Process for preparing novel derivatives of xanthine

PATENT DESCRIPTION

<img file="PL119413B1_D0001.tif" />

OFFICE

Pool PATENTOWT

Additional patent to patent No. Pending: 19.10.79 (P. 219065)

Int. Cl.³

C07D 473/06. Priority: 20.10.78 (Sweden)

The application was announced: 16.06.80

Patent description published: 25.07.1983

Creators of the Invention: Per Gunnar Kjellin, Carl Goran August Persson Patent holder: Aktiebolaget Draco, Lund (Sweden)

Method of producing new xanthine derivatives and

The present invention relates to a process for the preparation of new xanthine derivatives, which are used as cardiac agents and agents for chronic airway obstruction.

Theophylline and its various salts are known for the treatment of chronic airway obstruction and heart disease. The main therapeutic effect of theophylline is bronchial smooth muscle relaxation and cardiac muscle stimulation. However, theophylline often causes side effects associated with the toxicity of this drug. The most common symptoms are nausea and stomach upset, and the most serious symptoms are seizures that can lead to death.

It has now been found that the compounds of the present invention have bronchodilatory and cardiac tonic properties without causing convulsions, making them valuable therapeutic agents in the treatment of heart disease and chronic airway obstruction.

The method of the invention produces new xanthine derivatives of the general formula (I) in which R1 is n-propyl, n-butyl, isobutyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylmethyl, and R² is a hydrogen atom or a methyl group, wherein R² means the mety2 group

Iowa when R¹ means n-propyl, n-butyl or isobutyl, as well as pharmacologically acceptable salts of compounds of formula 1 with pharmacologically acceptable bases.

The term "pharmacologically acceptable salts" means salts whose cations act relatively harmlessly on animal organisms at pharmacological doses, with beneficial pharmacological effects of the parent ¹⁰ compounds of the formula I are not reduced by side effects associated with the presence of these cations.

Suitable salts are alkali metal salts, e.g. sodium and potassium, ammonium and known salts ¹⁵ pharmacologically acceptable amines such as glycine, ethylene diamine, choline, diethanolamine, triethanolamine, 1-aminopropanol-2,2-amino-2- {hydro'xymethyl) propanediol-1,3, and 1- (3,4-dihydroxyphenyl) - 2-izopropyloaminoetanol.

* As a therapeutic agent, compounds with a structure different from those of formula I can also be used, which are transported after introduction into a living organism / are converted into compounds of formula 1 with therapeutic effect²⁵ peutyczne.

According to the invention, the method for producing the new xanthine derivatives of formula 1 is that the compound of general formula 2 in which R¹ has the above meaning, submits to re³⁰ shares with a compound of formula R²-X in which X

119 413

119 413 is a carboxy group, the group of formula -CONH₂ or a group of formula 3 and in which R² has the meaning given above, after which the resulting compound is optionally dehydrated and optionally converted to a physiologically acceptable salt. '

Dehydration can be carried out, for example, by heating the reaction mixture without solvent or by heating the mixture with alkali or by keeping the mixture boiling in a high boiling solvent.

According to the invention, the compounds of formula 1 can also be prepared by subjecting a compound of formula 2 in which R¹ has the meanings given above, reacting with a compound of formula R²-X¹in which X¹ is a group of formula -CHO or a group of formula 4 in which O¹ represents a hydrogen atom or an alkyl group with 1-3 carbon atoms and Q² is a ^ alkyl group with 1-3 carbon atoms and R² has the abovementioned meaning and then subjecting the resulting compound to oxidative cyclization and optionally converting the resulting compound of Formula 1 into a physiologically acceptable salt.

Substituents and Q² are preferably methyl or ethyl groups.

Oxidation cyclization can be carried out using various means, e.g. thionyl chloride.

Pharmacologically acceptable salts can be prepared by reacting the compound of Formula 1 and the base in stectimetric amounts, e.g., at elevated temperature and with or without a solvent. The resulting salt is preferably recrystallized from a suitable solvent, e.g. a hydroxyl-containing solvent, such as water.

The starting compounds of formula 2 can be prepared, e.g., by the method illustrated in scheme 1, in which R¹ in the drawings of the form has the above meaning.

Compounds of formula 2 in which R¹ means n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-idimethylpropyl, cyclopropyl, diglobutyyl, cyclopentyl or cyclohexylmethyl group, they are new compounds.

In clinical practice, the compounds of formula I, or their pharmacologically acceptable salts, are submitted in the form of pharmaceutical preparations containing a pharmacologically acceptable carrier, in the form of a solid, semi-solid or liquid substance, or a drinkable capsule. The preparations are usually administered orally, rectally, nasally, under the tongue, by injection or as an inhalation agent. The amount of the compound of formula I or its salt, i.e. the active substance, is generally 0.1-99% by weight based on the weight of the preparation, e.g. 4.5-20% by weight for the Injection preparation and 0.1-30 % by weight for preparations administered orally.

To prepare pharmaceutical preparations in the form of unit dosage forms for oral administration, the active ingredient may be mixed with a solid powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch, such as potato or corn starch, amylopectin, tin blend or powdered citrus fruit pulp, cellulose derivative, polyvinylpyrrolidone or gelatin, and optionally with magnesium stearate, such as magnesium stearate, , Carbowax or other polyethylene glycols, and then compress the mixtures into tablets or dragee cores. If you want to obtain dragees, the cores can be coated with, e.g., concentrated sugar solutions containing acacia, talc and / or titanium dioxide or film-forming agents dissolved in volatile organic solvents or other suitable solvents, or mixtures of organic solvents. Dyes can be incorporated into coatings, e.g. to distinguish between different active substance contents.

For the preparation of soft gelatin capsules (closed pearl-shaped capsules) containing gelatin and, for example, glycerol as a softener, or similar closed capsules, the active substance can be mixed with Carbowax or a suitable oil, e.g. sesame, peanut or olive oil. Hard capsules may contain granules consisting of the active substance and a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, polyvinylpyrrolidone or gelatin, optionally with the addition of lubricants such as magnesium stearate and stearic acid.

The compounds of the present invention can also be formulated in sustained-dose formulations using appropriate excipients. The active substance may be made available by the preparation by various means, e.g. diffusion or ion exchange. Examples of preparations which release the active substance by diffusion are coated granules, embedded drugs and sparingly soluble preparations.

Effervescent powders are made by mixing the active substance with non-toxic carbonates or bicarbonates, e.g. sodium, potassium or calcium, such as calcium carbonate, potassium carbonate and potassium bicarbonate, solid non-toxic acids, such as tartaric, ascorbic and citric acid, and e.g. fragrances.

Liquid preparations for oral administration may be in the form of aqueous-alcoholic solutions, syrups or suspensions, e.g. a solution containing about 0.1-20% by weight of the active substance, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally a fragrance and saccharin and / or carboxymethylcellulose as a dispersant.

Injectable preparations intended for parenteral administration may be aqueous solutions or suspensions of the active substance, preferably containing 0.5-10% of the compound of formula 1, and optionally a stabilizer and / or buffering agents in aqueous solution. Unit doses of the solution are preferably placed in ampoules.

Dosages of the active substance can vary widely and depend on various factors

119 413 such as the individual needs of the patient. A suitable dose for oral administration is 50-1000 mg, with 1 to 4 times daily. A suitable dose for parenteral administration is 20-500 mg.

Pharmacological preparations are preferably prepared so that they contain the above-mentioned doses, either as unit doses or as multiple doses.

The best therapeutic results are obtained when using the active substance 3-cyclopentyl-3,7-diliy dro -1H -purine ion-2,6.

The pharmacological action of the compounds of formula I is confirmed by the results of the following tests.

Test A. Toxicity studies. Male NMRI mice weighing 20-26 g, which had not been fed for 6 hours, were used for the study. Test compounds were dissolved in 0.5 m NaOH and 0.85% NaCl solution (PH 10.6-12.1) administered:

a) intravenously, at a dose of 0.1 ml / 10 g at a rate of 0.3 ml / minute,

b) orally, at a dose of 0.1 ml / 10 g.

At least seven dose ranges were tested with doses increasing exponentially at a factor of 1.2. Each dose was administered to 5 animals that were observed for signs of toxicity for 14 days from the time of compound administration. The position of the limbs of dead animals indicated whether they died in seizures or without convulsions.

Studies have shown that many xanthine derivatives cause seizures, with recurrent symptoms of this type also found in theophylline. During the studies, however, it was not observed that the compounds produced according to the invention caused convulsions in animals (e.g. manifested in the tonic stress of the hind paws in dead animals).

Convulsive effects were also investigated by administering test compounds to mice with vitiligo by slow infusion into the tail vein. These studies confirmed the fact that 1-alpha-substituted xanthine derivatives (theophylline and caffeine) invariably cause phonic seizures, whereas when using compounds of formula 1, phonic seizures do not occur (Table 1).

Test B. Guinea pigs of both sexes, weighing 150-2 g, were killed by blows to the heads and bled. The removed tracheas were helically cut, obtaining 1 or 2 preparations. The tracheal preparations were placed in a bath containing Krebs solution, maintained at 37 ° C and saturated with a mixture of oxygen and carbon dioxide (95%₂+ + 5% CO₂).

An isometric voltage was measured using an energy converter, which is mainly a measure of tracheal muscle motility. The initial voltage was set at 0.5 g, which value corresponded approximately to the basic voltage maintained during the experiment. 0.1 ug / ml carbaccholine was added to the bath, which caused the formulations to shrink and the tension to be determined, followed by an evaluation of the tension-reducing effect. EC values ​​were obtained from a concentration-response graph prepared on a logarithmic scale_g0, i.e. molar concentrations of xanthines at which 50% of the maximum reaction occurs. These values ​​were used to calculate the potency of theophylline relative to the potency of the study drug. After elution of the drugs, the trachea regained basal tension, after which it was left to stabilize for 15 minutes before the next attempt. The effect of study drug and EC value were evaluated between two attempts to evaluate theophylline activity₅₀ determined for this drug was compared with the mean EC ^ values ​​determined for theophylline in the pre-drug and post-drug trials.

Table 1 gives the values ​​of the relative potency assuming that the potency of theophylline is 1. When the potency of a given compound exceeds 1, it means that it is greater than the potency of theophylline.

Test C. Hearts were removed immediately from the killed and bled guinea pigs and according to the Lagendorff method they were saturated with oxygenated Krebs solution at 37 ° C. The hearts were placed in a thermostatic bath (25 ml) containing Krebs solution. A polyethylene catheter with an open end filled into the right ventricle through the pulmonary artery. The catheter was attached to the pulmonary artery with a ligature just above the valvular plane, and then connected to a pressure transducer (P 23 AC), which enabled recording of pressure changes in the heart chamber. Based on this data, the frequency of contractions was determined. - Investigations were introduced into the loading solution by single injection.

The results of the tests described above are summarized in Table 1. The first column lists the compounds tested. The second column gives the values ​​of the ratio of bronchodilator potency versus the potency of theophylline. The third column lists pre-death toxic effects in mice given intravenous test medication at a constant rate. For theophylline and caffeine, tonic seizures were invariably present (30 animals out of 30 test animals and 20 animals out of 20 test animals, respectively). Each of the other compounds was tested in 10 animals, but in no case did these compounds cause tonic seizures.

From the data in Table 2, it appears that for several animals that received compounds D 4164, D 4161 or D 4169, clonic seizures or mixed tonic / clonic seizures occurred. However, the seizure intensity was very moderate compared to the effects of theophylline and caffeine. The last column gives data illustrating the effect of cardiac tonicity (positive chronoprotective effect).

The method of the invention is illustrated by the following examples.

Example 1. Preparation of 3-cyclopropyl-3,7-dihydro-1H-purinedione-2,6 (compound of formula 10).

119 413

Table 1

<td>Test compound</td><td>The ratio of the strength of the test compound to strength theophylline effects (guinea pig tracheal test)</td><td>Attempt to cause convulsions in mice (intravenous compounds)</td><td>Lethal dose when administered intravenously (mg / kg)</td><td>Chronotropic effect. Ratio of test compound's potency to theophylline's potency (guinea pig heart test)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td>theophylline</td><td> 1</td><td>tonic convulsions 30 / 3-0</td><td> 446,3±9,6</td><td> 1</td>

<td>Caffeine</td><td>rv&gt; l</td><td>20/20 tonic seizures</td><td> 391,7±17,7</td><td> 0,5</td>

<td>Compound D 4034 of formula 33</td><td> 3</td><td>loss of balance, salivation</td><td> 519,1+16,6</td><td> 3</td>

<td>Compound D 4070 3,7-dihydro-3- -) 2,2-dimethylpropyl (-8-methyl-1H-purinedione-2,6)</td><td> 1,8</td><td>loss of balance</td><td> 693,3±22,2</td><td> 1,5</td>

<td>Compound D 4138 of formula 28</td><td> 5</td><td>loss of balance, salivation</td><td> 543,6+31,7</td><td> 15</td>

<td>Compound D 4137 (3,7-dihydro-8 ^ methyl-3-cyclohexylmethyl-1H-purinedione-2,6)</td><td> 4</td><td>loss of balance, salivation</td><td> 493,1 ±19,4</td><td> 10</td>

<td>Compound D 4132 of formula 22</td><td> 5,65</td><td>loss of salivation</td><td> 593+21,9</td><td> 3,4</td>

<td>Compound D 4134 3-cyclopentyl-3,7-dihydro-8-anethyl-1H ^ purinedione-2,6)</td><td> 5,85</td><td></td><td></td><td></td>

<td>Compound D 4164 of formula 16</td><td> 3,8</td><td>loss of balance clonic / tonic seizures 3/10</td><td> 519,2 ±16,86</td><td> 2,1 .</td>

<td>Compound &lt;D 4161 of formula 10</td><td> 0,5</td><td>single cramps and clonic seizures 1/10 loss of balance</td><td> 1030±39,3</td><td></td>

<td>Compound D 4169 3,7-d'ihydro-8-me^;methyl-3 -) - 2-methylpropyl) -lH-2,6-purynodaon)</td><td> 10,3</td><td>loss of balance single clonic convulsions</td><td> 488,2±8,1</td><td> 4</td>

a) Preparation of 6-amino-1-cyclopropyl- (1H, 3H) -pyrimidinedione-2,4 (compound of formula 6).

To a solution of 64 g (0.75 mol) of cyanoacetic acid and 250 ml of acetic anhydride are added 70 g (0.7 mol) of cyclopropylurea, after which the solution is stirred at 60-70 ° C for 2 hours. After cooling the solution, the white colored crystals are filtered off and washed with ethanol. 76.7 g (66% of theory) of the compound of formula 5 is obtained, which is suspended in 200 ml of hot liquid. 55 ml of 5N NaOH are added portionwise to the suspension so that the solution is basic all the time. The reaction mixture is heated at reflux for 20 minutes and then neutralized with 5N HC-1. After cooling, the white colored crystals are filtered off, to obtain 31.7 g (42% of theory) of the compound of formula 6, whose structure is confirmed by NMR.

b) Preparation of 6-amimo-1-cyclopropyl-5-nitro-zod (1H, 3H) -pyrimidinedione-2,4.

31.7 g (0.19 mol) of 6-amino-1-cyclopropyl- (1H, 3H) -pyrimidinedione-2,4 (compound of formula 6) are suspended in 250 ml of water, then 45 ml of 5n are added HCl and 15 g (0.22 mol) NaNO₂, previously dissolved in water. The reaction mixture is stirred for 2 hours and after cooling, the red colored crystals are filtered off and washed with water. 31.9 g (86% of theory) of the compound of formula 7 is obtained, whose structure is confirmed by NMR. .

c) Preparation of 1-cyclopropyl-5,6-diamino- (1H, 3H) -pyrimidinedione-2,4.

15.9 g 6-amino-1-cyclopropyl-5-nitroso (1H, 3H) -pyrimidinedione-2,4 (compound of formula 7) is catalytically hydrogenated in 1 liter of dimethylformamide and in the presence of 0.1 g PtO₂by carrying out the reaction for 4 hours at room temperature and 200 kPa pressure. The catalyst and crystals are filtered off and washed with ethanol to give

12.9 g (87% of theory) of the compound of formula 8.

d) Preparation of 3-cyclopropyl-3,7-dihydro-1 H -puridinedione-2,6 (compound of formula 10).

A solution of 12 g of 1-cyclopropyl-5,6-diamino- (1H, 3H) -pyrimidinedione-2,4 (compound of formula 8) in 50 ml of formic acid is heated under reflux for 2 hours. The hot solution is filtered, then 30 ml of chloroform are added, then ether is slowly added and the resulting crystals are filtered off. 11 g of the amide of formula 9 are obtained, which is refluxed with 40 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals are filtered off to give 7 g (60% of theory) of the compound of formula 10, the structure of which is confirmed by NMR (Table 2). The above reactions are illustrated in diagram 2.

Example II Preparation of 3-cyclobutyl-3,7-dihydro-1H-purinedione-2,6 (compound of formula 16). a) Preparation of 6-amino-1-cyclobutyl- (1H, 3H) -pyrimidinedione-2,4 (compound of formula 12).

119 413

To a solution of 30 g (0.35 mol) of cyanoacetic acid and 100 ml of acetic anhydride, 36.1 g (0.32 mol) of cyclobutylurea are added. The solution is stirred at 60-70 ° C for 2 hours, and after cooling, the white colored crystals are filtered off and washed with ethanol. 36.4 g (63% of theory) of the compound of formula 11 is obtained, which is suspended in 100 ml of hot water. 50 ml 2N NaOH is added portionwise to the suspension so that the solution is alkaline all the time. The reaction mixture is heated at reflux for 20 minutes, and after cooling, the white colored crystals are filtered off. 3.6 g (20% of theory) of the compound of formula 12 is obtained, whose structure is confirmed by NMR.

b) Preparation of 6-amino-1-cyclobutyl-5-nitroso - (1H, 3H) -pyrimidinedione-2,4 (compound of formula 13).

3 g (0.0166 mol) of 6-amino-1-cyclobutyl- (1H, 3H) -pyrimidinedione-2.4 are suspended in 25 ml of water, then 4 ml of 5N HCl and 1.3 g (0.019 mol) are added. ) NaNO₂, previously dissolved in water. The reaction mixture is stirred for 3 hours, then the red colored crystals are filtered off and washed with water to obtain 3.1 g (89% of theory) of the compound of formula 13, whose structure is confirmed by NMR.

c) Preparation of 1-cyclobutyl-5,6-diamino.nc- (1H, 3H) -pyrimidinedione-2,4 (compound of formula, 14).

6.9 g of 6-amino-1-cyclobufyl-5-nitroso-1H, 3H) -pyrimidinedione-2,4 of formula 13 is catalytically hydrogenated in 120 ml of dimethylformamide and in the presence of 0.1 g of PtO₂ conducting the reaction for 2 hours at room temperature and pressure of 200 kPa. The catalyst and crystals are filtered off and washed with ethanol to obtain 3.5 g (5 ±% of theory) of the compound of formula 14.

d) Preparation of 3,3-cyclobutyl-3,7-dihydro-1H-purinedione (compound of formula 16).

A solution of 3.5 g of 1-cyclobutyl-5,6-diamino- (1H, 3H) -pyrimidinedione-2,4 of formula 14 in 20 ml of formic acid is heated under reflux for 2 hours. The hot solution is filtered, 20 ml of chloroform are added, then ether is slowly added and the precipitated crystals are filtered off. 2.7 g of the amide of formula 15 are obtained, the kifers are heated with 20 ml of 2N NaOH at reflux for 1 hour and then neutralized with 5N HCl. The crystals are filtered off and recrystallized from 150 ml of ethanol to obtain 1.4 g (38% of theory) of the compound of formula 16, the structure of which is confirmed by NMR (see Table * Table 2). The above reactions are illustrated in diagram 3.

Example III. Preparation of 3-cyclopentyl-3,7-dihydro-1H-purinedione-2,6 (compound of formula 22).

a) To a solution of 136 g (1.6 mol) of cyanoacetic acid and 400 ml of acetic anhydride are added 192 g (1.5 mol) of cyclopentylurea, after which the solution is stirred at 60-70 ° for 2 hours. After cooling, the white colored crystals are filtered off and washed with ethanol, 192 g (66% of theory) of the compound of formula 17. The tein compound is stirred in 500 ml hot water and 195 ml of 5N NaOH are added in portions so that the solution has acid reaction all the time. The reaction mixture is heated and refluxed for 20 minutes, followed by neutralization with 5N HCl. After cooling, 159 g of white colored cyclopentylurea crystals are filtered off. The filtrate is evaporated and the residue is heated to reflux with 200 ml IN NaOH. After cooling, the cyclopentyl urea is filtered off and the filtrate is neutralized with 5N HCl. Filtration of the crystals gives 3.8 g (2% of theory) of the compound of formula 18, whose structure is confirmed by NMR.

b) Preparation of 6-amino-1-cyclopentyl-5-nitroso (1H, 3H) -pyrimidinedione-2,4 (compound of formula 19).

12.4 g (0.064 mol) of 6-amino-1-cyclopentyl- (1H, 3H) -pyrimidinedione-2,4 of formula 18 are suspended in 200 ml of water. 14 ml of 5N HCL and 4.8 g (0.07 mol) NaNO are added to the suspension₂, previously dissolved in water. The reaction mixture is stirred for 1 hour and washed with water. 12.9 g (90% of theory) of compound 19 is obtained, whose structure is confirmed by NMR.

c) Preparation of 1-cyclopentyl-5,6-diammonio- (1H, 3H) -pyrimidinedione-2,4 (compound of formula 20).

12.9 g 6-amLene-1-cyclopentyl-5-nitroso (1H, 3H) -pyrimidinedione-2,4 of formula 19 is catalytically hydrogenated in 30 ml 2N HCl and in the presence of 0.1 g PtO₂by carrying out the reaction for 3 hours at room temperature and pressure of 200 kPa. The catalyst is filtered off and the filtrate is neutralized with 5N NaOH. The crystals are filtered off to obtain 6.1 g (50% of theory) of the compound of formula 20.

d) Preparation of 3-cyclopentyl-3,7-dihydro-1H-purinedione-2,6 (compound of formula 22).

A solution of 6.1 g of 1-cyclopentyl-5,6-diamino- (1H, 3H) -pyrimidinedione-2,4 of formula 20 in 25 ml of formic acid is heated to reflux for 1 hour. The hot solution is filtered, 20 ml of chloroform are added, followed by the slow addition of ether. 5.9 g of the amide of formula 21 is obtained by filtration of the resulting crystals. This amide is heated with 30 ml of 2N NaOH at reflux for 1 hour, and then the solution is neutralized with 5n HCl. The crystals are filtered off and recrystallized from 400 ml of ethanol to obtain 3.4 g (53% of theory) of the compound of formula 22, whose structure is confirmed by NMR (see Table 2). The above reactions are illustrated in diagram 4.

Example IV Preparation of 3,7-dihydro-3-cyclohexylmethyl-1H-purinedione-2,6 (compound of formula 28).

a) Preparation of 6-amino-1-cyclohexylmethyl- &lt;1H, 3H) -pyrimidinedione-2,4 of formula 24 is carried out using the procedure given in Example UI a).

b) Preparation of 6-amino-1-cyclohexylmethyl-5-nitroso (1H, 3H) -pyrimidinedione-2,4 of formula 25 is carried out using the procedure given in example III b).

c) Preparation of 5,6-diamino-1-cyclohexylmethyl- (1H, 3H) -pyrimidinedione-2,4 of formula 26 is carried out using the procedure given in example II c).

d) Preparation of SJ-diliydro-S-cyclohexylmethyl-1H-purinedinedione-2,6 (compound of formula 28).

g 5,6-diamino-1-cyclohexylmethyl- (1H, 3H) -pyrimidinedione-2,4 of formula 26 and 10 ml formic acid are heated to reflux for 1 hour. 5 ml chloroform is added to the reaction mixture, followed by the slow addition of ether. The resulting crystals are collected by filtration, to obtain 2.1 g of the amide of formula 27. This amide and 15 ml of 2N NaOH are refluxed for 1 hour, followed by neutralization with 5N HCl. 1.7 g of compound of formula 28 are obtained, whose structure is confirmed by NMR (see Table 2). The above reactions are illustrated in diagram 5.

Example V. Preparation of 3,7-di'hydro (2,2-dimethyl'-propyl) -1H-purinediomium-2,6 (compound of formula 33).

a) The preparation of 6-amino-1- (2,2-dimethylpropyl) - (1H, 3H) -pyrimidinedione-2,4 of formula 30 is carried out using the procedure given in example III a).

b) Preparation of 6-amino-1- (2,2-dimethylpropyl) -5-nitroso (1H, 3H) -pyrimidinedione-2,4 (compound of formula 31).

To a solution of 7.0 g of the compound of formula 30 in 50 ml of dimethyl sulfoxide is added 8 ml of 5N HCl and 2.7 g NaNO₂ dissolved in 5 ml of water. The reaction mixture is stirred for 10 minutes at 50 ° C, then 160 ml of water are added. Red crystals are filtered off to obtain 6 g of compound of formula 31.

c) Preparation of 5,6-diimino- (2,2-dimethylpropyl) - (1H, 3H) -pyrimidinedione-2,4 (compound of formula 32).

To a suspension of 6.0 g of the compound of formula 31 in 100 ml of water, 13.0 g of sodium bisulfite are added portionwise, the green colored crystals are filtered off and washed with water. He receives. 4.0 g of compound of formula 32.

d) Preparation of 3,7-dihydro-3- (2,2-di-methylpropyl) -1H-purinedione-2,6 (compound of formula 33).

4.0 g of the compound of formula 32 and 20 ml of formamide are heated under reflux for 30 minutes. After cooling, 30 ml of ethanol are added, the yellow colored crystals are filtered off and they are recrystallized from 15 ml of dimethylformamide. 2.0 g of compound of formula 33 are obtained, whose structure is confirmed by the NMR spectrum (see Table 2). The above reactions are illustrated in diagram 6.

Example VI. Preparation of 3,7-dihydro-8-methyl-3-cyclohexylmethyl-1H-purinedione-2,6 (compound D 4137).

g 5,6-diamino-1-cyclohexylmethyl- (1H, 3H) -pyrimidinedione-2,4 of formula 26 and 5 ml acid

119 The acetic acid mixture is heated to reflux for 1 hour, then 2 ml of chloroform are added, followed by the slow addition of ether. The resulting crystals are filtered off to obtain 1 g of amide. Amide and 10 ml of 2 N NaOH · and refluxed for 1 hour, followed by neutralization with 5 N HCl. The crystals are filtered off and recrystallized from 80 ml of ethanol to give 0.6 g of compound D 4137, whose structure is confirmed by the NMR spectrum (see Table 2).

Example VII. Preparation of 3-cyclopentyl-3,7-dihydro-8-methyl-1H-purinedione-2,6 (compound D 4137).

1.6 g of 1-cyclopeinyl-5,6-diamin3- (1H, 3H) -pyridine and mid-2,4-dihydride of formula 20 and 10 ml of acetic acid are heated under reflux for 15 minutes after 10 ml of chloroform are added, followed by the slow addition of ether. The crystals are filtered off to give 2.0 g of amide. The amide and 5 ml of 2N NaOH are heated to reflux for 1 hour. The crystals are filtered off and recrystallized from 25 ml of 80% ethanol to give 0.7 g of compound D 4137, whose structure is confirmed by 2: NMR spectrum (see Table 2).

Example VIII. Preparation of 3,7-dihydro-3- (2,2-dimethylpropyl) -8 &lt;netyl-1H-purinedione-2,6 (compound D 4070).

10.4 g of diamino-1- (2,2-dimethylpropyl) - (1H, 3H) -pyrimidinedione-2,4 of formula 32 and 73 ml of acetic acid are heated under reflux for 1 hour, then 50 ml are added, followed by the slow addition of ether. The resulting crystals are filtered off to afford

11.4 g of amide. The amide and 50 ml of 1N NaOH are heated under reflux for 1 hour, followed by neutralization with 5N HCl. 7.2 g of compound D 4070 are obtained, whose structure is confirmed by NMR (see Table 2).

Example IX. Preparation of 3,7-dihydro-6-methyl-3- (2-methylprapyl) -1H-purinedinedicine-2,6 (compound D 41.69).

-g 5,6-diamino-1- (2-methylpropyl) -GH, 3H) - pyrimidinedione-2,4 and 50 ml of acetic acid are heated under reflux for 1 hour, after which 30 ml chloroform and then ether is slowly added. The resulting crystals * are filtered off to obtain 10.8 g of amide. The amide and 30 ml of 2N NaOH are heated to reflux, followed by neutralization with 5n PICI. The crystals are filtered off and recrystallized from 50 ml acetic acid to give 3.3 g of compound D 4169, whose structure is confirmed by NMR (see Table 2).

Table 2 presents the results of NMR analysis conducted at δ = 2.83 (DMSO-d₆).