylmethyl)- xanthine. t 11. l-Methyl-3-(2-furylmethyl)-8-ethylxanthine. 12. 1/8-Dimethyl-3-(2-thienylmethyl)-xanthine.

13. Pharmacologically-acceptable salts of a compound claimed in any one of daims 5 to 12 formed with an alkali métal or a nitrogen-containing organic base. 14. l-Methyl-3-(2-furylmethyl)-8-sec-butyl-xanthine, l-methyl-3-(2-furylmethyl)-8-propylxanthine, l-methyl-3-(2-tetrahydrofurylmethyl)-8-ethylxanthine, l-methyl-3- ( 2-tetrahydrofurylmethyl ) -8-propylxanthine, l-methyl-3-(2-tetrahydrofurylmethyl)-8-isopropylxanthine, A «r - 24 - l-methyl-3-(cyclohex-3-enylmethyl)-8-sec-butylxanthine, l-methyl-3-(2-tetrahydrofurylmethyl)-8-t-butylxanthine, l-methyl-3-(cyclohex-3-enylmethyl)-8-propylxanthine, l-methyl-3-(2-thienylmethyl)-8-sec-butylxanthine, ‘ l-methyl-3-(2-tetrahydrofurylmethyl)-8-butylxanthine * ‘ l-methyl-3- ( cyclohex-3-enylmethyl ) -8-t-butylxanthine t l-propyl-3-( 2-tetrahydrofurylmethyl)-8-methylxanthine and ; l-propyl-3-(cyclohex-3-enylmethyl)-8-methylxanthine, and pharmacologically-acceptable salts of any such compound fomed with an alhali métal or a nitrogen-containing organic base.

15. A process for the préparation of a xanthine derivative as claimed in Claim 1 which comprises cyclizing a uracil compound of the general formula: O r1^ NHC0_r3 ch9 I2 R (wherein R1* R2 and R3 are as defined in Claim 1) by a method hnown per se.

16. A process according to claim 15 in which cyclization of the uracil compound is effected by heating /> with an aqueous solution of sodium or potassium hydroxide. » t - 25 -

17. A process for thé préparation of a xanthine derivative as claimed in Claim 1 which comprises heating a 5»6-diaminouracil of the general formula: > O : kX CH 1 2 (wherein R and R are as defined in Claim 1) with an excess of an anhydride of a carboxylic acid of the general formula: R3 - COOH 3 wherein R is as defined in Claim 1.

18. A process according to claim 15# 16 or 17 followed by the step of converting by a method known per se a xanthine derivative of the general formula : specified in claim 1 thus obtained into a pharmacologically- acceptable alXali métal sait or a sait with a pharmacologically-acceptable nitrogen-containing organic base.

19. Xanthine derivatives of the general formula specified in claim 1 and pharmacologically-acceptable / salts thereof with alkali métal and nitrogen-containing - 26 - V * f organic bases when prepared by the process claimed in any one of daims 15 to 18·.

20. Pharmaceutical compositions which comprise, as active ingrédient, a xanthine derivative as claimed in any .one of daims 1 to 12 and 14, or a pharmacologically-acceptable alkali métal sait thereof or a sait thereof formed witb a pharmacologically-acceptable nitrogen- ; containing organic base, in association with a pharmaceutically-acceptable carrier or diluent.

21. Pharmaceutical compositions according to daim 20 substantially as hereinbefore described with especial reference to Example 6, 7, 8 or 9.

22. Xanthine derivatives of the general formula specified in daim 1, and pharmacologically-acceptable salts thereof formed with an alkali métal or a nitrogen-containing organic base, for therapeutic use in the treatment of respiratory and cardiovascular conditions such as bronchial as'thma, reversible obstructive * respiratory disease and obstructive peripheral and cardiac vascular disease. \Mxu