Xantina derivatives and their pharmacologically tolerated salts

 

(57) Abstract:

Describes the new xanthine derivatives of the formula I, where the values of R1, R2, R3R4specified in paragraph 1 of the formula, which has antagonistic adenosine properties. 5 C.p. f-crystals, 2 tab.

The invention relates to new chemical substances with valuable biological properties, in particular a derivative of xanthine, which has antagonistic adenosine activity.

Known xanthine derivatives having antagonistic adenosine activity (see application EP N 0 374 808, C 07 D 473/06, A 61 K 31/52, 1990).

Object of the invention is the expansion of the range of xanthine derivatives having antagonistic adenosine activity.

The problem is solved, we offer xanthine derivatives of General formula I

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where R1is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 3-6 carbon atoms,

R2is hydrogen, alkyl with 1-8 carbon atoms, substituted by cyano, at least one hydroxyl group, halogen, a group of the formula-SO2R5, -S-R5where R5means unsubstituted or substituted UB>7in which R6denotes hydrogen, alkyl with 1-10 carbon atoms, cycloalkyl with 3 to 6 carbon atoms or benzyl and phenyl, unsubstituted or singly or multiply substituted by a methoxy group, a R7denotes hydrogen, alkyl with 1-10 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group, or R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may be substituted unbranched or branched alkyl with 1-4 carbon atoms or may have one the rest of the group, including balance = O, ketal, groups of the formula-OR8, -SO2-R8, -COR9in which R8denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group, and R9is alkyl with 1-4 carbon atoms, or a group of the formula-OR8, -NHCOR8, -OCOR8, -SO2-CH2-CH2-O-COR8, -COOR8, -CH=NOR8and-COR9where R8and R9have the above significance, or cycloalkylation carbon alkalinous part, unsubstituted or substituted in the phenyl by one or more residues from the group consisting of cyano, halogen, nitro, hydroxyl, groups of formula-CH2NR6R7, -OR8, -CH2-NH-SO2-R8, -OCOR8, -OCH2COOR8, -OCH2-CONR6R7, -OCH2CH2OR8, -COOR8, -CONR6R7, -SO2NR6R7and-OCH2-CH2OCOR8where R6- R8have the above meanings, or a residue of the formula A - alkylen or A-CONH-alkylene with 1 to 6 carbon atoms in alkalinous part where A means is connected through a carbon atom or nitrogen 5-or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur, and which may be substituted one or more times by alkyl with 1-4 carbon atoms, hydroxyl, remainder =O, Cetelem, group-COR9or-SO2R8where R8and R9have the above values, with R1may not have the same meaning as R2,

R3- cyclopentyl,

R4is hydrogen, benzyl,

and their pharmacologically tolerable salts.

The first group preferred xanthine derivatives include compounds of the above General formula is headed the remainder, selected from the group comprising halogen, cyano, hydroxyl, groups of the formula-OR8where R8have the above values, -NR6R7where R6and R7have the above values, -NHCOR8where R8have the above values, -OCOR8where R8has the above value, -SR5and-SO2R5where R5have the above values, -OCH2-CH2-NR6R7where R6and R7have the above values, -COOR8where R8have the above values, - CONR6R7where R6and R7have the above values,

-COR9where R9have the above values, benzyl, phenylethyl or phenylpropyl substituted by a residue from the group comprising halogen, cyano, nitro, hydroxyl, groups of formula-CH2NR6R7where R6and R7have the above values, -OR8where R8have the above values, -OCOR8where R8have the above values, -OCH2COOR8where R8have the above values,

-OCH2-CONR6R7where R6and R7have the above values,

-OCH2CH2OH, -OCH2CH2OR8where R8is the B>6and R7have the above values, -OCH2-CH2OCOR8where R8have the above values, cycloalkylation with 3 to 6 carbon atoms in cycloalkyl part and 2-3 carbon atoms in alkalinous part,

the rest of the formulas A-CH2-, A-CH2-CH2-, A-CH2-CH2-CH2-, A-CO-NH-CH2-, A-CO-NH-CH2-CH2- or A-CO-NH-CH2-CH2-CH2- where A denotes the bound through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur, and can be substituted one or more times by alkyl with 1-4 carbon atoms, a residue, a hydroxyl group COR9where R9have the above values, a group of SO2-R8where R8have the above values, and the radicals R3and R4have the above meanings, and their pharmacologically tolerated salts.

The second group preferred xanthine derivatives include compounds of the above General formula (I), where R1- propyl, R2and R3have the above values, R4means hydrogen, and their pharmacologically tolerated salts.

In a third preferred group produced 2 or 3 carbon atoms, substituted by cyano, hydroxyl, carboxyla, groups of the formula-COOR8where R8have the above meanings, in particular methyl, ethyl, -OCOCH3-EA2H5, -CONR6R7or-NR6R7in which R6and R7have the above meanings, and their pharmacologically tolerated salts.

In the fourth group of preferred xanthine derivatives include compounds of the above General formula (I), where R2means the residue of formula (A-alkylen or A-CONH-alkylene, each with 1-3 carbon atoms in alkalinous part, And where means bound through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur and may be substituted one or more times by alkyl with 1-4 carbon atoms, hydroxyl, groups =O, -SO2-R8where R8have the above values, -COR9where R9have the above meanings, and their pharmacologically tolerated salts.

In the fifth group of preferred xanthine derivatives include compounds of the above General formula (I), where R2-H2CH2OH, -CH2CH2OCOCH3, (CH2)3OCOCH3, (CH2)3OCHH2CONH2, (CH2)3CONH2CH2CH=NOH, (CH2)3CN, -CH2CH2SCH2CH3,

-CH2CH2SCH2CH2OH, -CH2CH2SO2CH2CH2OH, CH2CH2SO2CH2CH2OCOCH3,

A-(CH2)2or A-(CH2)3- where A is bound through a carbon atom or nitrogen 5-or 6-membered heterocyclic ring containing as heteroatoms nitrogen, oxygen or sulfur, and their pharmacologically tolerated salts.

Xantina derivatives with high affinity for adenosine A1help neurotransmission in the brain, and they can be considered, for example, as a functional tool, which stimulates choline.

These substances play an important role for therapy of symptoms of degenerative diseases of the Central nervous system, such as senile dementia and Alzheimer's disease.

High affinity receptors allows the use of small doses of active substances, so that hardly any adverse actions that are not caused by blocking adenosine receptors. In addition, the above antagonists of adenosine can be used not only as psihotvoreniya and respiratory diseases, in particular bronchial asthma. In addition, xantina General formula (I) exhibit diuretic properties, so that they are suitable for the treatment of diseases of the kidneys and due to diuresis - also for the treatment of high blood pressure.

Further possible indications are degenerative diseases, such as, for example, organic brain syndrome, Parkinsonism, depression, traumatic injury of the Central nervous system, post-infarction neurological disorder, respiratory depression (intoxication after) related to early childhood trauma, dyslexia and hyperactivity. Compounds of General formula (I), where R3contains unsubstituted or substituted phenylidole possibly suitable for the treatment of Parkinson's disease.

Cystic fibrosis, also known as mucoviscidosis, is a hereditary metabolic disorder caused by a genetic defect of a certain chromosome. Ill only homozygous carriers of the trait. Genetic defect leads to dysfunction of the exocrine glands. Due to increased production of secretions of the mucous glands in the bronchi and its high viscosity can be udalenie chloride ions, for example, when cells CF PAC, and CF stands for cystic fibrosis, and PAC - pankreas adenocarcinoma (cancer of the pancreas). These cells belong to the cell line carcinoma of the pancreas secreted from patients with cystic fibrosis. In the experience of the action block agonists, such as 2-chlorobenzene. Increased excretion was observed only in cells from diseased patients and the cells having the corresponding gene defect.

From these results, it can be expected that in patients with cystic fibrosis (mucoviscidosis), proposed connection govern violated the electrolytes in the cells, making soften the symptoms of the disease.

Antagonists of adenosine can be used for the treatment of lung diseases, in particular asthma, allergic lung diseases and chronic capsules lung diseases. Expect that due to the high activity of the proposed compounds can also be used to treat diseases of the lungs by inhalation.

Of particular interest is the combination of the proposed compounds of General formula (I), in particular specifically mentioned compounds, with finalisations dei is ical diseases.

Data binding receptors define similarly Ensinger and others, "Cloning and functional characterization of human A1adenosine Receptor - Biochemical and Biophysical Communications, volume 187, No. 2, pp. 919 -926,1992 year).

The action caused by the agonist adenosine inhibition of locomotor activity in mice: antagonism of adenosine

Subcutaneous giving agonist adenosine causes in mice during the next after application hours locomotor inhibition. Determine the influence of the studied compounds on hypokinesis.

When performing experience measures the number of movements of mice by installed in suitable chambers poliacek. Reading begins immediately after giving the matter, and it is carried out by means of a computer. The measurement is carried out only within one hour after application, because the action of the agonist adenosine there is only during this period. Get ED50in mg/kg (see table. 1).

While one group of mice and give agonist adenosine, and investigated the connection, another group of animals given a placebo (a solution of tylose and sodium chloride), third - agonist adenosine and the solution of tylose, and the fourth - highest dose tested compound and the sodium chloride solution. Individual animals swetnam method (see, for example, scheme I, II and III). Synthesis of xantina specialist well known, but below are explained on the example of the important joints.

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Characteristic is shown in scheme I synthesis is that R2'put on the stage (III) of diaminoanisole. The remainder R2'is the functional residue selected from the group of the remainder R2with the proviso that the residue R2'should not interfere with the synthesis of xanthine and before or after removal of the protective group R4(preferably benzyl) (General formula (VIII) can be converted to the desired balance of R2the General formula (I). Preferred radicals R2'is, for example, methoxybenzyl. By acylation of the amino group and subsequent cyclization to xanthine enter the remainder R3. For targeted alkylation in position 1 protection group in position 7, for example, benzyl group. The alkylation is carried out by interaction with the group R4Z, and R4means benzyl or methyl, a Z means easy tsepliaeva group, such as halogen, mesyl or tosyl. If in the final compound of General formula (I) residue R4means methyl group, xanthine of the formula (V) melirovanie. By removal of the protective group at position 7 can be transfer radical R4in hydrogen. If R2'not yet has the desired value R2the target compound of formula (I), at this stage, the radical R2'transferred to R2(formula (VIIa)), and, if necessary, then otscheplaut protective group. Examples for this are described in the following example, sections 12 and 14 - 23. Compounds of General formula (II) and (III) are important intermediate compounds.

Unexpected was that the n-methoxybenzyloxy group, or di-, or trimethoxybenzyl group in the 3 position of the xanthine of the formula (IX) can be selectively split with getting benzyl protective group in position 7. Thus, the new method can be obtained xanthine derivatives of General formula (I). By alkylation of xantina General formula (X) with R2'-X, where X is a halogen, a hydroxyl group, mesyl or tosyl, removal of the protective benzyl groups and the possible transfer of the radical R2'in the radical R2simple way it is possible to obtain compounds of General formula (I).

Thus the invention relates to a simple, common way of getting substituted in positions 1 and 3 proizvoditeli by the following schema.

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The compound of General formula (X) in which R4means benzyl, can be obtained in simple manner by acidic hydrolysis (using, for example, the compound of formula (IX) in which R4means benzyl, and R2- p-methoxybenzyl).

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The following example illustrates the obtaining of the proposed connections.

Example

1. Monosubstituted urea

In a solution of 18.3 ml (0.34 mol) of concentrated sulfuric acid in 1000 ml of distilled water dissolve 0.69 mol amine. The mixture is heated to a temperature of 85oC add 55.8 g (0.69 mol) of potassium cyanate and stirred at this temperature for 30 to 90 minutes to complete the reaction. The reaction mixture is diluted with ethanol, cooled to room temperature and filtered. The filtrate is concentrated and the solid residue dried in a drying Cabinet.

Thus have, for example, the following monosubstituted urea:

a) p-methoxybenzylamine with access to 85.5% of theory, and so pl. 156 - 158oC

b) 2-(p-methoxyphenyl)-utilmately with access to 91.4% of theory, and so pl. 127oC

C) 3-(p-methoxyphenyl)- propylacetic with access to 91.8% of theory, and so pl. 170 - 173oC

g) 2 - methoxyethylamine with the release of 97.3% of theory, and so pl. 72who cawino with access to 73.2% of theory, and so pl. 150 - 151oC

W) 2-(p-bromophenyl)-utilmately with access 92,3% of theory, and so pl. 183 - 184oC

C) 3-(p-chlorophenyl)-propylacetic with access to 82.4% of theory, and so pl. 146 - 150oC.

2. Substituted cancerologie

200 ml of acetic anhydride is mixed with 57.6 g (of 0.68 mol) tsianuksusnogo acid and 0.62 mol obtained in stage 1 monosubstituted urea. The original mixture is heated to a temperature of 75 - 80oC and stirred at this temperature for 30 to 90 minutes to complete the reaction. Then cooled, diluted with ordinary air, is sucked off and the crystalline product is washed with simple ether.

Thus get the following cancerologie:

a) N-(p-methoxybenzyl)-N'-ciancimino with the release of 81.3% of theory, and so pl. 185oC

b) N-(2-(p-methoxyphenyl)-ethyl)-N'-ciancimino with yield 69% of theory, and so pl. 142 - 151oC

C) N-(3-(p-methoxyphenyl)-propyl)-N'-ciancimino with access to 83.7% of theory, and so pl. 162 - 164oC

g) N-2-methoxyethyl-N'-ciancimino with the release of 78.9% of theory, and so pl. 129 - 132oC

d) N-3-methoxypropyl-N'-ciancimino with the release of 74.4% of theory, and so square 138 - 140oC

e) N-(2-(p-chlorophenyl)-ethyl)-N'-ciancimino with the release of 59.5% of theory o
C.

3.1-substituted 6-aminouracil

0.5 mol obtained in stage 2 substituted cancerologie served in 1250 ml of absolute ethanol and heated to a temperature of 50 - 80oC. Then was added dropwise a solution of 3.8 g (to 0.17 mol) of sodium in 190 ml of absolute ethanol and the resulting suspension is stirred at a temperature of phlegmy within 30 minutes. The reaction mixture is diluted with distilled water, cooled, if necessary, neutralized by adding hydrochloric acid and the crystalline product is sucked off.

Thus get, for example, the following 1-substituted 6-aminouracil:

a) 6-amino-1-(p-methoxybenzyl)-uracil with the release of 63.3% of theory, and so pl. 276 - 278oC

b) 6-amino-1-(2-(p-methoxyphenyl)-ethyl)-uracil with yield 69% of theory, and so pl. 233 - 236oC

C) 6-amino-1-(3-(p-methoxyphenyl)-propyl)-uracil with access to 69.3% of theory

g) 6-amino-1-(2-methoxyethyl)-uracil with access to 41.6% of theory, and so pl. 229 - 230oC

d) 6-amino-1-(3-methoxypropyl)-uracil with the release of 68.1% of theory, and so pl. 208 - 210oC

e) 6-amino-1-(2-(p-chlorophenyl)-ethyl)-uracil with the release of 78,1% of theory, and so pl. 282 - 283oC

g) 6-amino-1-(2-(p-bromophenyl)-ethyl)-uracil with access to 56.1% from theory, and so pl. 291 - 292oC.

4.1-substituted l of distilled water; in the case of particularly sparingly soluble starting compounds add ethanol. The reaction mixture is heated to a temperature of 80oC and mixed with a solution of 0.36 g (5.3 mmol) of sodium nitrite in 3 ml of distilled water. Then add 0.7 ml of glacial acetic acid and stirred at a temperature of 80oC to complete the reaction. The reaction mixture is cooled, purple-red residue is sucked off and washed with distilled water.

Thus receive, among other things, the following 1-substituted 6-amino-5-nitrosourea:

a) 6-amino-5-nitroso-1-(p-methoxybenzyl)-uracil with the release of 90.6% of theory, and so pl. 233oC

b) 6-amino-5-nitroso-1-(2-(p-methoxyphenyl)-ethyl)-uracil with the release of 75.8% of theory, and so pl. 227oC

C) 6-amino-5-nitroso-1-(3-(p-methoxyphenyl)-propyl)-uracil with access 49,1% of theory

g) 6-amino-5-nitroso-1-(2-methoxyethyl)-uracil with the release of 80% of theory, and so pl. 222oC

d) 6-amino-5-nitroso-1-(3-methoxypropyl)-uracil with the output of 58.5% of theory, and so pl. 227 - 228oC

e) 6-amino-5-nitroso-1-(2-(p-chlorophenyl)-ethyl)-uracil with access and 88.5% of theory, and so pl. 235 - 236oC

g) 6-amino-5-nitroso-1-(2-(p-bromophenyl)-ethyl)-uracil with the release of 76.6% of theory, and so pl. 248oC.

5.1-substituted 5,6-diamino-Uraz the data of ammonia. Especially when sparingly soluble source connections add ethanol. Then at a temperature of 30oC drops add a solution of 2.35 g (13.5 mmol) of dithionite sodium in 24 ml of distilled water. Stirred at room temperature until completion of the reaction. The crystalline product is sucked off and washed with distilled water.

Thus get the following 1-substituted 5,6-diaminodecane:

a) 5,6-diamino-1-(p-methoxybenzyl)-uracil with the release of 93,2% of theory, and so pl. 252oC

b) 5,6-diamino-1-(2-(p-methoxyphenyl)-ethyl)-uracil with access and 88.5% of theory, and so pl. 249 - 250oC

C) 5,6-diamino-1-(3-(p-methoxyphenyl)-propyl)-uracil with the release of 80.5 per cent of theory, and so pl. 252 - 253oC

g) 5,6-diamino-1-(2-methoxyethyl)-uracil with the release of 84.4% of theory, and so pl. 246oC

d) 5,6-diamino-1-(3-methoxypropyl)-uracil with the output of 58.5% of theory, and so pl. 248oC (decomposition)

e) 1-(2-(p-chlorophenyl)-ethyl)-5,6-diaminofurazan with access to 66.3% of theory, and so pl. 279 - 280oC

W) 1-(2-(p-bromophenyl)-ethyl)-5,6-diaminofurazan with access 79,7% of theory, and so pl. 273oC (decomposition).

6. 1-substituted 6-amino-5-acylaminoacyl or 1-substituted 5-amino-6-acyl-aminouracil

The position of acylation (position 5 and 6) has no isobutane product, which acelerou in position 5.

0.46 mol obtained at stage 5 1-substituted 5,6-diaminoanisole suspended together from 78.2 g (0.64 mol) of 4-dimethylaminopyridine in 2400 ml of absolute dimethylformamide. At a temperature of 0 to 5oC was added dropwise a solution of 0.55 mol of the corresponding carboxylic acid in 200 ml of dimethylformamide, stirred with ice cooling until the reaction and left to warm to room temperature. The reaction mixture is concentrated to dryness and the residue is mixed with distilled water. Then the crystalline product is sucked off and washed with distilled water and simple diethyl ether.

Thus get the following connections:

a) 6-amino-5-cyclopentanecarbonyl-1- (p-methoxybenzyl)-uracil with the release of 88.3% of theory, and so pl. 261 - 262oC

b) 6-amino-5-cyclopentanecarbonyl-1-(2- (p-methoxyphenyl)-ethyl)-uracil with the release of 80.6% of theory, and so pl. 217 - 222oC

C) 6-amino-5-cyclopentanecarbonyl-1-(3-(p-methoxyphenyl)- propyl)-uracil with the release of 84.8% of theory, and so pl. 126 - 128oC

g) 6-amino-5-cyclopentanecarbonyl-1-(2-methoxyethyl)-uracil with the release of 84.4% of theory, and so pl. 209 - 213oC

d) 6-amino-5-cyclopentanecarbonyl-1-(3-methoxypropyl the om to 66.3% of theory, and so pl. 258 - 259oC

g) 6-amino-5-cyclopentanecarbonyl-1-(2-(p-bromophenyl)-ethyl)- uracil with the release of 68.5% of theory, and so pl. 245 - 246oC.

7. Substituted in positions 3 and 8 xantina

0.01 mol obtained at stage 6 1-substituted 6-amino-5-acylaminoacyl (or 1-substituted 5-amino-6-acylaminoacyl) is suspended in 10 ml of tetrahydrofuran and mixed with a solution of 2.38 g (0,056 mol) of hydrate of lithium hydroxide in 70 ml of distilled water. The reaction mixture is stirred at a temperature of 70 - 80oC to complete the reaction is acidified by adding hydrochloric acid and cooled. The crystalline product is sucked off and washed with distilled water.

If you want to clear recrystallized from ethanol.

Thus get the following substituted in positions 3 and 8 xantina:

a) 8-cyclopentyl-3-(p-methoxybenzyl)-xanthine with access 77,8% of theory, and so pl. 311oC

b) 8-cyclopentyl-3-(2-(p-methoxyphenyl)-ethyl)-xanthine with access 42.3% of theory, and so pl. 256 - 258oC

in) 8-cyclopentyl-3-(3-(p-methoxyphenyl)-propyl)-xanthine with access 90,5% of theory, and so pl. 292 - 293oC

g) 8-cyclopentyl-3-(2-methoxyethyl)-xanthine with access to 68.3% from theory, and so pl. 293 - 294oC

d) 8-cyclopenta the Teal)-xanthine with access 81.3% of theory, and so pl. 298 - 299oC

W) 8-cyclopentyl-3-(2-(p-bromophenyl)-ethyl)-xanthine with access for 60.1% of theory, and so pl. 306 - 307oC.

8. Substituted in positions 3 and 8 7-benzylcyanide

0.02 mol obtained in stage 7 substituted in position 3 and 8 xantina and 3.0 g (0,022 mol) of potassium carbonate are suspended in 140 ml of absolute dimethylformamide. Then stirred at room temperature for one hour and added dropwise 2,62 ml (0,022 mol) of benzylbromide. The mixture is then stirred at room temperature. If the response ends before full conversion of all parent compounds, then again add up to 35 mol.% potassium carbonate and benzylbromide. After completion of the reaction the mixture is condensed to dryness, the residue absorbed in methylene chloride and extracted with water. The organic phase is dried over sodium sulfate and concentrated to dryness. The residue is purified by crystallization or chromatography.

Thus get the following substituted in positions 3 and 8 7 - benzylcyanide:

a) 7-benzyl-8-cyclopentyl-3-(p-methoxybenzyl)-xanthine with access 66,2% of theory, and so pl. 165oC

b) 7-benzyl-8-cyclopentyl-3-(2-(p-methoxyphenyl)-ethyl)-xanthine with yield 77% of theory, and so pl. 152oC

C) 7-benzyl-8-cyclopentyl-3-(3-(p-methoxyphenyl)-providedon 69,1% of theory, and so pl. 140oC

d) 7-benzyl-8-cyclopentyl-3-(3-methoxypropyl)-xanthine with access to 77.7% of theory, and so pl. 130 - 132oC

e) 7-benzyl-8-cyclopentyl-3-(2-(p-chlorophenyl)-ethyl)-xanthine with access 39.8% of theory, and so pl. 179 - 180oC.

9. Substituted in positions 1,3 and 8 7-benzylcyanide

6.5 mmol received at stage 8, substituted in positions 3 and 8 7-benzylcyanide, 1.0 g (7,15 mmol) of potassium carbonate and to 7.15 mmol alkyl-, alkenyl or alkylhalogenide mix in 56 ml of absolute dimethylformamide until complete conversion of the educt (if necessary, then again add the potassium carbonate and alkylhalogenide). The reaction mixture is neutralized, concentrated, the residue is mixed with methyl chloride and extracted with distilled water. The organic phase is dried over sodium sulfate and concentrated to dryness and, if necessary, the residue is purified by crystallization or chromatography.

Thus get the following substituted in positions 1, 3 and 8 7-benzylcyanide:

a) 7-benzyl-8-cyclopentyl-3-(p-methoxybenzyl)-1-profilkanten with a yield of 99% of theory, and so pl. 110 - 111oC

b) 7-benzyl-8-cyclopentyl-3-(2-(p-methoxyphenyl)-ethyl)-1 - profilkanten with yield 77% of theory, and so pl. 151oC

C) 7-benzyl-8-cyclopentylmethyl-3-(2-methoxyethyl)-1-profilkanten exit 97.7 per cent of theory, and so pl. 80 - 81oC

d) 7-benzyl-8-cyclopentyl-3-(3-methoxypropyl)-1-profilkanten with the release of 61.8% of theory, and so pl. 76 - 80oC

e) 7-benzyl-8-inclemency-3-(2-(p-chlorophenyl)-ethyl)-1 - profilkanten with the release of 67.9% of theory in the form of a colorless oil

W) 1-allyl-7-benzyl-8-cyclopentyl-3-(3-methoxypropyl)-xanthine with access 86,5% of theory in the form of a colorless oil.

From the thus obtained of xantina by varying the substituents in position 3 well-known specialist method you can get a lot further xanthine derivatives covered by the General formula (I).

10. Substituted in positions 1 and 8 7-benzylcyanide

6.3 mmol received at stage 9, substituted in positions 1 and 8 7-benzyl-3-p-methoxybenzylidene mixed with 30 ml triperoxonane acid and stirred at a temperature of 60oC in a protective gas atmosphere for 4 days. The resulting mixture was diluted with distilled water, extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated to dryness. The residue is purified by crystallization or chromatography.

Thus obtained 7-benzyl-8-cyclopentyl-1-profilkanten of 7-benzyl-8-cyclopentyl-3-(2-p-methoxybenzyl)-1-propylene 1 and 8 7-benzyloxyethanol

Method a:

0.5 mmol of substituted at positions 1 and 8 7-benzylcyanide obtained at stage 10, 75 mg (0.55 mmol) of potassium carbonate and 0.55 mmol (unsubstituted or substituted specified for R2substituents) alkyl-, alkenyl or alkylhalogenide, mix 3.5 ml of absolute dimethylformamide until completion of the reaction, if necessary under heating. Then neutralized, concentrated to dryness and the residue is distributed between methylene chloride and distilled water. The organic phase is dried over sodium sulfate, concentrated and the residue purified, if necessary, by crystallization or chromatography.

Similarly, from 7-benzyl-8-cyclopentyl-1-propylketone get 7-benzyl-8-cyclopentyl-3-(Z-(p-ethoxycarbonylphenyl)- ethyl)-1-profilkanten in the form of a viscous oil; yield: 67% of theory.

Method B:

To a solution of 0.56 g (2.1 mmol) of triphenylphosphine in 3.5 ml of absolute tetrahydrofuran successively added to 0.37 g (2.1 mmol) of a compound diethyl ester of azodicarboxylic acid and 1.4 mmol of substituted at positions 1 and 8 7-benzylcyanide obtained at stage 10. The mixture is cooled to a temperature of 5oC. At this temperature, was added dropwise 1.4 mmol (unsubstituted or substituted uke and room temperature until complete conversion of the educt. Concentrated to dryness and the residue purified by crystallization or chromatography.

Thus from 7-benzyl-8-cyclopentyl-1-propylketone receive the following connections:

a) 7-benzyl-8-cyclopentyl-1-propyl-3-(2-(2-pyridyl)- ethyl)-xanthine with a yield of 87% of theory in the form of a colorless oil

b) 7-benzyl-8-cyclopentyl-1-propyl-3-(3-(3-pyridyl)- propyl)-xanthine

C) 7-benzyl-3-(2-(p-cyanophenyl)-ethyl)-8-cyclopentyl-1 - propyl)-xanthine with access 29.7% of theory in the form of a colorless oil.

Similar methods 11. A) and 11.B) you can obtain the derivatives of xanthine, which are the radical R2already with the above values, or with values that can then be translated into values according to General formula (I) values.

12. Hydrolysis containing methyl ether derivatives of xanthine

Method a:

0.5 mmol contains a simple methyl ether derivative of xanthine are dissolved in 5 ml of absolute acetonitrile. Then add 300 mg (50 mmol) of sodium iodide and 0.39 ml (3.0 mmol) of chlorotrimethylsilane and the resulting suspension is stirred at room temperature or at a temperature of phlegmy to complete the reaction. The reaction mixture is cooled to room temperature, mixed with disti is lipata sodium, dried over sodium sulfate and concentrated to dryness. If necessary, the product is purified by crystallization or chromatography.

A similar method receive the following connections:

a) 7-benzyl-8-cyclopentyl-3-(3-oksipropil)-1-profilkanten with the release of 78.4% of theory in the form of a yellowish oil

b) 7-benzyl-8-cyclopentyl-3-(3-oxyethyl)-1-profilkanten with the release of 90% of theory with so pl. 208 - 209oC.

Method B:

4.8 mmol derived simple methyl ester are dissolved in 60 ml of absolute methylene chloride. At -20oC +5oC was added dropwise a solution of 0.65 ml (6.5 mmol) of tribromide boron in 7 ml of absolute methylene chloride and stirred at room temperature until completion of the reaction. The reaction mixture is washed with distilled water, the organic phase is dried over sodium sulfate and concentrated to dryness. The residue is purified by crystallization or chromatography.

Similarly receive the following connections:

a) 8-cyclopentyl-3-(2-oxyethyl)-1-profilkanten with the release of 80.7% of theory, so pl. 216oC

b) 8-cyclopentyl-3-(2-(p-oxyphenyl)-ethyl)-1-profilkanten with the release of 83.5% of theory, so pl. 270 - 272oC

C) 7-benzyl-8-inclemency-3-(3-(p-oxyphenyl)-propyl)-1 - profilkanten with the release of 97.3% TL. 116 - 117oC

13. Hydrogenolysis of N-benzyl-substituted xanthine derivatives

Method a:

0.1 mol of N-benzyl-substituted xanthine derivative is subjected to hydrogenation under pressure in the presence of 0.5 g of palladium on active coal or catalyst Perlman in the environment of methanol, tetrahydrofuran or glacial acetic acid, if necessary while heating, until complete conversion of the starting compound. Filtered from the catalyst, the filtrate is concentrated to dryness and the residue purified by crystallization or chromatography.

A similar method receive, for example, the following connections:

a) of 7-benzyl-8-cyclopentyl-3-(2-(p-methoxyphenyl)-ethyl)- 1-propylketone:

8-cyclopentyl-3-(2-(p-methoxyphenyl)-ethyl)-1-propichshagin with access 70,6% of theory with so pl. 208oC

b) from 1-allyl-7-benzyl-8-cyclopentyl-3-(3-methoxypropyl)- xanthine:

8-cyclopentyl-3-(3-methoxypropyl)-1-profilkanten with 71.4% of theory with so pl. 174 - 175oC

in) of 7-benzyl-8-cyclopentyl-3-(3-(oksipropil)-1 - propylketone:

8-cyclopentyl-3-(3-oksipropil)-1-profilkanten with the release of 26.6% of theory with so pl. 213 - 215oC

g) of 7-benzyl-8-cyclopentyl-3-(3-(p-methoxyphenyl)-propyl)-1 - propylketone:

8-cyclopentyl-3-(3-(n-m is I active coal in a mixture of methanol and hydrochloric acid from

7-benzyl-3-(2-carboxyethyl)-8-cyclopentyl-1-propylketone:

8-cyclopentyl-3-(2-methoxycarbonylethyl)-1-profilkanten with the release of 16.3% of theory with so pl. 201 - 203oC

e) from 7-benzyl-8-cyclopentyl-3-(3-p-1 oksifenil)- propyl))-1-propylketone:

8-cyclopentyl-3-(3-(p-oxyphenyl)-propyl)-1-profilkanten with the release of 26.8% of theory with so pl. 239 - 241oC

g) of 7-benzyl-8-cyclopentyl-3-(2-(methylaminomethyl)- ethyl)-1-propylketone:

8-cyclopentyl-3-(2-(methylaminomethyl)-ethyl)-1-profilkanten with the release of 67.7% of theory so pl. 297 - 298oC

C) from 7-benzyl-8-cyclopentyl-3-(2-(3,4,5 - trimethoxybenzylamine)-ethyl-1-propylketone:

8-cyclopentyl-3-(2-(3,4,5-trimethoxybenzylamine)- ethyl)-1-profilkanten with the release of 77.2% of theory with so pl. 231 - 233oC

and) of 7-benzyl-8-cyclopentyl-3-(3-(p-methylcarbamoylmethyl)- propyl)-1-propylketone:

8-cyclopentyl-3-(3-(p-methylcarbamoylmethyl)-propyl)-1 - profilkanten with the release of 63.9% of theory with so pl. 181 - 183oC

K) of 7-benzyl-8-cyclopentyl-3-(2-(N-morpholinomethyl)- ethyl)-1-propylketone:

8-cyclopentyl-3-(2-(N-morpholinomethyl)-ethyl)-1-profilkanten with the release of 50% of theory with so pl. 169 - 171oC

l) of 7-benzyl-8-cyclopentyl-3-(3-(N-morpholino)-propyl)-1 - propylketone:
the 7-benzyl-8-cyclopentyl-3-(2-(2,4,6 - trimethoxybenzylamine)-ethyl)-1-propylketone:

8-cyclopentyl-3-(2-(2,4,6-trimethoxybenzylamine - carbonyl)ethyl)-1-profilkanten with access to 47.2% of theory with so pl. 241 - 243oC

n) of 7-benzyl-8-cyclopentyl-3-(3-(n-(ethoxycarbonylmethoxy)- phenyl)-propyl)-1-propylketone:

8-cyclopentyl-3-(3-(n-(ethoxycarbonylmethoxy)-phenyl)-propyl)- 1-profilkanten with the release of 77.4% of theory with so pl. 141 - 143oC

o) of 7-benzyl-8-cyclopentyl-3-(3-acetoxyphenyl)-1 - propylketone:

8-cyclopentyl-3-(3-acetoxyphenyl)-1-profilkanten with access to 93.5% of theory so pl. 157 - 159oC

p) of 7-benzyl-8-cyclopentyl-3-(3-oxobutyl)-1-propylketone:

8-cyclopentyl-3(3-oxobutyl)-1-profilkanten with access 60,0% of theory with so pl. 198 - 199oC

R) of 7-benzyl-8-cyclopentyl-3-(3-(n-(2-acetoxy)-phenyl)- propyl)-1-propylketone:

8-cyclopentyl-3-(3-(n-(2-acetoxy)-phenyl)-propyl)-1 - profilkanten with access to 59.6% of theory with so pl. 168 - 169oC

(C) from 7-benzyl-8-cyclopentyl-3-(3-(n-(2-(methylcarbonate)- ethoxy)-phenyl)-propyl)-1-propylketone:

8-cyclopentyl-3-(3-(n-(2-(methylcarbonate)-ethoxy)- phenyl)-propyl)-1-profilkanten with the release of 48.1% of theory with so pl. 139 - 140oC

t) of 7-benzyl-8-cyclopentyl-3-(3-(N-piperidinyl)- propyl)-1-propylketone:

8-cyclopentyl-3-(3-(N-piperidinyl)-preinit)-propyl)- 1-propylketone:

8-cyclopentyl-3-(3-(N-pyrrolidinyl)-propyl)-1-profilkanten with access for 52.6% of theory with so pl. 162 - 163oC

f) of 7-benzyl-8-cyclopentyl-3-(3-(n- (ethoxycarbonylmethoxy)-phenyl)-propyl)-1-propylketone:

8-cyclopentyl-3-(3-(n-(ethoxycarbonylmethoxy)-phenyl)- propyl)-1-profilkanten with the release of 86,5% of theory,1H-NMR (250 MHz, DMSO-d6) (h/mill) = 7,11 (d, J = 8,8 Hz, 2H), 6,79 (d, J = 8,8 Hz, 2H), 4.72 in (c, 2H), 3,98 (t, J = 7,3 Hz, 2H), 3,80 (t, J = 7,3 Hz, 2H), 3,69 (s, 3H), of 3.13 (m, 1H), to 2.55 (m, 2H), 2,07 - of 1.45 (m, 12H), of 0.85 (t, J = 7,6 Hz, 3H)

x) of 7-benzyl-8-cyclopentyl-3-(2-methoxyethyl)-1 - propylketone:

8-cyclopentyl-3-(2-methoxyethyl)-1-profilkanten with the release of 81.2% of theory with so pl. 185oC

C) from 7-benzyl-3-(2-(cyclohexyl)ethyl)-8-cyclopentyl-1 - propylketone:

3-(2-(cyclohexyl)ethyl)-8-cyclopentyl-1-profilkanten with so pl. 188 - 189oC

h) of 7-benzyl-8-cyclopentyl-3-(2-phenylethyl)-1-propylketone:

8-cyclopentyl-3-(2-phenylethyl)-1-profilkanten with the release of 34.5% of theory with so pl. 215 - 216oC

W) of 7-benzyl-8-cyclopentyl-3-(3-(phenyl)-propyl)-1 - propylketone:

8-cyclopentyl-3-(3-(phenyl)-propyl)-1-profilkanten with the release of 28.6% of theory with so pl. 153oC (decomposition)

y) of 7-benzyl-3-(3-cyanopropyl)-8-cyclopentyl-1 - propylketone:

3-(3-cyanopropyl)-8-cyclopentyl-1-propylketone:

3-(5-cyanophenyl)-8-cyclopentyl-1-profilkanten with the release of 21.1% of theory with so pl. 160oC (decomposition)

Yu) of 3-(3-(aminocarbonyl)-propyl)-7-benzyl-8-cyclopentyl - 1-propylketone:

3-(3-(aminocarbonyl)-propyl)-8-cyclopentyl-1-profilkanten with so pl. 164 -165oC.

Method B:

3.3 mmol of N-benzyl-substituted xanthine derivative is dissolved in 70 ml of absolute methylene chloride. Then add to 3.36 g (of 52.8 mmol) of ammonium formate and of 1.32 g of the catalyst Perlman and the resulting suspension is stirred at a temperature of phlegmy within two hours. After cooling, is filtered over silica gel and the filtrate concentrated to dryness. If necessary, the residue is purified by crystallization or chromatography.

Similarly, we can obtain other gidrogenizirovannye xanthine derivatives, such as 8-cyclopentyl-1-propyl-3-(2-(2 - pyridyl)-ethyl)-xanthine with so pl. 201 - 202oC, from the corresponding 7-benzyl-8-cyclopentyl-1-propyl-3-(2-(2-pyridyl)-ethyl)-xanthine.

14. Hydrogenation of the nitrile groups in the xanthine derivatives

3.3 mmol containing nitrile derivative of xanthine are dissolved in 40 ml of methanol and 10.5 ml of 25% aqueous ammonia solution and hydronaut in the presence of Raney Nickel under a pressure of, if not the example, 3-(4-aminobutyl)-8-cyclopentyl - 1-profilkanten with the release of 40.9% from theory, and so pl. 159 - 161oC.

15. The acylation containing hydroxyl group derivatives of xanthine

1.3 mmol hydroxyl-containing derivative of xanthine and of 0.53 ml (6.5 mmol) of pyridine are dissolved or suspended in 10 ml of absolute methylene chloride. Under stirring at room temperature was added dropwise a solution of 1.44 mmol of acid chloride of the carboxylic acid in 1 ml of absolute methylene chloride and the reaction mixture is stirred until complete reaction of the starting compound. Then extracted with distilled water and diluted hydrochloric acid, the organic phase is dried over sodium sulfate and concentrated to dryness. The residue is purified by crystallization or chromatography.

Thus get the following O-acyl compounds:

a) 8-cyclopentyl-3-(2-(methylcarbonate)-ethyl)-1 - profilkanten with the release of 47% of theory, and so pl. 149oC

b) 8-cyclopentyl-3)-(2-(n-(methylcarbonate)-phenyl)-ethyl)- 1-profilkanten with the release of 47% of theory, and so pl. 232oC

C) 7-benzyl-8-cyclopentyl-3-(3-(n-(methylcarbonate)- phenyl)-propyl-1-profilkanten with the release of 77.5% of theory, slowly crystallizing oil

g) 7-benzyl-8-cyclopentyl-3-(3-(�7-benzyl-8-cyclopentyl-3-(3-(n-(2-(methylcarbonate)- ethoxy)-phenyl)-propyl)-1-profilkanten with access to 82.1% of theory, a colorless oil.

16. The hydrolysis of esters of carboxylic acid derivatives of xanthine

0.6 mmol containing ester group derived xanthine are dissolved in about 4 ml of tetrahydrofuran and mixed with a solution of 0.17 g (4.0 mmol) of hydrate of lithium hydroxide in 10 ml of distilled water. Then the reaction mixture was stirred until complete conversion of the starting compound, acidified with diluted hydrochloric acid and the product is filtered or the aqueous phase is shaken out with organic solvents. For cleaning, if necessary, recrystallized or subjected to chromatography.

Thus get the following connections:

a) from 8-cyclopentyl-3-(3-(p-ethoxycarbonylmethoxy)-phenyl)- propyl)-1-propylketone:

3-(3-(n-(carboxymethoxy)-phenyl)-propyl)-8-cyclopentyl-1 - profilkanten with access to 85.2% of theory, and so pl. 190 - 192oC

b) from 8-cyclopentyl-3-(2-(methyloxycarbonyl)-ethyl)- 1-propylketone:

3-(2-(carboxyethyl)-8-cyclopentyl-1-profilkanten with the release of 78.5% of theory, and so pl. 265 - 267oC.

17. Hydrolysis containing methoxybenzylamine xanthine derivatives

1.1 mmol containing methoxybenzylamine derivative of xanthine suspended forexpros acid in 5 ml of absolute methylene chloride, the resulting mixture was warmed to room temperature and stirred until complete conversion of the starting compound. Then the reaction mixture is washed with distilled water, the organic phase is dried over sodium sulfate and concentrated to dryness. The crude product is purified by crystallization or chromatography.

Thus get the following connections:

a) from 8-cyclopentyl-3-(2-(2,4,6-trimethoxybenzylamine - carbonyl)-ethyl)-1-propylketone:

3-(2-carbamoylethyl)-8-cyclopentyl-1-profilkanten with the release of 64,9% of theory, and so pl. 289 - 291oC

b) from 3-(3-(n-(2,4,6-trimethoxybenzylamine-carbonyl-methoxy)- phenyl)-propyl)-8-cyclopentyl-1-propylketone:

3-(3-(n-(carbamoylmethyl)-phenyl)-propyl)-8-cyclopentyl-1 - propylketone with the release of 49.0% of theory, and so pl. 224 - 226oC.

18. A receipt containing the oxime derivatives of xanthine

2.5 mmol containing aldehyde derivative of xanthine, 0.17 g (2.5 mmol) of hydroxylamine hydrochloride and 0.13 g (1.3 mmol) of sodium carbonate are mixed in 15 ml of distilled water and stirred at room temperature until complete conversion of the starting compound. The resulting mixture was mixed with methylene chloride and the solid is sucked off or the aqueous phase is shaken out with Machaut, for example, 8-cyclopentyl-3 - examinati-1-propylketone with the release of 64% of theory, and so pl. 247oC 8-cyclopentyl-3-formylmethyl-1-propylketone.

19. Oxidation of the alcohol group in the xanthine derivative to aldehyde or ketone group

0.4 mmol containing an alcohol group xanthine derivative is stirred, together with 180 mg (0.84 mmol) chlorochromate pyridinium in 5 ml of absolute methylene chloride to complete conversion of the starting compound. The reaction mixture is washed with distilled water, the organic phase is dried over sodium sulfate and concentrated to dryness. The crude product is purified by crystallization or chromatography.

Thus get, for example, 8-cyclopentyl-3-(3 - oxobutyl-1-profilkanten with the release of 73,3% of theory, and so pl. 223 - 224oC 8-cyclopentyl-3-(3-oxobutyl)-1-propylketone.

20. Receipt containing thioester group xanthine derivatives

3.6 mol containing alkylhalogenide group xanthine derivative is dissolved or suspended in 0,42 g (7.5 mol) of a solution of potassium hydroxide in 60 ml of ethanol. Then add 3.6 mmol of the substituted thiol and the reaction mixture is heated under reflux until complete conversion of the starting compound. Then thicken the basics dried over magnesium sulfate and concentrated to dryness. The residue is purified by crystallization or chromatography.

Similarly receive the following connections: 8-cyclopentyl-3-(2-Jodeci)-1-propylketone:

a) 8-cyclopentyl-3-(2-(2-ethylthio)-ethyl)-1-profilkanten with the release of 71.3 per cent of theory, and so pl. 144 - 145oC

b) 8-cyclopentyl-3-(2-(2-oxyethyl)-thioethyl)-1-profilkanten with access 95,0% theory and so pl. 160 - 161oC.

21. Saponification nitrile group in xanthine derivatives

0.5 mmol containing nitrile group, a derivative of xanthine suspended or dissolved at a temperature of 10oC in 1 ml of 95-97% sulfuric acid. The resulting mixture was stirred at room temperature for 3.5 hours, add 5 ml of water and 5 ml of methylene chloride, the organic phase is separated and concentrated to dryness. The residue is purified by crystallization or chromatography.

Similarly receive, for example, from 7-benzyl-3-(3 - cyano-propyl)-8-cyclopentyl-1-propylketone:

3-(3-(aminocarbonyl)-propyl)-7-benzyl-8-cyclopentyl-1 - profilkanten with so pl. 180 -181oC.

22. The receipt contains alkylidene group derived from the corresponding xanthine xanthine derivatives containing an alcohol group

3.1 mmol 8-cyclopentyl-3-(2-oxyethyl)-1-propylsulfonyl refrigerator for two hours. Then the reaction mixture is diluted with toluene and the organic phase is washed with water and sodium thiosulfate solution. The precipitated crystals filtered off, the organic phase of the filtrate was separated, washed with water, dried and concentrated to dryness. The residue and filtered crystals unite, stirred at room temperature for 16 hours in acetonitrile and the solid is allocate by filtration.

Yield: 1.0 g (77.5% of theory) of 8-cyclopentyl-3- (2-Jodeci)-1-propyl-xanthine in the form of colorless crystals with so pl. 223 - 226oC.

23. Oxidation containing a thioester group xanthine derivatives to derivatives of xanthine containing sulfonyloxy group

0.55 g of neutral aluminium oxide mixed 0.11 ml of water and shaken to obtain a fine powder. Then add 8 ml of methylene chloride, 1.0 g (of 1.65 mmol) oxone [= 2KHSO5KHSO4K2HSO4] and a solution of 0.2 g (0.55 mmol) of 8-cyclopentyl-3-(2-(2-oxyethyl)- thioethyl)-1-propylketone in 4 ml of absolute methylene chloride and the resulting mixture is heated with stirring under reflux for two hours. After cooling, is filtered from the solids, the latter intensively washed with methylene chloride and obeyed,3% of theory) of 8-cyclopentyl-3-(2-(2 - oxyethyl)-sulfonylated)-1-propyl-xanthine in the form of colorless crystals with so pl. 213 - 214oC.

24. Synthesis of 8-cyclopentyl-7-benzyl-3-p-methoxy-xanthine

50 g (0.20 mol) of 6-amino-1-p-methoxybenzyl-uracil with 17.5 g (0.21 mol) of sodium bicarbonate serves in 200 ml of methanol and at a temperature of 5oC slowly added dropwise 11 ml of bromine (strong foaming). Then stirred in an ice bath for two hours. Sucked off and washed twice, each time using 150 ml of methanol.

Output: to 54.3 g of light yellow crystals (82.2% of theory)

6-amino-5-bromo-1-p-methylbenzyl-uracil

Thin-layer chromatography using as eluent a mixture of methylene chloride and methanol in the ratio 95:5.

Melting point: 245oC (decomposition).

To 121, 1million g (of 0.37 mol) of 6-amino-5-bromo-1-p-methoxybenzyl-uracil add 396,5 g (3.7 mol) of benzylamine and stirred at a temperature of 80oC for two hours. Cool, bring to a boil together with 1000 ml of ethanol, cooled and sucked off. Then further washed with cold ethanol.

Output: 110,0 g of white crystals (82.3% of theory)

5-amino-5-benzyl-amino-1-p-methoxybenzyl-uracil

Thin-layer chromatography using as eluent a mixture of methylene chloride and methanol in the ratio of 90 : 10.

oC was added dropwise a solution to 66.0 g (0.50 mol) of acid chloride of cyclopentanecarbonyl acid and 165 ml of dimethylformamide. Then stirred at a temperature of 5 - 25oC for three days. Concentrated in vacuo, the residue is boiled twice, each time using 700 ml of ethanol, cooled and sucked off.

Output: level 113.0 g of white crystals (81.3% of theory)

6-cyclopentyl-carbylamine-5-benzylamino-1-p - methoxybenzylidene

Thin-layer chromatography using as eluent a mixture of methylene chloride and methanol in the ratio 95 : 5.

level 113.0 g (0.25 mol) of 6-cyclopentyl-carbylamine-5-benzylamino - 1-p-methoxybenzimidazole mixed with 1300 ml of water and 650 ml of ethanol, add and 83.3 g (1.1 mol) of calcium hydroxide and 330 ml of 50% sodium hydroxide and stirred at a temperature of 100oC for 20 hours. The mixture is concentrated in vacuum (only distilled ethanol). The aqueous residue cooled under ice cooling is brought to pH 2 by adding concentrated hydrochloric acid and sucked off.

Yield: 93.0 g of beige crystals (86,4% of theory)

7-benzyl-8-cyclopentyl-3-p-methoxybenzyl-xanthine

Thin-layer chromatography using as eluent a mixture of methylene chloride and methanol are summarized in table 2 compounds of General formula (I)

< / BR>
where R1- n-propyl, R3- cyclopentyl, R4- hydrogen.

Compounds of General formula (I) can be used in combination with other proposed active substances, where necessary, also in combination with further pharmacologically active substances. As suitable drugs should be called, for example, tablets, capsules, suppositories, solutions, juices, emulsions or capable of dispersing the powders. Appropriate tablets can be obtained, for example, by mixing the active substance or active substances with known excipients, such as inert diluents, such as, for example, carbonate or calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatinous, lubricants such as magnesium stearate or talc and/or means to provide prolonged action, as, for example, carboxymethylcellulose, acetamitaphen cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Tablets can be obtained by coating the obtained analogously to the tablets of nuclei usually isetan or sugar. To provide after-school activities or prevent the incompatibility of the core may also consist of several layers. In addition, to achieve the prolonged effect of shell beans can also consist of several layers, and you can use mentioned for tablets excipients.

Juices containing the proposed active substances or combinations thereof, can optionally contain sweet substances, such as saccharin, cyclamate, glycerol or sugar, and improves the taste of substances, such as aromatic substances, as vanillin or orange extract. In addition, they may also contain promotional suspendirovanie substances or thickeners, such as sodium carboxymethyl cellulose, cross-linking agents, such as condensation products of fatty alcohols and ethylene oxide, or protective substances, such as p-oxybenzoic.

The injectable solutions prepared in the usual manner, for example, by adding a preservative means, as, for example, p-oxybenzoates or stabilizers, such as, for example, salts of alkali metals or ethylenediaminetetraacetic acid and fill in injection bottles or ampoules.

To the th, that the active substance is mixed with inert carriers, such as milk sugar or sorbitol, with subsequent incorporation into gelatin capsules.

Suitable suppositories can be obtained, for example, by mixing with established media, such as neutral fats or polyethylene glycol or its derivatives.

Therapeutically active dose for an adult is from 1 to 800 mg, preferably from 10 to 3000 mg per day.

The following examples illustrate possible pharmaceutical compositions.

A)

Tablets per tablet

Active ingredient 100 mg

Milk sugar - 140 mg

Corn starch - 240 mg

Polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mg

A total of 500 mg

Melkoizmelchennye active substance, lactose and part of the corn starch are mixed with each other. The mixture is passed through a sieve, then moistened with a solution of polyvinylpyrrolidone in water, mix in the wet state is switched to the granules and dried. The granulate, the remainder of the corn starch and magnesium stearate are passed through a sieve and mix. The mixture is pressed into tablets of suitable shape and size.

Milk sugar - 55 mg

Microcrystalline - cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Sodium salt carboxymethylated starch - 23 mg

Magnesium stearate 2 mg

Total - 400 mg

Melkoizmelchennye active substance, part corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed with each other, the mixture is passed through a sieve and, together with the remainder of the corn starch and water processed into a granulate which is dried and passed through a sieve. Then add sodium salt carboxymethylated starch and magnesium stearate are mixed and the mixture is pressed into tablets of suitable size.

1. Xantina derivatives of General formula I

< / BR>
where R1is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 3-6 carbon atoms;

R1is hydrogen, alkyl with 1-8 carbon atoms, substituted by cyano, at least one hydroxyl group, halogen, a group of the formula-SO2R5, -S-R5where R5means unsubstituted or substituted by hydroxyl alkyl with 1-4 carbon atoms, a group-NR6R7, -CONR6R7, -OCH2-CH2-NR6R7in which R6denotes hydrogen, alkyl with 1-10, atomo substituted by a methoxy group, and R7denotes hydrogen, alkyl with 1-10 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group, or R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may be substituted unbranched or branched alkyl with 1-4 carbon atoms or may have one the rest of the group comprising oxygen, ketal, groups of the formula-OR8, -SO2-R8, -COR9in which R8denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group, and R9is alkyl with 1-4 carbon atoms, or a group of the formula-OR8, -NHCOR8, -OCOR8, -SO2-CH2-CH2-O-COR8, -COOR8-CH= NOR8and-COR9where R8and R9have the specified values, or cycloalkylation with 3-7 carbon atoms in cycloalkyl parts and 1-6 carbon atoms in alkalinous part, phenylalkyl with 1-6 carbon atoms in alkalinous part, unsubstituted or substituted in the phenyl by one or neskolku>8, -CH2-NH-SO2-R8, -OCOR8, -OCH2COOR8, -OCH2-CONR6R7, -OCH2CH2OR8, -COOR8, -CONR6R7, -SO2NR6R7and-OCH2-CH2OCOR8where R6-R8have the specified values, or a residue of formula a-alkylen or A-CONH-alkylene with 1-6 carbon atoms in alkalinous part, And where means bound through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur and which may be substituted one or more times by alkyl with 1-4 carbon atoms, hydroxyl, remainder =O, Cetelem, the group fulfills I TS cor9or-SO2R8where R8and R9have the specified values, with R1may not have the same meaning as R2;

R3- cyclopentyl;

R4is hydrogen, benzyl,

and their pharmacologically tolerated salts.

2. Xantina derivatives of General formula I on p. 1, where R1is methyl, ethyl, n-propyl, n-butyl, allyl, R2- ethyl, alkyl with 2 to 3 carbon atoms, substituted residues selected from the group comprising halogen, cyano, hydroxyl, groups of the formula-OR8where R8has specified in paragraph 1 values, -NR8where R8has specified in paragraph 1 values, -SR5and-SO2R5,

where R5has specified in paragraph 1 of the value-OCH2-CH2-NR6R7where R6and R7are specified in paragraph 1 values, -COOR8where R8has specified in paragraph 1 of the value-NR6R7where R6and R7are specified in paragraph 1 values, -COR9where R9has above in paragraph 1 values, benzyl, phenyl, ethyl or phenylpropyl substituted by a residue from the group comprising halogen, cyano, nitro, hydroxyl, groups of formula-CH2NR6R7where R6and R7are specified in paragraph 1 of the value-OR8where R8has specified in paragraph 1 of the value-R8where R8has specified in paragraph 1 of the value-och2CR8where R8has specified in paragraph 1 of the value-OCH2-CONR6R7where R6and R7are specified in paragraph 1 of the value-OCH2CH2OH, -OCH2CH2OR8where R8has specified in paragraph 1 of the value-R8where R8has specified in paragraph 1 of the value-CONR6R7where R6and R7are specified in paragraph 1 values, -O-CH2-CH2OCOR8where R8has specified in paragraph 1 values, cycloalkylation with 3-6 atoman-CH2-, A-CH2-CH2-CH2A-CO-NH-CH2A-CO-NH-CH2-CH2- or A-CO-NH-CH2-CH2-CH2- where And means connected through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur, and can be substituted one or more times by alkyl with 1-4 carbon atoms, residue =O, a hydroxyl group COR9where R9has specified in paragraph 1 values, a group of SO2-R8where R8has specified in paragraph 1 values, while the radicals R3and R4are specified in paragraph 1 values, and their pharmacologically tolerated salts.

3. Xantina derivatives of General formula I on p. 1, where R1- propyl, R2and R3are specified in paragraph 1, the values of R4means hydrogen, and their pharmacologically tolerated salts.

4. Xantina derivatives of General formula I according to one of paragraphs.1-3, where R2represents alkyl with 2 or 3 carbon atoms, substituted by cyano, hydroxyl, carboxyla, groups of formula-R8where R8has specified in paragraph 1 values, in particular methyl, ethyl, -OCOCH3, -OCOC2H5, -CONR6R7or-NR6R7in which R6and R7have the criminal code of the crystals I on one of the PP.1-4, where R2means the residue of formula a-alkylen or A-NH-alkylen, each with 1-3 carbon atoms in alkalinous part, And where means bound through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur and may be substituted one or more times by alkyl with 1-4 carbon atoms, hydroxyl, groups =O, -SO2-R8where R8has specified in paragraph 1 of the value-R9where R9has specified in paragraph 1 values, their pharmacologically tolerated salts.

6. Xantina derivatives of General formula I according to one of paragraphs.1-5, where R2-CH2CH2OH, CH2CH2OCOCH3, (CH2)3OCOCH3, (CH2)3OCH3CH2CH2COCH3CH2CH2CH(OH)CH3CH2CH2COOCH3CH2CH2CONH2, (CH2)3CONH2CH2CH= NOH, (CH2)3CN, -CH2CH2SCH2CH3, -CH2CH2SCH2CH2OH, -CH2CH2SO2CH2CH2OH,

CH2CH2SO2CH2CH2OCOCH3, A-(CH2)2- or A-(CH2)3- where And is connected through a carbon atom or nitrogen 5 - or 6-cichecki portable salt.

Priority points and features: 10.08.92 on p. 1: xanthine derivatives of General formula I, where R1, R3and R4are all specified in the claims, the values of R2is specified in the claims values except for the following;

13.11.92 on p. 1: xanthine derivatives of General formula I, where R2- alkyl with 1-8 carbon atoms, substituted by the groups-NR6R7, -CONR6R7-OCH2-CH2-NR6R7in which R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may have one the rest of the group, including balance =O, ketal and a group of the formula-SO2-R8in which R8denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group or a group of the formula-SO2-CH2-CH2O-COR8where R8has the specified value, the remainder of the formula A-NH-alkylene with 1-6 carbon atoms in alkalinous part, And where means bound through a carbon atom a 5 - or 6-membered heterocyclic ring, which, as the hetero what Cetelem, the group-COR9or-SO2R8where R8and R9have the specified values; p. 2 if R2is alkyl with 2 to 3 carbon atoms, substituted by groups of the formula-NR6R7, -OCH2-CH2-NR6R7and-CONR6R7where R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may have one the rest of the group, including balance =O, ketal and a group of the formula-SO2-R8in which R8denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group, or a group of the formula-SO2-CH2-CH2-O-COR8where R8has the specified value, or R2- the rest of the formula A-CO-NH-CH2- ,- CO-NH-CH2-CH2- or A-CO-NH-CH2-CH2-CH2- where And means connected through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur, and may be singly or multiply substituted by a residue = O group fulfills I TS cor9where R9has specified in paragraph 1 or 3 carbon atoms, substituted by groups of the formula-ONR6R7or-NR6R7in which R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may have one the rest of the group, including balance =O, ketal and a group of the formula-SO2-R8in which R8denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl or benzyl, unsubstituted or singly or multiply substituted by a methoxy group; p. 5 if R2- the remainder of the formula a-DOUBT-alkylen with 1-3 carbon atoms in alkalinous part, And where means bound through a carbon atom or nitrogen 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur and may be substituted one or more times by groups =O, -SO2-R8where R8has specified in paragraph 1 of the value-R9where R9is mentioned in paragraph (1 value;

10.03.95 on p. 1 xanthine derivatives of General formula I, where R2- alkyl with 1-8 carbon atoms, substituted by the groups-NR6R7, -NR6R7, -OCH2-CH2-NR6R7in which R6and Reste further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may have a group of formula R9in which R9is alkyl with 1-4 carbon atoms, and a residue of the formula A-N - alkylene with 1-6 carbon atoms, where And means associated with the nitrogen atom a 5 - or 6-membered heterocyclic ring, which as contains heteroatoms nitrogen, oxygen or sulfur and which may be single - or multi-substituted by a group =O, Cetelem, a group of SO2R8or R9where R8and R9have the specified values; p. 2 if R2is alkyl with 2 to 3 carbon atoms, substituted by groups of the formula-NR6R7, -OCH2-CH2-NR6R7or NR6R7in which R6and R7together with the nitrogen atom form a saturated or unsaturated five - and six-membered ring, which as further heteroatoms may contain nitrogen, oxygen or sulfur, and the heterocycle may have a group of formula R9in which R9is alkyl with 1-4 carbon atoms; p. 4 if R2is alkyl with 2 or 3 carbon atoms, substituted group of the formula-NR6R7or-NR6R7in which R6and R7together with the nitrogen atom form a saturated or unsaturated five - or six-membered ring to a group of the formula-R9in which R9is alkyl with 1-4 carbon atoms.

 

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FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

FIELD: organic chemistry, biochemistry, biology.

SUBSTANCE: invention relates to a pharmaceutical composition eliciting the inhibitory effect on activity of serine protease (caspase-3) in the form of tablet, capsule or injections placed into acceptable package, to a method for its preparing and a method for treatment of diseases associated with enhanced activation of apoptosis. The composition comprises compound 2,3-dihydro-1H-benzo[g]pteridine-4-one of the general formula (1) (1)

or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with antiviral preparations that contain aliphatic alcohol C21-C28 in combination with either nucleoside or nucleotide analog or phosphoformic acid in pharmaceutically acceptable carrier. It is necessary to mention that n-docosanol is considered to be a preferable aliphatic alcohol. Concentration of aliphatic alcohol C21-C28 corresponds to 0.05% to 40% by weight. Concentration of either nucleoside or nucleotide analog or phosphoformic acid corresponds to 0.1% to 10% by weight. The innovation, also, deals with the ways to treat viral infections due to applying such compositions. Aliphatic alcohols C21-C28 synergistically intensify antiviral activity of nucleoside analogs directed against replication of several herpetic viruses and that of cow's pox.

EFFECT: higher efficiency of inhibition.

28 cl, 13 dwg, 21 ex, 6 tbl

FIELD: veterinary science.

SUBSTANCE: about 20-25 d before calving one should introduce intramuscularly 0.5%-sodium selenite solution for cows at the dosage of 10 ml. Twice before and twice after calving at 10-d-long interval - tetravit at the dosage of 10 ml at the content of 50000 IU vitamin A, 25000 IU vitamin D, 20 mg vitamin E and 5 mg vitamin F per 1 ml. Succinic acid should be introduced 20-25 d both before and after calving at the dosage of 1.0 g. The method provides efficient correction of the main values of homeostasis in cows after calving.

EFFECT: higher efficiency of normalization.

2 ex, 4 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

FIELD: veterinary science.

SUBSTANCE: one should introduce endovit complex preparation once daily for dogs. Moreover, during the first 5 d endovit should be introduced at the dosage of 30 mg/kg, during the next 10 d - 25 mg/kg and during the last 5 d 20 mg/kg body weight. The suggested innovation provides normalization of myocardial trophic nature, interrupts dystrophic processes in it, improves functional state of cardiac conductory system and, thus, provides the chance to treat both the main and secondary disease by the mentioned scheme without applying any additional cardiological remedies.

EFFECT: higher efficiency of therapy.

1 tbl

FIELD: obstetrics and gynecology.

SUBSTANCE: over a 2-5 day period, 2.0 ml of Ginipral is administered once a day intravenously in a drop-by-drop manner followed by intravenously drop-by-drop administered 30-40 min later 2.0 ml of Instenone and, in the evening, 1 dragee Instenone orally. Afterwards, Instenone and Ginipral are administered orally: the former in dose of 1 dragee thrice a day with meal and the latter in dose of 1 pellet four times a day after meal until symptoms of the risk of prevention of pregnancy disappear.

EFFECT: prolonged pregnancy and prevented premature birth, which favors reduced irritation, normalized tonus, contractive activity of uterus, and improved psychic and emotional state of women.

2 ex

FIELD: vitamins, chemical technology, food industry, pharmacy.

SUBSTANCE: invention relates to crystalline alkaline-earth salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid with the content of at least one equivalent of crystallizing water per equivalent of 5-methyltetrahydrofolic acid, in particular, 5-methyl-(6R)-tetrahydrofolic acid crystalline calcium salt or to different types of 5-methyl(6S)-tetrahydrofolic acid crystalline calcium salts. These salts can be used in preparing medicinal agents or as a nutrition supplement for treatment or prophylaxis of folic acid-mediated diseases. Also, invention relates to a method for preparing crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid by crystallization of the corresponding salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid from a polar medium by using heat treatment at temperature above 60°C followed, if necessary, by drying the prepared product. Also, invention relates to a composition for pharmaceutical agents or nutrition supplements.

EFFECT: improved preparing method, valuable properties of salts and composition.

13 cl, 5 dwg, 4 tbl, 11 ex

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