HRP920559A2 - Oxadiazole-alkyl-purine derivatives - Google Patents

Description

The field of technology

The invention is from the field of preparative organic and pharmaceutical chemistry.

Technical problem

According to the aspect of the invention, new oxadiazole-alkyl derivatives of the general formula 1 and their pharmaceutically acceptable salts are provided.

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where:

A denotes C1-4 alkylene and

R1 represents C1-6alkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, C5-6cycloalkyl or aminoalkyl of the general formula -(CH2)n-NR2R3 where n is an integer of L-3;

R2 and R3 each represent hydrogen or C1-4alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring containing nitrogen which can further optionally contain a further nitrogen atom or an oxygen atom as a heteroatom or

R1 represents phenyl, hydroxyphenyl, carboxyphenyl, benzyl or dimethoxybenzyl.

The term "alkyl" includes both normal and branched chain groups. The benzyl group can preferably be 3,4-dimethoxy benzyl.

State of the art

The new compounds of this invention are particularly successful anti-cough agents in the treatment of diseases of the respiratory organs.

Salts of compounds of general formula I can be salts obtained with inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids, e.g. carboxylic or sulfonic acids (e.g. acetic acid, tartaric acid, maleic acid, lactic acid, citric acid , ascorbic acid, benzoic acid, hydroxy benzene benzoic acid, nicotinic acid, methanesulfonic acid or toluene sulfonic acid, etc.). The mentioned salts are addition salts of acids. Compounds of the general formula I form salts with bases (eg alkali and alkaline earth metal bases, such as sodium, potassium, calcium, magnesium, etc.) also. The salts may also be complex salts (eg salts made with ethylene diamine).

Organic substances distributed in nature and their derivatives have been used for treating diseases of the respiratory organs as antitussives for a long time. Compounds of the morphine type are especially used for these purposes, and their most famous representative is codeine. The mentioned compounds act on the central nervous system in a non-specific way and have more unwanted side effects. A particularly dangerous side effect of codeine is respiratory blocking activity. In the last decade, attempts have been made to obtain an anti-cough agent, which in therapeutic doses does not completely reduce the mentioned side effects, but reduces them to a small extent.

Certain organic compounds containing a 1,2,4-oxadiazole ring (eg OXOLAMIN AND PRENOXOIAZNIN) can be mentioned as upper level antitussives.

Recently, the group of antitussives containing a 1,2,4-oxadiazole ring has been enriched with a new group of compounds where the 1,2,4-oxadiazole ring is attached to the nitrogen atom in position 7 of the purine-structured theophylline via an alkyl chain. In addition to the anti-cough effect, the mentioned compounds show a significant improvement in breathing and a broncholytic effect and have desirable toxicity (Hungarian patent no. 186,007).

Description of the solution to the technical problem with examples of implementation

The subject of the invention is the provision of new purine derivatives substituted with a 1,2,4-oxadiazole ring that have stronger therapeutic properties than previously known compounds.

The above goal is achieved by providing new 1,2,4-oxadiazole derivatives of the general formula I. It was found in a surprising way that the mentioned new compounds of the general formula I have an extremely strong anti-cough effect.

When studying the relationship between chemical structure and therapeutic activity, we came to the unexpected conclusion that in compounds of general formula I, the purine ring potentiates the anti-cough effect of 1,2,4-oxadiazole agents to a greater extent than analogous derivatives substituted in position 1 with a methyl group.

The compounds of general formula I differ from the theophylline-oxadiazoles described in Hungarian patent no. 186,607 in the absence of a methyl group on the nitrogen atom in position 1 of the purine ring, said methyl group was present in the compounds of the prior art.

The new effect is as surprising as the higher biological activity of theophylline than the biological activity of theobromine.

The 1,2,4-oxadiazole ring plays a fundamental role in the extremely high antitussive activity as demonstrated by comparative tests performed with compounds of general formula II.

Compounds of general formula II

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comprise the same purine ring as the compounds of general formula I, but do not contain a closed 1,2,4-oxadiazole ring. The mentioned compounds of the general formula II practically do not show an anti-cough effect.

The antitussive effect of the compounds of general formula I is so strong that it is higher not only than that of the above-mentioned oxadiazole type of antitussives, but surprisingly several times higher than that of codeine.

A further therapeutic advantage of compounds of general formula I lies in favorable toxicity.

It was further observed according to tests on rats and rabbits that contrary to the morphine type of antitussives, the compounds of the general formula I do not show a respiratory blocking effect, but show a suitable bronchopulmonary activity.

The above substituted facts are confirmed by Table I where the ID50 mg/kg values are given for 3,7-dihydro-3-methyl-7-(methyl-1,2,4-oxadiazol-3-yl)-methyl/-1H -purine-2,6-dione (the simplest compounds of general formula I); for two known 1,2,4-oxadiazole-type antitussives, codeine and dextromethorphan (morphine-type reference compounds) in relieving cough induced by 15% citric acid spray. Tested compounds were added orally, one hour before the determination of antitussive activity. Guinea pigs were used as test animals. /Method: Arzneimittel Forschung 1966, 617-621/. Tested compound no. 5 is 2-(3-methyl-xanthine-7-yl)-acetamidoxime (starting material of general formula II).

Table I shows that the absolute strength of the anti-cough effect of compounds no. 1 is significantly higher than that for reference compounds no. 2-4 and 6. Effect of xanthine amidoxime derivative no. 5 is practically negligible.

Table I

Cough relief induced by 15% citric acid spray in guinea pigs, test compounds administered orally

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The oral antitussive effect of compound number 1 is very long-lasting, as can be seen from the data in Table I/A

Table I/A

Antitussive effect of orally administered 3,7-dihydro-3-methyl-7-0/(5-methyl-1,2,4-oxadiazol-3-yl)-methyl/1H-purine-2,6-dione on cough induced by 15% citric acid spray on guinea pigs.

pretreatment time ID50 mg/kg

__________________ __________

0.5 7.5

1.0 8.5

2.0 14.4

4.0 13.8

8.0 32.6

Acute toxicity of compound no. 1 in Table I and that of reference compounds 2 and 4 given in Table I/B.

Tested animals: rats, intraperitoneal administration.

Table I/B

Tested compound no. Toxicity in rats

(see Table 1) LD50 mg/kg

____________________________________________________________________________

1 700.0

2 (reference) 529.7

4 (reference) 72.4

_____________________________________________________________________________

Connection no. 1 has a strong anti-cough effect not only when administered orally but also when administered intravenously. The mentioned compound in a dose depending on the method of introduction (introduction 0.5-8.0 mg/kg i.v.) cough induced by mechanical stimulation of the trachea of a rabbit intoxicated with nembutil. Two minutes after intravenous administration, the ED50 value is 2.24 (1.85-2.72 mg/kg) calculated according to Lichfield-Wilcoxon reference compounds no. 4 and 6 have the same or slightly lower effect on cough. Also taking into consideration the data on toxicity, the therapeutic index of compounds no. 1 j 10 and several times more favorable than those for reference compounds 4 and 6. The second compound of general formula I shows a similar strong anti-cough effect as compound no. 1 of table 1.

According to a further aspect of this invention, a procedure for obtaining compounds of the general formula I and their pharmaceutically acceptable salts is provided, which includes:

a) reaction of amidoxane of general formula II

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(wherein A is as given above) with a carboxylic acid of general formula III

R4---CO2H (III)

(where R4 has the same meaning as R1 or denotes a group that is suitable for building the group R1) or its reactive derivative and if it is desired to convert the group R4 into the group R1; or

b) reacting an amidoxime of general formula II (where A is as given above) with a carboxylic acid of general formula III (where R 4 is as given above) or a reactive derivative thereof, subjecting a compound of general formula IV

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so obtained (wherein A and R4 are as given above) by cyclization by dehydration after or without isolation and if it is desired to convert the group R4 into the group R1; or

c) reaction of oxadiazole derivatives of general formula V

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(wherein A and R4 are as given above and N represents a halogen or sulfonic acid ester group) in the presence of a base catalyst with 3-methyl-xanthine of formula VI

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or its sodium or potassium salt and if it is desired to convert the group R4 to the group R1; or

d) to obtain a compound of the general formula I (where A denotes -(CH2)2- and R1 is as given above), reacting an olefin of the general formula VII

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(wherein R 4 is as given above) with 3-methyl-xanthine of the general formula VI in the presence of a base catalyst, and if it is desired to convert the group R 4 into the group R 1 , and if it is desired to convert the compound of the general formula I thus obtained into its pharmaceutically acceptable salt.

According to procedure a), it may be desirable to react the amidoxane of the general formula II with the ester of the general formula VIII

R4CO2R5 VIII

(where R4 is as given above and R5 is alkyl, preferably methyl or ethyl) in the presence of a base (preferably an alkali or alkaline earth metal hydride, carbonate or alcoholate, especially sodium methylate or sodium ethylate) in a polar or non-polar solvent and/or diluent with heating, preferably at the boiling temperature of the solvent and/or diluent. Preferably C1-4 alcohols, N-alkyl amides of acids (eg dimethyl formamide), aromatic hydrocarbons (eg benzene, chlorobenzene, preferably toluene or xylene) can be used as solvent and/or diluent. If polar solvents are used, the prized water and alcohol can conveniently be removed by azeotropic distillation.

According to a further preferred embodiment of the procedure a) the amidoxime of the general formula II is heated with an acid of the general formula III

R4---CO2H III

and/or its anhydride in the presence of an organic solvent. Aromatic hydrocarbons can preferably be used as an organic solvent. Particularly preferably, it can be used as an organic solvent of acid and/or acid anhydride so that the mentioned compound acts simultaneously as an agent for acylation and cyclization and as a reaction medium. Acylation and cyclization can be carried out at 50-150°C, especially at 90-110°C.

The reaction time of procedure a) varies between 30 minutes and 24 hours depending on the reactants and the solvent used and the reaction temperature.

According to procedure b) the acylation can preferably be carried out using an anhydride of the general formula (R4CO)2O or an acid halide of the general formula R4COX (where R4 is as given above and X represents a halogen) preferably acid chloride in the presence of an organic solvent and/or diluent (e.g. acetone, pyridine, benzene, dimethyl, formamide or when anhydrides are used as acylating agents, an excess of acid anhydride, preferably dichloromethane, chloroform, etc.). If acid halides are used, the acylation is conveniently carried out in the presence of an acid binding agent. It is preferable to use inorganic acid binding agents (e.g. carbonates of alkali and alkaline earth metals, such as sodium carbonate, potassium carbonate or calcium carbonate or acidic carbonates, e.g. sodium bicarbonate, etc.), but organic acid binding agents can also be used. (eg tertiary amines such as pyridine or triethyl amine). If acylating agents are used where R4 is a basic group, compounds of general formula IV

[image]

it can also serve as an acid binding agent.

According to procedure b) the oxadizole ring is built in a polar organic solvent and/or water as a solvent and/or diluent or in a non-polar solvent and/or diluent or in the absence of a solvent by means of pyrolysis.

The cyclization of the compound of general formula IV is preferably carried out at a pH value of 6-8. Said pH is conveniently adjusted with inorganic or organic bases (preferably sodium carbonate or thiethyl amine). The use of Britton-Robinson buffer is particularly desirable. Cyclization in water of a dissolved compound of general formula IV can preferably be carried out in water at pH 7.

According to procedure c) compound of general formula V

[image]

(wherein A is as given above and X is a halogen or sulfonic acid ester group) is reacted with 3-methyl-xanthine of formula V

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in an organic solvent and/or diluent (preferably dimethyl formamide or alcohol, preferably n-butanol) in the presence of an inorganic base (e.g. some alkali hydroxide, sodium hydroxide preferably or potassium hydroxide; or alkali metal carbonate, e.g. sodium or potassium carbonate) or organic bases (eg pyridine triethyl amine or piperidine). It can also be performed by reacting a compound of general formula V with the sodium or potassium salt of 3-methylxanine of formula VI. The above reactions can be carried out in a solvent, suspension, preferably with heating.

In compounds of general formula Ia

[image]

the thus obtained R4 group can be translated, if desired, into the R1 group.

According to procedure c) of the compound of general formula Ib

[image]

(e.g. compounds of general formula I (where A is -(CH2)2) are obtained by the reaction of compounds of general formula VII

[image]

(where R 4 is as given above) with 3-methyl-xanthine in the presence of a base catalyst, preferably quaternary ammonium hydroxide, especially Triton-B in an organic solvent and/or diluent with heating. In the compound of general formula Ia thus obtained, the R4 group can be transformed, if desired, into the R1 group.

Carboxylic acid amidoximes of 3-methyl-xanthine-7-yl-alkane of the general formula II used as starting material in procedures a) and b) can be obtained by known procedures by reacting the corresponding 3-methyl-xanthine-7-yl-carbonitrile with hydroxylamine while heating in methanol or ethanol or aqueous methanol or ethanol.

Oxadisoles of the general formula V used as starting material in process c) can be obtained by known methods by the reaction of the corresponding 3-(n-hydroxyalkyl)-1,2,4-oxadiazole with thionyl chloride, tosyl chloride or methyl chloride (J.Chem.Res. /M/1979, 801).

Starting olefins of the general formula VII used in procedure d) can also be obtained by known procedures (J.Shem.Res./M/ 1979, 801).

Compounds of the general formulas Ia and IV, where R1 or R4 denotes halogenoalkyl, can be obtained from amidoximes of the general formula II by reacting the same with the corresponding chlorides of haloalkane carboxylic acids in a known manner (Hungarian patent no. 186,607).

Compounds of the general formula I, where R1 denotes aminoalkyl can be obtained not only by process a) but also by subjecting the corresponding compound of the general formula Ia and IV, where R4 is haloalkyl, to a substitution reaction or a substitution reaction and cyclization respectively with the corresponding amine in a known manner (Hungarian patent No. 186,607).

According to a further aspect of this invention, pharmaceutical preparations are provided which include as an active ingredient at least one compound of the general formula I or its pharmaceutically acceptable salt in a mixture with appropriate inert carriers. The active composition can be formulated in the usual forms, for example, syrups, tablets, pills, coated pills, dragees, capsules, suppositories, injections, etc. Pharmaceutical preparations contain known commonly used solvents, diluents, carriers, excipients, etc. The mentioned pharmaceutical preparations are obtained known procedures of the pharmaceutical industry.

The content of the active composition of pharmaceutical preparations according to this invention is from 0.1 to 100% and preferably 1-30%. The daily dose can usually be 200 mg, depending on the method of administration, age and body weight of the patient, etc.

Further details of this invention are found in the following examples without limiting the scope of protection in said examples.

A/ Chemical examples

Example 1

35 g (0.25 mol) of 3-methylxanthine (chem. Ber. 83, 209 (1950) was dissolved in 81.4 ml (0.25 mol) of a 10% sodium hydroxide solution with shaking; crystallization began within a few minutes Water is distilled off under vacuum and traces of water are removed by azeotropic distillation with toluene. The residue is suspended in 35 ml of dimethyl formamide, after which a solution of 18.9 g (0.25 mol) of chlorocetonitrile in 80 ml of dimethyl formamide is added dropwise at 100° C for 30 minutes. The reaction mixture was stirred at 100°C for the next hour, filtered while warm and the precipitate (sodium chloride) was washed with warm dimethyl formamide and the combined solvents were evaporated to dryness under reduced pressure. The residue was treated with 100 ml of acetone, crystals were filtered with suction and washed well with acetone, thus obtaining 7-cyanomethy-3-xanthine (m.p.: 285-287°C), which can be used in further reactions.

Example 2

To a solution of 3.2 g of hydroxylamine hydrochloride and 36 ml of water, 2.5 g of sodium bicarbonate was added in portions. 10.0 g of 7-cyanomethyl-3-methyl-xanthine and 30 ml of ethanol were added to the thus obtained solution, the mixture was stirred at 80°C for 4 hours. After cooling, the precipitate of 2-(3-methyl-xanthine-7-yl)-acetamidioxime was filtered with suction and washed with some cold water. Yield 11.0 g 86%, m.p.: above 320°C.

1H-NMR(DMSO-d6): 3.35(s, 3h, 3-Me); 4.85(s, 2H, NCH2-),

8.03(s, 1H, 8-H); 9.79(s, 1H, N-OH); 11.21 (bs, 1H, 1-NH).

Example 3

A mixture of sodium ethylate solution obtained from 6.76 g of sodium metal and 290 ml of anhydrous ethanol, 35 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime and 43.0 g of ethyl acetate was heated to boiling and stirred for 4 hours. The warm reaction mixture was filtered, the filtrate was evaporated under vacuum and the residue was dissolved in 200 ml of water. The pH of the solution was adjusted to 7 by adding 10% hydrochloric acid, the precipitate was washed with suction and recrystallized twice from water. Thus, 18.0 g of 3,7-dihydro-3-methyl-7-(/5-methyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione were obtained , mp: 262-264°C.

1H-NMR(DMSO-d6): 2.57(s, 3H,5-Me);

3.37(s, 3H,3-Me); 5.66 (s, 2H, -CH2);

8.18(s, 1H, 6-H); 11.19 (bs, 1H, 1-NH).

Example 4

a mixture of 3.76 g (20 mmol) of 3-methyl-xanthine-sodium, 100 ml of dimethyl formamide and 2.6 g (19.6 mmol) of 3-chloromethyl-5-methyl

-1,2,4-oxadiazo was stirred at 100°C for an hour and a half. The warm reaction mixture was filtered and 50 ml of methanol was added to the filtrate. Thus, 3.65 g of 3,7-dihydro-3-methyl-7-(/5-methyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione were obtained , mp: 262-264°C. Yield 69%.

Example 5

A solution of 3.7 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime and 45.0 ml of acetic anhydride was stirred at 140°C for 1 hour. The cooled solution was diluted tenfold with water and stirred for 30 minutes. The precipitated O-acetyl-2-(3-methyl-xanthine-7-yl)acetamidoxime was filtered off with suction, and washed with some methanol. Yield 3.6 g m.p.: above 220°C.

1H-NMR (DDMSO-d6): 2.01(s, 3H, OAc), 3.34(s, 3H, 3Me) 4.97(s, 2H,

NCH2-), 6.70 (bs, 2H, NH2), 8.07 (s, 1H, 6-H, 11.24 (bs, 1H, 1-NH).

Example 6

2.0 g of O-acetyl-2-(3-methyl-xanthine-7-yl)-acetamidoxime was mixed in a mixture of 160 ml of Britton-Robinson buffer (pH 7) and 200 ml of dimethylformamide at 95°C for 6 hours. The reaction mixture was evaporated in vacuo and the residue was crystallized from water. Thus, 1.22 g of 3,7-dihydro-3-methyl-7-(/5-methyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione were obtained mp: 262-264°C.

Example 7

A solution of 2.38 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime in 40.0 ml of anhydrous acetone was acylated with a solution of 1.13 g of chloroacetyl chloride and 5.0 ml of acetone in the presence of 0.86 g of sodium bicarbonate. Thus, 2.1 g of O-chloroacetyl-2-(3-methyl-xanthine-7-yl)-acetamidoxime were obtained. The product was heated at 105°C and 133 Pa to a constant mass for 40 minutes. The residue was crystallized from methanol. 1.6 g of 3,7-dihydro-3-methyl-7-(/5-chloromethyl-1,2,4-xa-diazol-3-yl/-methyl)-1H-purine-2,6 -Dion.

Example 8

a) A mixture of 1.5 g of 3-(/3-methyl-xanthine-7-yl/-methyl)-5-chloromethyl-1,2,4-oxadiazole, 10 ml of diethylamine and 10 ml of toluene was heated on a water bath with stirring for 8 hours in a closed bottle equipped with a magnetic stirrer. The mixture was evaporated, washed with water, dissolved in 5 ml of warm ethanol and purified with activated carbon. The hydrochloride salt is made by adding ethanol containing hydrogen chloride. After crystallization from water, 1.4 g of 3,7-dihydro-3-methyl-7-(/5-diethylaminoethyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2, 6-dione hydrochloride.

b) 1.41 g of O-chloroacetyl-2-(3-methyl-xanthine-7-yl)-acetamidoxime obtained according to the example was dissolved in 15 ml of toluene, after which 1.5 ml of diethylamine was added dropwise with vigorous stirring. The reaction mixture was heated to boiling for 8 hours. The residue was washed with water and the hydrochloride salt was made in ethanol. After crystallization from water, 1.2 g of 3,7-dihydro-3-methyl-7-(/5-diethylaminoethyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2 was obtained. 6-dione hydrochloride.

c) A mixture of 2.38 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime, 3.0 g of diethylamino acetyl chloride and 20 ml of pyridine was mixed at a temperature not exceeding 20°C, after which the reaction mixture was heated in the water bath for 2 hours. The reaction mixture was evaporated, the residue was washed with water and the hydrochloride salt was made in ethanol. After crystallization from water, 2.1 g of 3-(/3-methyl-xanthine-7-yl)-methyl-5-diethylaminomethyl-1,2,4-oxadiazole hydrochloride was obtained.

d) A mixture of 2.38 g of 3-(3-methyl-xanthine-7-yl)acetamidoxime, 200 ml of toluene, 1.36 g of sodium ethylate and 3.46 g of ethyl-beta-diethyl-amino-propionate was heated to boiling with stirring in a bottle equipped with a water separator for 12 hours. The reaction mixture was evaporated in vacuo, the pH was adjusted to 7, the precipitate was washed with water, dried and the hydrochloride salt was made in ethanol. 2.0 g of 3,7-dihydro-3-methyl-7-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione- hydrochloride.

Example 9

A solution of 2.38 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime in 25 ml of ethanol was mixed with a solution of 0.46 g of sodium metal in 25 ml of ethanol and 3.02 g of ethyl cyclohexane carboxylate. The reaction mixture was heated to boiling with stirring for 10 hours, then evaporated. The residue was mixed with water and the pH was adjusted to 7. The precipitate was crystallized from aqueous ethanol. 2.51 g of 3,7-dihydro-3-methyl-7-(/5-cyclohexyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione were thus obtained , mp: 245-248°C.

Example 10

238 g of 2-3-methyl-xanthine-7-yl)-acetamidoxime was reacted with 3.28 g of ethyl phenyl acetate and sodium ethylate in ethanol in an analogous manner as in the previous example. Thus, 2.7 g of 3,7-dihydro-3-methyl-7-(/5-benzyl-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione were obtained , mp: 188-190°C.

Example 11

A mixture of 2.52 g of 3-(3-methyl-xanthine-7-yl)-propionic acid amidoxime, 4.0 ml of ethyl acetate and a solution of 0.46 g of sodium metal in 25 ml of ethanol was heated to boiling with stirring for 5 hours. . The warm reaction mixture was filtered and evaporated. The residue was treated with 20 ml of water, the pH was adjusted to 7 and the settled product was recrystallized from water. Thus, 1.7 g of 3,7-dihydro-3-methyl-7-(2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl)-1H-purine was obtained. -2,6-dione, m.p.: 258-260°C.

Example 12

A mixture of 2.52 g of 3-(3-methyl-xanthine-7-yl)-propionic acid amidoxime, 25 ml of toluene, 1.12 g of powdered potassium hydroxide and 3.70 g of ethyl-beta-piperidino-propionate was heated to boiling with stirring with a water separator for 10 hours. The reaction mixture was evaporated, the residue was treated with water, the pH was adjusted to 7, the settled product was washed with water and converted into the hydrochloride salt in ethanol. 2.6 g of 3,7-dihydro-3-methyl-7-(2-(5-(2-piperidino-ethan-1-yl)-1,2,4-oxadiazol-3-yl)- of ethan-1-yl/-1H-purine-2,6-dione hydrochloride.

Example 13

A mixture of 2.66 g of 4-(3-methyl-xanthine-7-yl)-butyric acid amidoxime, 4.0 ml of ethyl acetate and a solution of 0.46 g of sodium metal in 25 ml of ethanol was heated to boiling for 6 hours. Thus, 1.8 g of 3,7-dihydro-3-methyl-7-(3-(5-methyl-1,2,4-oxadiazol-3-yl)-propan-1-yl)-1H-purine were obtained. -2,6-dione.

Examples 14-34

The compounds listed in Table II of the substituted compounds were obtained in an analogous manner to examples 1-13. In the mentioned Table II, the substituted number of examples, definitions of A and R1 are given.

Table II

[image] [image]

B/ Examples of preparations

Example 35

a) Tablets

Component Quantity mg

3-(/3-methyl-xanthine-7-yl/-methyl)-

5-methyl-1,2,4-oxadiazole 10.0

wheat starch 130.0

calcium phosphate 199.0

magnesium stearate 1.0

total mass 340.0

The above components are mixed, the powdered mixture is crushed into 100 tablets, weighing 340 mg each, in a known manner. Each tablet contains 10 mg of the active ingredient.

b) Dragee depot

Component Quantity mg

3-(/3-methyl-xanthine-7-yl/-methyl)-

5-methyl-1,2,4-oxadiazole 50.0

carboxymethyl cellulose 300.0

stearic acid 20.0

cellulose acetate phthalate 30.0

total mass 400.0

The mixture of active ingredient, carboxymethyl cellulose and stearic acid is mixed well with a solution of cellulose acetate phthalate in 200 ml of ethyl acetate. From this mixture, 400 mg of honey are pressed and coated with 5% aqueous polyvinyl pyrrolidine in a known manner. Each dragee contains 50 ml of active ingredients.

c) Syrup

Component Quantity

3-(3-3-methyl--xanthine-7-yl/-propan-1-yl)-

5-(2-diethylamino-ethan-1-yl)-1,2,4-oxadiazol-

hydrochloride 5g

lemon syrup 200ml

solution of benzoic acid 20 ml

water 100ml

sugar syrup up to 1000 ml

The active composition was dissolved in water with heating, after which 500 ml of sugar syrup and other components were added and the mixture was topped up to 1000 ml with sugar syrup. The content of the active component in the syrup is 5 mg/ml.

Claims (4)

1. Compounds of general formula I [image] where A denotes C1-4 alkylene and R1 represents C1-6alkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, C5-6cycloalkyl or aminoalkyl of the general formula -(CH2)nNR2R3 where n is an integer 1-3; R 2 and r 3 each represent hydrogen or C 1-4 alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered ring containing a heterocyclic ring which may optionally include the following nitrogen atom or oxygen atom as a heteroatom; or R1 represents phenyl, hydroxyphenyl, carboxyphenyl, benzyl or dimethoxybenzyl and their physiologically acceptable addition salts rewarded with inorganic bases. 2. The following compounds according to claim 1: 3,7-dihydro-3-methyl-7-(/5-methyl-1,2,4-oxadiazol-3-yl-methyl)-1H-prin-2,6-dione; 3,7-Dihydro-3-methyl-7-(/5-(propan-1-yl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-butan-1-yl)-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-penten-1-yl)-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-Dihydro-3-methyl-7-(/5-(propan-2-yl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-cyclohexyl)-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl 7-([5-chloromethyl-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(/5-(2-hydroxy-ethan-yl)-1,2,4-oxadiazol-3-yl/-methyl)-1N-purine-2,6- part 3,7-dihydro-3-methyl-7-((5-diethylaminomethyl)-1,2,4-oxadiazol-3-yl)-1H-purine-2,6-dione; 3,7-Dihydro-3-methyl-7-((5-piperidinomethyl-1,2,4-oxadiazol-3-yl)-1H-purine-2,7-dione; 3,7-dihydro-3-methyl-7-([5-morpholinomethyl-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-benzyl-1,2,4-oxadiazol-3-yl]-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-(3,4-dimethoxybenzyl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(/5-(3-carboxy-propan-1-yl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2, 6-dione; 3,7-dihydro-3-methyl-7-([5-phenyl-1,2,4-oxadiazol-3-yl-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-([5-(2-hydroxyphenyl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione; 3,7-Dihydro-3-methyl-7-(/5-(2-carboxyphenyl)-1,2,4-oxadiazol-3-yl/-methyl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(2-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(2-(5-piperidinomethyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(2-(5-(2-piperidino-ethan-1-yl)-1,2,4-oxadiazol-3-yl/-ethan-1-yl)- 1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(2-(/5-(2-diethylamino-ethan-1-yl)-1,2,4-oxadiazol-3-yl/-ethan-1-yl) -1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(3-(/5-methyl-1,2,4-oxadiazol-3-yl)-propan-1-yl)-1H-purine-2,6-dione ; 3,7-dihydro-3-methyl-7-(3-/5-(2-diethylamino-ethan-1-yl/-1,2,4-oxadiazol-3-yl/-propen-1-yl)- 1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(3-/5-(2-piperidino-ethan-1-yl/-1,2,4-oxadiazol-3-yl/-propan-1-yl)- 1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(4-(5-methyl-1,2,4-oxadiazol-3-yl/-butan-1-yl)-1H-purine-2,6-dione; 3,7-dihydro-3-methyl-7-(4-(5-(2-diethylamino-ethan-yl)-1,2,4-oxadiazol-3-yl/-butan-1-yl)-1H- purine-2,6-dione; 3,7-Dihydro-3-methyl-7-(4-[5-(2-piperidino)ethan-1-y]/-1,2,4-oxadiazol-3-yl/-butane)-1H-purine -2,6-dione. 3. Process for obtaining new compounds of general formula I [image] where A and R1 have the same meaning as given in claim 1 and their pharmaceutically acceptable salts, characterized in that it comprises the reaction of the amidoxime of the general formula II [image] where A is as given above, with a carboxylic acid of general formula III R4--CO2H III where R 4 has the same meaning as R 1 or denotes a group convenient for building the group R 1 , or its reactive derivative and if desired, converting the group R 4 to R 1 ; or reacting an amidoxime of general formula II, where A is as given above, with a carboxylic acid of general formula III, where R4 is as given above) or with a reactive derivative thereof, subjecting a compound of general formula IV [image] so obtained, where X and R 4 are as given above, to cyclization by dehydration after or without isolation and if it is desired to convert the group R 4 to the group R 1 ; or reaction of oxadiazole derivatives of the general formula V [image] where A and R4 have the meanings given above and X denotes a halogen or an ester group of sulfonic acid, in the presence of a base catalyst with 3-methyl-xanthine of formula VI [image] or its sodium or potassium salt and if it is desired to convert the group R4 to the group R1; or to obtain a compound of general formula I [image] where A denotes -(CH2/2-i) R1 is as given above, the reaction of an olefin of general formula VII [image] wherein R 4 is as given above with 3-methyl-xanthine of formula VI in the presence of a base catalyst, and if it is desired to convert the group R 4 to the group R 1 and if it is desired to convert the compound of general formula I thus obtained into its pharmaceutically acceptable salt. 4. Pharmaceutical preparations comprising as an active ingredient at least one compound of the general formula I, where A and R1 are as given above or their pharmaceutically acceptable salts in a mixture with suitable inert carriers.