DK169336B1 - 1-Hydroxyalkylxanthines, Methods of Preparation and Pharmaceutical Preparations Containing Such Compounds - Google Patents

Abstract

Compound of formula: <IMAGE> or a physiologically acceptable salt of this compound, in which formula R1 is a C2-C5 omega -hydroxy-n-alkyl or C3-C5 ( omega -1)-hydroxy-n-alkyl, R3 is a C1-C4 alkyl group, R8 is H, methyl or ethyl, and the sum of the carbon atoms in R1 and R3 is between 4 and 9. Pharmaceutical composition containing this compound.

Description

in DK 169336 B1

The invention relates to novel 1-hydroxyalkylxanthines, processes for their preparation and pharmaceutical compositions containing them.

EPO Patent No. 39,780 relates to 1,3- or 5 1,3,8-substituted xanthines with sedative and anxiolytic properties. These compounds were developed to enhance or specify certain therapeutically useful physiological effects of natural xanthines such as caffeine or theophylline. The compounds of the above patent, despite indisputable neuroleptic and anxiolytic properties, exhibit side effects, especially of cardiovascular nature. In contrast, the heart-stimulating activity of the compounds of the invention has in itself opened up a new field of research in this direction.

U.S. U.S. Patent No. 2,517,410 discloses hydroxyalkylxanthines having at least one unsubstituted nitrogen atom. The compounds are described as useful and improved therapeutic compounds without any actual indication of the improvement achieved by the therapeutic use of the compounds.

Surprisingly, it has now been found that the compounds of this invention exhibit superior inotropic activity over similar compounds 25 known from the foregoing, as well as with theophylline.

Accordingly, the compounds of this invention are peculiar in that they are described by the following general formula: wherein:

R 1 represents a C 2 C 5 ω-hydroxy-n-alkyl group or a C 3 -C 5 (co-1) -hydroxy-n-alkyl group; R 3 represents a C 1 -C 4 alkyl group; R8 represents H, methyl or ethyl; and the sum of the number of carbon atoms in R-1 and R 3 is between 4 and 9, 15 or is physiologically acceptable salts thereof.

The following compounds are more fully encompassed by the invention: 1- (2-Hydroxyethyl) -3-propylxanthine, 1- (2-Hydroxyethyl) -3-isobutylxanthine, 1- (2-Hydroxyethyl) -3-isobutyl-8-methylxanthine, 1 - (2-Hydroxypropyl) -3-propylxanthine, 1- (2-Hydroxypropyl) -3-propyl-8-methylxanthine, 1- (2-Hydroxypropyl) -3-butylxanthine, 1- (3-Hydroxypropyl) -3- propylxanthine, 1- (3-Hydroxypropyl) -3-propyl-8-methylxanthine, 1- (3-Hydroxypropyl) -3-propyl-8-ethylxanthine, 1- (3-Hydroxypropyl) -3-butylxanthine, 1- ( 3-Hydroxypropyl) -3-isobutylxanthine, 1- (3-Hydroxypropyl) -3-isobutyl-8-methylxanthine, 1- (3-Hydroxybutyl) -3-methylxanthine, 1- (3-Hydroxybutyl) -3-ethylxanthine 1- (3-Hydroxybutyl) -3-ethyl-8-methylxanthine, 1- (3-Hydroxybutyl) -3-propylxanthine, 1- (3-Hydroxybutyl) -3-isobutylxanthine, 1- (4-Hydroxybutyl) ) -3-Ethylxanthine, 1- (4-Hydroxybutyl) -3-propylxanthine, 1- (4-Hydroxybutyl) -3-propyl-8-methylxanthine, 1- (4-Hydroxybutyl) -3-butylxanthine, 1- ( 4-Hydroxybutyl) -3-isobutyl-8-methylxanthine, 1- (4-Hydroxypentyl) -3 -methylxanthine, 1- (4-hydroxypentyl) -3-propylxanthine, 1- (5-hydroxypentyl) -3-methylxanthine, 1- (5-hydroxypentyl) -3-propylxanthine, and 1- (5-hydroxypentyl) -3 -propy1-8-methylxanthine.

Physiologically acceptable salts of the compounds of general formula I are understood to be salts which these compounds form with pharmaceutically acceptable bases. The salts mentioned are those in which the cations are harmless to animal organisms and do not produce side effects in therapeutic doses. Such salts include salts of alkali metals such as sodium and potassium, pharmaceutically acceptable salts of ammonium and amines known to those skilled in the art. These salts are prepared by heating the compound of general formula I in the presence of the relevant base and in the presence or absence of a solvent, preferably followed by recrystallization.

The compounds of the invention are prepared by a process which is characterized by the characterizing part of claim 3, and in more detail as follows: DK 169336 B1 4 A) A uracil compound of the following formula 59 is allowed. h-nVnh-cr «<1J:> R 3 is reacted with an alkylating agent of formula R 1 -X X wherein R 1, R 3 and R 8 are as defined by the general formula I, however, R 1 does not represent ω-hydroxybutyl, and wherein X is halogen, preferably bromine, monosulfate, disulfate or p-toluenesulfonate, in a solvent suitable for all the reactants, such as e.g. dimethylformamide (DMF), dimethylsulfoxide (DMSO) or hexamethylphosphoric triamide (HMPT), at a temperature in the range of 20-40 ° C, and in the presence of an alkali metal hydroxide, e.g. solid sodium hydroxide. The reaction is preferably carried out in DMF at 20 ° C according to the following reaction scheme: 25 x. The product of general formula III is then cyclized at 20-100 ° C in a solution of an alkali metal hydroxide according to the following reaction scheme:

0 S 0 H

RiVy hh-c-rs riVV \ _, (I) 10 r3 r3

Although it is possible to isolate the derivative of the general formula III, it is preferable to carry out the cyclization directly without isolating or purifying the said derivative. To this end, the reaction mixture is neutralized and the solvent evaporated, then the residue is dissolved in a solution of an alkali hydroxide and heated to reflux.

B) In a variant of this process, the uracil compound (II) is alkylated with an agent containing a function which can be converted to a hydroxy group, e.g. a -C00R4 function, in accordance with the following reaction scheme: DK 169336 B1 6

O J

H. JL / NH-C-R.

N | f

ANX. + X-1CH, -COO-R, cr | NH2 y R3 O o - »R4-OOC- (CH2) y ^ NA ^ NH-C-R8 10 o i nh2 * 3

IV

Wherein Rg, Rg and X are as defined above, y is a number between 1 and 4 and R4 represents an alkyl group. The reaction of this alkylation is similarly carried out under A) in a solvent suitable for all the reactants, such as DMF, DMSO or HMPT, at a temperature of 20-40 ° C, and 20 in the presence of a solid alkali metal hydroxide. The alkylation step is followed by cyclization and simultaneous hydrolysis of the ester (IV) at 20-100 ° C, in a solution of an alkali metal hydroxide according to the following reaction scheme: 25 7 DK 169336 B1

0 O

R4-OOC- ^ Vy ^ N NH-C-Rg σ in NH, ->

5 R

R3

1 H

HOOC- (CH) vn ^ V

η ^ Λί

0 I

R3 (V) 15

Although it is possible to directly reduce the acid (V) to an alcohol, it is preferable to re-esterify the acid with an alcohol such as methanol, ethanol or propanol under reflux to obtain the corresponding ester, which is then reduced according to the prior art, f. eg. in the presence of LiAlH 4 in THF to give the following product of the invention: 25 Oj HO-CH, - <CH

It can be seen that in this second embodiment of the process according to the invention, ω-hydroxyalkylxanthines are always obtained.

(5) DK 169336 B1 C) In a final embodiment of the process according to the invention (oo-1) -hydroxyalkylxanthines are prepared by alkylating the uracil compound (II) 0 9 0 * V 2 NH, (II> R 3 10 with an alkylating agent). means of formula R5-X wherein R3, Rg and X are as defined above and R5 represents a C3-C5 (ω-1) alkenyl group. The alkylation reaction 15 is carried out under the same conditions as under A) and B), a solvent suitable for all reactants, such as DMF, DMSO or HMPT, at a temperature in the range of 20-40 ° C and in the presence of an alkali metal hydroxide in solid form. Then the intermediate product is cyclized at 20-100 ° C in a solution of an alkali metal hydroxide according to the following reaction scheme:

25 «e l | H

8 \ V \ _s 0 9 NH2 l (VI)

Rj r3 30

The final step involves hydration of the double bond in R5 by a Markovnikov type addition reaction. This addition can be performed in two ways: 35 9 DK 169336 B1

Method A: Using dilute sulfuric acid at a temperature of approx. 100 ° C over several days.

Method B: In the process of reductive oxymercuration 5-demercuration in the presence of mercury silver acetate and then NaBH4 (Larock, R.C.: Solvomercuration / Demercuration Reactions in Organic Synthesis, Springer Verlag, Berlin, 2986, Chapter 2).

10

The invention also relates to a pharmaceutical composition which is characterized by the characterizing part of claim 4.

The composition of the invention may be in 15 different pharmaceutical forms containing usual excipients or carriers, such as tablets, capsules, suppositories, solutions, suspensions, and must be administered orally, sublingually, rectally, subcutaneously, intramuscularly, intravenously or by inhalation.

Before the real examples of synthesis of the compounds of the invention, we should mention that Table 1 below shows the preparation methods and the alkylating agent for use for 27 compounds of the invention. Table II shows the melting point and solvent for recrystallization of the same 27 compounds, and Table III shows 13 C NMR data.

10 DK 169336 B1

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U 00 (1) U U U I I I I I I

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11 DK 169336 B1

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C C S 3 3 C C

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3> i 3 A S, 3 φ -H -H -H -H P

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TABLE II

12 DK 169336 B1

Xanthine No. Snip (° C) Solvent for Recrystallization 1 178-179 Acetone 2 200-202 Acetone 3 227-229 Chloroform 10 4 150-152 Chloroform 5 196-197 Methanol 6 157-158 Water 7 145-146 Methanol 8 221 -222 Methanol 15 9 196-198 Water 10 111-112 Water 11 159-160 Acetone 12 248-250 Ethanol 13 200-201 Acetone 20 14 217-218 Water 15 212-213 Water 16 163-164 Acetone 17 141-142 Acetone 18 207-208 Water 25 19 173-174 Acetone 20 192-193 Water 21 122-123 Acetone 22 211-212 Methanol 23 180-181 Acetone 30 24 153-154 Acetone 25 190-191 Water 26 152-252 Water 27 184- 185 Dioxane 35 13 DK 169336 B1

CN

•

ONE

r, 00 M% *

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3 Η Η Η ΉΗΗ iHrH ΗΗΗΗ Ή Ή »-H

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ft nr σι ω νΊβ β «· π« | νιη «oon co t— nr oo ιο io io nr io <f n g ··· · * ·,.«. ·· ..... ..... ·. ...

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l_l tlC CM CM CM CM CM φ ιΟΟ Λ O ID VO COCOCO

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^ 1 ® CMCMCM LClLn ^ lClLflLD O ID IO ID IO CM CO CO CO CM CO CO CM CM CM

Φ + J OIOIOI f "01 ^ Q J.-IHOIOI CM CM CM CM CM CN No ΙΛ ΙΛ CN CM cH No No No µ η m ·····,.» ··· ..... .. ... ·· ...

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Em to Ό _ 1 00 0 I nr co co inn * «» m in nr m cn o nr to m in ro o in m in o nr nr ro nr in ρλ r) * ·· ··· *. »* · · · »··· · · · · · ·· · ♦ · s ^ o OOOOO οοιΛΟΟιΟ ooooo ooooo ooooo 2 n? nr in nr in ^ nr m in nr ro in m · nr <λ> r nf mvi / ιμιπ nr nr nr in QH ri ri rlrlrl η Η Η H ι-l rlrlrlHrl rlrlHHrl H ri ri ri ri _ * nr nr 00 eoifl CM 00 σι CO rM IO CO CO Γ- CO CM O CO CO CO ID CM CM CM CM ΓΦ m no nr co nrnrna1 .r ro co nr nr co nr nr ro nr nr nr nr co nr co nr nr nr co Ό I iQ (5 i 2 2 2 mmmm in in mminmin m in in in in in in) J] jn

TQ O rlHrl ri ri H 34 r-H. — I.— I.— I.— I H ri ri ri ri ri ri ri ri H HH HHH

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c ........... · ........... · ..

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• 222 229 ο o ο o ο o ooooo ooooo oo 292

H HHH Η H rl r | rt Η Η Η Η Η H ri rl rl H —I »H rH HHH

Π in V

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g 5-1 HHH H rl rl ^ rl r | rl rl Η Η rl Η H rl rl rl rl l H HHH

Di C oo o o O o o vor> i- i- co co σι «τ nr t— oo co so in» o co σι so σι io in

ft CM OHH HHH O O O O Ο O OOOOO OOOOO O O OOO

to 3 i 222 222 m in in m in m in m in m in 2 2 2 2 2 22 2 2 2

___Q (-Il-Il — I HHH rl H rl rl Η H i — I rH rl i — I i — I I — I 1-1 H rl rH Η H HHH

id +> ·

Id ft Ό 3 n> r * Or — ICNCOnTintØI— COO'OrHCNfOM'insOr- K C H CM Γ0 nr m ID ^ CO σ rH 3 rH rH rH rH rH H rH H CM CN CM CM CM CMCMCM 1

A

1 +> u c co id h in 14 DK 169336 B1

The invention is illustrated by the following Examples in which amounts are by weight unless otherwise indicated.

Example 1 1- (5-Hydroxypentyl) -3-propyl-8-methylxanthine (Method A: xanthine no. 27) 22.6 g (0.1 mole) of 1-propyl-5-acetylamino are suspended under nitrogen. 6-aminouracil (II) (R 3 = methyl,

Rq = methyl) in 200 ml of anhydrous dimethylformamide (DMF).

21.7 g (0.13 mole) of 5-bromo-1-pentanol are added and then stirred 6 g (0.15 mole) of powdered solid NaOH, 1 g at a time, at one hour intervals. After the third addition, the suspension changes to a solution. The solution is left overnight to complete the reaction, after which the solvent is evaporated in a rotary evaporator at 40 ° C / 0.1 mm Hg. The 20 oily residue, constituting the uracil compound (III) (R 2 = 5-hydroxypentyl, R 3 = propyl, R g = methyl), which is not purified, is dissolved in 100 ml of 10% NaOH and the solution is heated under reflux for two hours. then cool in an ice bath and neutralize to pH 5 with acetic acid. The precipitated product is filtered off, washed with cold water and dried in a vacuum oven. The dried product is dissolved in 500 ml of ethanol and the solution is decolorized overnight with activated charcoal. The product is precipitated by adding one liter of water, filtering and repeating the activated charcoal treatment. The dried product is recrystallized twice from 120 ml of dioxane. Yield: 23.5 g (80%); colorless crystals; mp. 184-185 ° C.

35 DK 169336 B1 15

Example 2 1- (4-Hydroxybutyl) -3-butylxanthine (Method B: xanthine no. 21)

11.3 g (0.05 mole) of 1-butyl-5-formylamino-6-aminouracil (II) (+ = butyl, R ) ethyl 4-bromobutyrate and then 2 g (0.05 mol) of solid NaOH in 10 powder form with thorough stirring in 0.5 g portions at one hour intervals. When the addition is over, the mixture is allowed to react overnight, then the solvent is evaporated and the oily residue of (IV) (substituent at the 1 position = 15 (CH 2) 3 COOEt) dissolved in 100 ml of 10% NaOH. This solution is heated at reflux for half an hour, then cooled, neutralized to pH 5 with acetic acid and filtered. The formed precipitate is dried. Yield: 9.2 g (60%) of crude xanthine (V) (substituent at the 1-position = 20 (CH 2) 3 COOH, R 3 = butyl, R g = H).

Without purification, the product is refluxed for five hours with 200 ml of methanol containing 1 ml of concentrated sulfuric acid. The solution is concentrated to a small volume and 50 ml of water is added. The resulting ester precipitate (substituent at the 1-position = (CH 2) 3 COOMe) is filtered, washed and dried. Yield: 9 g (93%).

Without purification, this product is dissolved in 200 ml of anhydrous tetrahydrofuran (THF), cooled to 0 - -10 ° C and added dropwise to a solution containing 2.13 g (0.056 mol) of LiAlH 4 in 150 ml of anhydrous THF. After complete addition, the mixture is allowed to react for two hours at 0 ° C, and excess LiAlH 4 is destroyed by the addition of 20 ml of water. The mixture is acidified to pH 2 with concentrated HCl and then evaporated THF. The remaining aqueous solution is extracted continuously with dichloromethane overnight. The slightly discolored solid residue (6.1 g) is twice recrystallized from acetone. Yield: 4.6 g (33% from II); colorless crystals; mp. 122-123 ° C.

5

Example 3 1- (3-Hydroxybutyl) -3-isobutylxanthine (Method C / Variant A, xanthine no. 17)

11.3 g (0.05 mole) of 1-isobutyl-5-for-mylamino-6-aminouracil (II) (R3 = isobutyl, Rg = H) are dissolved in 220 ml of DMF. 8.8 g (0.065 mole) of 4-bromo-1-butene is added and then 3 g (0.075 mole) of powdered NaOH is added while stirring in 0.5 g portions at one hour intervals. The mixture is left overnight, after which the solvent is evaporated under vacuum. The crude residue (R5 = 3-butenyl) is dissolved in 100 ml of 10% NaOH and heated at reflux for half an hour, then the solution is cooled and neutralized to pH 5 with acetic acid, the precipitate formed is filtered off and dried. 8.5 g of crude product (VI) are obtained (R5 = butenyl, Rg = isobutyl, Rg = H). This product is purified by passing through a silica column (85 g) with chloroform 25 as the eluent: 6.5 g of colorless product.

A mixture containing 6 g of the above compound is heated in 100 ml of 20% sulfuric acid to 100 ° C for four days, then cooled and neutralized to pH 5 with 50% KOH. The solution is evaporated to dryness, the residue is dissolved in 100 ml of boiling anhydrous ethanol and the insoluble fraction is filtered off. The filtrate is freed from the solvent to give a colored solid residue (6.4 g) which is passed through a silica column (650 g) eluting with a chloroform / methanol gradient (0-5% methanol). The xanthine is recrystallized twice from acetone. yield: 4.5 g (33% 17 based on II); snip. = 141-142 ° C.

Example 4 1- (2-Hydroxypropyl) -butylxanthine (Method C: Variant B / xanthine No. 6)

16 g (0.050 mole) of mercury (II) acetate are dissolved in 250 ml of water. 12.4 g (0.05 mole) of 1-allyl-3-butyl xan-10 (prepared as described above from 1-butyl-5-formyl-amino-6-aminouracil and allyl bromide) dissolved in 250 ml of THF are added. dropwise with stirring over ten minutes. After a few minutes, a precipitate is formed and stirring is continued for 30 minutes, after which the mixture is cooled in an ice bath. 68 ml of 3 N NaOH is added and then 60 ml of a freshly prepared 0.5 M solution of NaBH 4 in 3 N NaOH is added dropwise. After this addition, stirring is continued for a further 15 minutes, then the solution is neutralized to 20 pH 4-5 with 6 N HCl (about 60 ml), saturated with NaCl and the xanthine is extracted with dichloromethane (3 x 200 ml). The organic extract is dried and the solvent evaporated; 12.9 g of crude product containing 20% of starting product.

The products are separated by passing a mixture of silica column with chloroform as the eluant for the starting product and chloroform / methanol (95/5) for the hydroxylated xanthine (9.5 g). The xanthine is recrystallized twice from water: 8.5 g 30 (64%); mp. 157-158 ° C.

Example 5

It has been found that the compounds (I) of the invention exhibit low toxicity and that they have no or little effect on the central nervous system. In contrast, they were found to be active in in vitro assays for inotropic (cardiotonic) activity. Table IV shows the results of these tests.

TABLE IV

19 DK 169336 B1

Xanthine No. Cardiotonic Activity ^) (minimum effective concentration in µg / ml to achieve a significant response) 1 1 10 2 2'5 3 2 4 3.3 5 0.6 6 4 · 2 15 7 1 · 3 8 4 · 2 9 2 10 ° · 4 11 ° · 7 20 12 0.5 13 50 14 0.8 15 O · 6 16 0 · 1 25 17 1.3 18 3.3 19 ° · 4 20 O · 7 21 2 30 22 25 23 33.3 24 0.7 25 6 · 7 26 O · 2 35 27 ° * 3 DK 169336 B1 20

comparisons

Theophylline 15

Amrinon2) 100 5 Milrinon2) 0.5 IBMX3) 0.5 1) Measurement of contraction force on an isolated and electrically stimulated left ear muscle from a guinea pig in accordance with Erjavek, F. and Adamic, S., Arch.

Int. Pharmacodyn, 155: 251, 1965. A response is considered significant when the initial concentration power is increased by more than 40%.

2) Prior art cardiostimulant preparation.

3) 1-Methyl-3-isobutylxanthine.

20

Claims (5)

R 1A * XVR8 (I> 3) wherein r 1 represents a C 2 -C 5 ω-hydroxy-n-alkyl group or a C 3 -C 5 (ω-1) hydroxy-n-alkyl group; R 3 represents a C 1 -C 4 alkyl group; Rø represents H, methyl or ethyl, and the sum of the number of carbon atoms in Rj and R3 is between 4 and 9, or is a physiologically acceptable salt of this compound. 1 X /) - “» <V> In R 3, the compound (V) thus obtained esterifies and reduces the ester thus obtained to form compound (I), wherein R 1 represents the group - (CH 2) γ-CH 2 OH, or C) leaving a compound of the general formula: 0 i? O (N) 2 (11) * 3 is reacted with an alkylating agent of the general formula R5-X, wherein Rg, Rq and X are as defined above and Rg represents a C3-Cg alkenyl group, compound at 20-100 ° C in an alkali metal hydroxide solution, the double bond in R5 hydrates by a Markovnikov type addition reaction to form (I), denoting a C3-C5 (co-1) hydroxy-n-alkyl group. 1 I '/ 8 (I) In R3 wherein Represents a C2-C5 ω-hydroxy-n-alkyl group or a C3-C5 (ω-1) hydroxy-n-alkyl group; R 3 represents a C 1 -C 4 alkyl group; Rg represents H, methyl or ethyl; and the sum of the number of carbon atoms in R 1 and R 3 is between 4 and 9, or a physiologically acceptable salt of this compound, characterized by A) leaving a uracil compound of the following formula 50? * k nA / NH-C-H8 o ^ n '^ nh, (ii> I 2 R3 10 react with an alkyl end agent of the formula R ^ x, wherein R 1, R 3 and R 9 are as defined above, but RL is not ω-hydroxybetyl, and X represents halogen, monosulfate, disulfate or p-toluenesulfonate, and 15 cycles the compound thus obtained at 20-100 ° C in an alkali metal hydroxide solution, or B) leaves a compound of the general formula: 20 T>? (II) E3 reacts with an alkylating agent of the general formula X- (CH2) y-COO-R4 wherein R3, Rg and X are as defined above, y is a number between 1 and 4 and R4 represents a alkyl group, the compound obtained rings in aqueous alkaline medium to give the following compound: 35 DK 169336 B1 0 η 1! H HOOC- (CH Compound according to claim 1, characterized in that it is selected from: 1- (2-Hydroxyethyl) -3-propylxanthine, 1- (2-Hydroxyethyl) -3-isobutylxanthine, 1- (2-Hydroxyethyl) -3-isobutyl-8-methylxanthine, 1- (2-Hydroxypropyl) -3-propylxanthine, 1- (2-Hydroxypropyl) -3-propyl-8-methylxanthine, 1- (2-Hydroxypropyl) -3-butylxanthine 1- (3-Hydroxypropyl) -3-propylxanthine, 1- (3-Hydroxypropyl) -3-propyl-8-methylxanthine, 1- (2-Hydroxypropyl) -3-propyl-8-ethylxanthine, 1- (3- Hydroxypropyl) -3-butylxanthine, 1- (3-Hydroxypropyl) -3-isobutylxanthine, DK 169336 B1 1- (3-Hydroxypropyl) -3-isobutyl-8-methylxanthine, 1- (3-Hydroxybutyl) -3-methylxanthine, 1- (3-Hydroxybutyl) -3-ethylxanthine, 1- (3-Hydroxybutyl) -3-ethyl-8-methylxanthine, 1- (3-Hydroxybutyl) -3-propylxanthine, 1- (3-Hydroxybutyl) -3 -isobutylxanthine, 1- (4-Hydroxybutyl) -3-ethylxanthine, 1- (4-Hydroxybutyl) -3-propylxanthine, 1- (4-Hydroxybutyl) -3-propyl-8-methylxanthine, 1- (4-Hydroxybutyl) ) -3-Butylxanthine, 1- (4-Hydroxybutyl) -3-isobutyl-8-methylxyl hin, 1- (4-Hydroxypentyl) -3-methylxanthine, 1- (4-Hydroxypentyl) -3-propylxanthine, 1- (5-Hydroxypentyl) -3-methylxanthine, 1- (5-Hydroxypentyl) -3-propylxanthine and 1- (5-Hydroxypentyl) -3-propyl-8-methylxanthine. A process for the preparation of a compound of the following general formula: 20 Λγ. 4. A pharmaceutical composition, characterized in that it contains a compound of the general formula: 0 <^ Ν ^ Ν R 3 wherein R 1 represents a C 2 -C 5 ω-hydroxy-n-alkyl group or a C 3 -C 5 (ω-1) hydroxy-n-alkyl group; R 3 represents a C 1 -C 4 alkyl group; Rg represents H, methyl or ethyl; and the sum of the number of carbon atoms in R 1 and R 3 is between 4 and 9, or a physiologically acceptable salt of this compound, together with a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 4, characterized in that it contains a compound according to claim 2 or prepared according to claim 3.