NZ199340A - Xanthanide derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99340 1 9 9340 f»V•-if" S-B ' !& • #0? f 0 *,7; #/ r j iO'j y i • • ■ • ■ ■ ■ Corrspiets Specification Fiied:/<?.• Class: c°TPA7ty dkLKPJj.^....

PubEicaiLicn Date: 0.^. lr. 1994. . .

P.O< tic: ..

II ^ $ Wf M ^ Q li y l lips *21 DEC198I J ^ *j NEW ZEALAND N/3 4621- THE PATENTS ACT 1953 PATENTS FORM NO. 5 COMPLETE SPECIFICATION "XANTHINE DERIVATIVES" WE, FORDONAL S.A. , a Spanish Body Corporate, of Calle Lerida 9, 8° Madrid, Spain, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: -1- (followed by page la) 1 993 - 1<C-DESCRIPTION "XANTHINE! DERIVATIVES" This invention relates to new therapeutically useful xanthine derivatives* to processes for their preparation and pharmaceutical compositions containing them.

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

It has now unexpectedly been found after research and experimentation that xanthine derivatives 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 useful in the treatment of respiratory and cardiovascular conditions.

The xanthine derivatives of the present invention are accordingly those compounds of the general formula: 1 9 93 1 3 wherein R and R each represent an alkyl group containing 2 from 1 to 6 (preferably at most 4) carbon atoms* and R represents a cyclohexenyl* furyl* tetrahydrofuryl or thienyl group, and pharmacologically acceptable salts thereof formed with an alkali metal or a nitrogen- containing organic base .

Preferred compounds of general formula I are 2 those wherein R represents a cyclohex-3-enyl* 2-furyl* 1 3 2-tetrahydrofuryl or 2-thienyl group* and R and R are as hereinbefore defined and* more particularly* those wherein R^" represents a methyl group. of outstanding interest are l*8-dimethyl-3-(cyclohex-3-enylmethyl)- xanthine * 1 * 8-dimethyl-3-(2-furylmethyl)-xanthine * 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 and* more especially* the two first-mentioned compounds.

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: 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 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 specification and accompanying claims is meant methods heretofore used or described in the literature.

The 5-acylamido-uracil starting materials of general formula II are obtained by reaction of a corresponding 5#6-diaminouracil of the general formula: 199.7 1 2 (wherein R and R are as hereinbefore defined) with a carboxylic acid of the general formula: R3 - COOH IV 3 (wherein R is as hereinbefore defined) at a temperature 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 5,6-diaminouracil.

The 5t6-diaminouracils of general formula III can be prepared from a corresponding 6-aminouracil of the general formula: f 9 93 4 1 2 (wherein R and R are as hereinbefore defined) by reaction with a mixture of sodium nitrite and acetic acid at a temperature between 10°C and 80°C to give the corresponding 5-nitroso derivative# and reduction of the 5 5-nitroso compound with sodium dithionite in ammonium hydroxide aqueous solution at a temperature between 40°C and 90°C to the diamino compound.

The 6-aminouracils of general formula V can 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, ethanol# isopropanol# tetrahydrofuran# dioxan or ethyl acetate. . v»Y /" & 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 in vitro and in vivo and inhibit the bronchoconstriction induced by histamine« acetylcholine and other smooth muscle stimulants. Furthermore, this direct 10 bronchodilator activity is accompanied by inhibitory activity against the liberation of histamine and other 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 have 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 1) 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 1 99340 substituent on the 8-position carbon atom.

The compounds of general formula I tested were l,8-dimethyl-3-( 2-furylmethyl)-xanthine (R"1" and R3 = CH3 2 and R = 2-furyl; referred to in the following Tables as Compound 2); 1-methyl-3-(2-furylmethyl)-8-ethylxanthine (R^ = CH^» 3 2 R = <^2^ and R = 2-furyl; Compound 3) r 1i8-dimethyl-3-(cyclohex-3-enylmethyl)-xanthine 13 2 (R and R = CH^ and R = cyclohex-3-enyl; Compound 4); l-methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine 13 2 (R = R = isoC^H^ and R = cyclohex-3-enyl; Compound 5); 1,8-dimethyl-3-(2-tetrahydrofurylmethyl)-xanthine 13 2 (R and R = CH^ and R = 2-tetrahydrofuryl; Compound 6); l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine (R1 = CH3, R3 = -CH(CH3)CH2CH3 and R2 = tetrahydrofuryl; Compound 1), and 1 3 l»8-dimethyl-3-(2-thienylmethyl)-xanthine (R and R = CH3 2 and R = 2-thienyl; Compound 8).

The results obtained in the experiments with the various compounds are given in the following Tables. f 9934 TABLE 1 (1) No. of guinea-pigs protected (group of 10) by 100 mg kg~^" p.os. of compound against the broncho-constrictor effects of enforced inhalation of nebulized histamine. (2) Percentage reduction in peripheral resistance in the chloralose anaesthetised cat, + = 26-40; ++ = 41-55; +++ = 56-70: induced by 3 mg kg~^ i.v. (3) Approximate LD^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.

Compound Antagonism to histamine induced broncho- / ^* constriction Vasodilator Activity(2) (3) Toxicity The ophy11ine + ^ 500 1 4 ++ - 1000 2 +++ >100<500 3 9 +++ >100<500 4 6 +++ >500 6 +++ >500 6 6 +++ >500 7 6 +++ >500 8 6 +++ >100 <500 TABLE 2 Experimental Theophyl COMPOUND model Species line 1 2 3 4 6 7 8 (1) Konzett and Rossler Guinea-pig 6.5 2 4 0.7 2 .5 2 1.7 (2) Isolated tracheal chain (in vitro) Guinea-pig 7 2 4 1 6 7 2 3 (3) Passive cutaneous anaphylaxis Rat ++ ++ +++ +++ ++ ++ +++ +++ ++ (4) Schultz-Dale reaction in isolated ileum Guinea-pig _4 5jd0 _4 3x10 1x10" 4 3xl0"4 3xl0~5 -4 3x10 IxlO"5 _4 3x10 3xL0"5 (1) Approximate ED^q (mg kg i.v.) against bronchoconstriction induced by intravenous histamine (minimum 3 experiments). (2) Approximate ED,-q (Hg ml of organ bath fluid) for relaxation of tracheal smooth muscle (minimum 3 experiments). (3) Activity at 100 mg kg ^ p.os. against the PCA reaction induced by serum taken from rats sensitized to ovalbumin (groups of 12). (4) Molar concentration to inhibit both the induced contraction and the histamine released from ileum isolated from sensitized (ovalbumin) guinea pigs in response to a challenge with antigen (minimum 3 experiments). 1 993 4-0 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), (2) Castillo, J.C. and De Beer, E.J., J. Pharmac. Exp. Ther., 90, 104-109 (1947), (3) Ovary# Z., Fed. Proc., 24, 94 (1965), (4) Dale, M.M. and Zilletti, L., Br. J. Pharmac., 39, 542-555 (1970).

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 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 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 Table 1). This vascular activity is not accompanied by a corresponding positive chronotropic effect on the f 9 93 4 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 have very long half-lives (e.g.

Conqpounds 2 and 4 have 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 general 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 metal hydroxide or a nitrogen-containing organic base using, for example, water, methanol or ethanol as a solvent at a temperature between 40° and 100°C.

Also included within the scope of the present invention are pharmaceutical compositions which comprise, as active ingredient, at least one compound of general formula I, or a pharmacologically-acceptable salt 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, T 99340 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 5 compositions of this invention are well known per se and the actual excipients used depend 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 preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention? such preparations may be made by methods well known in the art. 15 The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, 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 ingredient or the equivalent amount of a pharmacologically-acceptable salt 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. 1 993 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 salt thereof in association 5 with, for example, sucrose or sorbitol to form a syrup. The suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with a suspending agent or flavouring 10 agent. derivatives depend on the desired effect and duration of the treatment; adult doses are generally between 15 mg and 150 mg per day. In general the physician will decide the posology taking into account the age and weight 20 intrinsic to the patient being treated.

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.

In human therapy, the doses of the xanthine 1 99340 The following Examples illustrate the preparation of xanthine derivatives of the present invention.

EXAMPLE 1 To a suspension of l-methyl-3-(2-furylmethyl)-6-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 temperature of 20°C. The mixture was stirred for 24 hours at this temperature and then the resulting insoluble l-methyl-3-(2-furylmethyl)-5-nitroso-6-aminouracil was collected by filtration/ washed with water, then with diethyl ether and dried (292.5 g; yield 99.3%); its melting point was 223-225°C.

A mixture of this l-methyl-3-(2-furylmethyl)-5-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; the colour of the mixture changed from violet to pale yellow. After cooling, the precipitated 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 g; yield 75.3%), m.p. 168-170°C.

A mixture of this l-methyl-3-(2-furylmethyl)-5,6-diaminouracil (11.8 g; 0.05 moles) and propionic acid (18.5 ml; 0.25 moles) was boiled under reflux for 2 hours. t 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. with a 2N sodium hydroxide 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 water, 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 76.7%), m.p. 233-235°C (after recrystallization from ethanol). appropriate starting materials were 20 1,8-dimethyl-3-(2-furylmethyl)-xanthine, m.p. 280-282°C; l-methyl-3-(2-furylmethyl)-8-sec-butylxanthine, m.p. 128-129°C, and l-methyl-3-(2-furylmethyl)-8-propylxanthine, m.p. 25 216-218°C.

This compound (10 g; 0.0342 moles) was treated Also prepared in a similar manner using the ff 99 16 EXAMPLE 2 A solution of l-methyl-3-(2-furylmethyl)- *6-diaminouracil (17.7 g: 0.075 moles) in acetic anhydride (150 ml) was boiled under reflux for 5 5 hours. After cooling, a solid crystallized which was collected by filtration and recrystallized from ethanol to give 1,8-dimethyl-3-(2-furylmethyl)-xanthine (14.2 g; yield 72.8%), m.p. 280-282°C.

EXAMPLE 3 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 gr yield 94%), m.p. 233-235°C. with a 10% sodium hydroxide aqueous solution (35 ml) 20 and the mixture boiled under reflux for half an hour.

After cooling the resulting 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 (Na2SO^) and the 25 solvent removed in vacuo to dryness. The solid residue This compound (11 gr 0.038 moles) was treated 1 9 934 0 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).

Also prepared in a similar manner starting from the appropriate 5,6-diaminouracil and carboxylic acid were l,8-dimethyl-3-(2-thienylmethyl)-xanthine, m.p. 297-299°C; l-methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine, m.p. 112-114°C; l-methyl-3-(2-tetrahydrofurylmethyl)-8-ethylxanthine, m.p. 191-193°C: l-methyl-3-(2-tetrahydrofurylmethyl)-8-propylxanthine, m.p. 184-186°C; 1-methyl-3-(2-tetrahydrofurylmethyl)-8-isopropylxanthine, m.p. 177-179°C: l-methyl-3-(cyclohex-3-enylmethyl)-8-sec-butylxanthine, m.p. 153-155°Ct 1-methyl-3-(2-tetrahydrofurylmethyl)-8-t-butylxanthine, m.p. 193-195°C t 1-methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine, m.p. 201-203°C: 1-methyl-3-(cyclohex-3-enylmethyl)-8-propylxanthine, m.p. 202-204°C; l-methyl-3-(2-thienylmethyl)-8-sec-butylxanthine, m.p. 148-150°Ct l-methyl-3-(2-tetrahydrofurylmethyl)-8-butylxanthine, m.p. 156-158°Ct 1993 4 0 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°Ci 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-5/6-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 ethanol to give 1,8-dimethyl-3-(2-tetrahydrofurylmethyl)-xanthine (9.3 g; yield 70.4%)/ m.p. 238-240°C.

EXAMPLE 5 A suspension of 1/8-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 complete. On 20 cooling/ the sodium salt 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 6 100/000 capsules each containing 100 mg of l-methyl-3-(2-furylmethyl)-8-ethylxanthine were prepared from the following formulation: l-methyl-3-(2-furylmethyl)-8- ethylxanthine 10 kg lactose monohydrate 8 kg corn starch 2 kg colloidal silicon dioxide 1 kg magnesium stearate 2 kg Procedure The above ingredients were sieved through a 60-mesh sieve, then mixed in a suitable mixer and filled into 100,000 gelatine capsules (230 mg).

EXAMPLE 7 1000 bottles of suspension (capacity 150 ml) each containing 1500 mg of 1,8-dimethyl-3- (2-f urylme thy1)- xanthine were prepared as follows: 1,8-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 glycerine 4, 500 g polysorbate 80 400 g sodium methyl p-hydroxybenzoate 240 g sodium propyl p-hydroxybenzoate 60 g anti-foam silicone 150 g sodium saccharin 300 g flavouring q.s • demineralised water q.s. 150 litres 1 9 93 Procedure To a solution of the sodium methyl g-hydroxy-benzoate, sodium propyl ]D-hydroxybenzoate and sodium saccharin in 30 litres of demineralised water/ a wet-5 milled suspension of the sodium carboxymethylcellulose in glycerine was added. After stirring for 1 hour, a suspension of the microcrystalline cellulose in 60 litres of demineralised water was added and then the sorbitol solution/ polysorbate 80/ 1,8-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 /000 bottles of solution (capacity 150 ml) each containing 300 mg of 1/8-dimethyl-3-(cyclohex-3-enylmethyl)-xanthine were prepared as follows: 1i8-dimethyl-3-(cyclohex-3-enylmethyl)- xanthine 6 kg ethanol 45 kg 70% sorbitol aqueous solution 1/050 kg sodium saccharin 3 kg sodium carboxymethylcellulose 60 kg flavouring q.s. demineralised water q.s. 3000 litres 1 9 93 4 0 Procedure A solution of the sodium carboxymethylcellulose in 1000 litres of water and 5 kg of ethanol was added to another solution of the 1,8-dimethyl-3-(cyclohex-3-5 enylmethyl)-xanthine in 40 kg of ethanol and 500 litres of water at a temperature 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 /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. 1 99340

Claims (22)

WHAT WE CLAIM IS:-

1. Xanthine derivatives of the general formula: 13 . . wherein R and R each represent an alkyl group containing 2 from 1 to 6 carbon atoms, and R represents a cyclohexenyl, furyl, tetrahydx"ofuryl or thienyl group, and pharmacologically-acceptable salts thereof formed with an alkali metal or a nitrogen-containing organic base.

2. Xanthine derivatives according to claim 1 2 ! wherein 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 metal 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 defined in claim 1, and pharmacologically- 1 9 9<*5 - 23 - acceptable salts thereof formed with an alkali metal or a nitrogen-containing organic base.

4. Xanthine derivatives according to claim 1/ 1 3 2 or 3 wherein the alkyl group represented by R and R 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. 1,8-Dimethyl-3-(cyclohex-3-enylmethyl)- xanthine.

7. 1,8-Dimethyl-3-(2-furylmethyl)-xanthine.

8. l-Methyl-3-(cyclohex-3-enylmethyl)-8-isopropylxanthine.

9. l-Methyl-3-(2-tetrahydrofurylmethyl)-8-sec-butylxanthine.

10. 1,8-Dimethyl-3-(2-tetrahydrofurylmethyl)- xanthine. I

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 claims 5 to 12 formed with an alkali metal 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, 19934 - 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, l-propyl-3-(2-tetrahydrofurylmethyl)-8-methylxanthine and l-propyl-3-(cyclohex-3-enylmethyl)-8-methylxanthine, and pharmacologically-acceptable salts of any such compound formed with an alkali metal or a nitrogen-containing organic base.

15. A process for the preparation of a xanthine derivative as claimed in claim 1 which comprises cyclizing a uracil compound of the general formula: 0 R1 Ji / NHCO-R3 N I ch~ '2 R 12 3 (wherein R , R and R are as defined in claim 1) by a method known 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. 1 1 9 93^ - 25 -

17. A process for the preparation of a xanthine derivative as claimed in claim 1 which comprises heating a 5t6-diaminouracil of the general formula: 0 R2: 11 ^ NH N ■k. 2 0^ ^2 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 - C00H 3 wherein R is as defined in claim 1. i

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 alkali metal salt or a salt 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 metal and nitrogen-containing 199340 - 26 - organic bases when- prepared by the process claimed in any one of claims 15 to 18.

20. Pharmaceutical compositions which comprise, as active ingredient, a xanthine derivative as claimed in any one 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, in association with a pharmaceutically-acceptable carrier or diluent.

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

22. Xanthine derivatives of the general formula specified in claim 1, and pharmacologically-acceptable salts thereof formed with an alkali metal or a nitrogen-containing organic base, for therapeutic use in the treatment of respiratory and cardiovascular conditions such as bronchial asthma, reversible obstructive respiratory disease and obstructive peripheral and cardiac vascular disease. DATED THIS ^ ( S^ DAY OF J>ecrc^u_^l9 ^ A. J. PARK & SON PER O/- AGENTS FOP. THE APPLICANTS H