Derivatives of xanthine in the form of mixtures of isomers or individual isomers, having the properties of antagonists of adenosine

 

(57) Abstract:

Usage: in medicine as an antagonist of adenosine. The essence of the invention: derivatives of xanthine f-ly I

where R1and R2is lower alkyl; R3- the rest of the group, including tetrahydrofurane, thiophene, dithiolane, substituted or unsubstituted furan, tetrahydrofuran or thiophene. 1 C.p. f-crystals, 2 tab.

The invention relates to new chemical substances suitable for use as medicaments, in particular to the xanthine derivative of General formula I

R3where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by a group: -CH2OH, CHO, COOH,

-CH=, where Alk denotes alkyl with 1-4 carbon atoms,

-CH=CH-CO-NO,

-CONHN-CH

-CH=C

-CH=C

-CONH-(CH2)2N(Alk)2where Alk has the specified value, tetrahydrofuran, optionally substituted lower alkyl or the group-CH2CH2-CO-NO, or furan or thiophene, substituted lower alkyl or nitro-group or the unsubstituted cycloalkyl with 6-8 carbon atoms, cycloalkane or cycloalkanes with 5-6 carbon atoms, unsubstituted cyclohexyl may be substituted,NOH, -OCONH-phenyl, and phenyl may be samisens-COOCH3, -CH2COOCH3, -CH2CH2NH2, -OC(C6H5)3, -OALK, where Alk has the specified value, R4where R4matter: the rest campanulas acid, lower alkyl, phenyl, substituted lower alkoxyl, phenyl, methoxymethyl, six-membered nitrogen-containing heterocycle; cyclohexane, substituted cyanomethylene or oxyalkyl1-C4or hydroxy-group, or cyclopentane, substituted lower alkyl or phenyl, which may have as a second Deputy in genialnom position relative to the first hydroxyl group or ketal formula

or R3residue selected from the group:

(CH2)1,2< / BR>
ororin the form of mixtures of isomers or individual isomers, having the properties of antagonists of adenosine.

New derivatives of xanthine of the formula I can be obtained by ways of peers, for example, as follows.

A. a Compound of General formula II

where R1and R2have a specified value, is subjected to the interaction with the compound of General formula III

R3CHO, where R3has a specified value, and a functional group in ostad the range of the target product of the formula I, if necessary, transferred to another target product of formula I.

B. a Compound of General formula IV

where R1and R2have a specified value, is subjected to the interaction with the compound of General formula V

R3X, where X is Cho or COOH, and a functional group in the residue R3may be protected or its reactive derivative with subsequent cyclization, removing the possible protective groups, and redefine, if necessary, the obtained target product of the formula I into another target product of the formula I

If used as a compound of the formula V in which R3means SNO, the cyclization is preferably carried out in the presence of diethylazodicarboxylate. In the case of the compounds of formula V in which R3means COOH, or its reactive derivative, the cyclization is preferably carried out in the presence of a hydroxide of calcium or phosphorus oxychloride.

C. the Compound of General formula VI

where R1, R2and R3have a specified value and a functional group in the residue R3can be protected, is subjected to cyclization and subsequent removal of the possible protective groups and redefine, if necessary, the resulting teletouch isolated in the form of mixtures of isomers or individual isomers. The possible transfer of the desired product of formula I into another target product of formula I is carried out by known techniques. Getting new xanthine derivatives of the formula I, as well as the possibility of transferring the target product of the formula I into another target product of formula I is illustrated by the following examples.

P R I m e R 1. 1,3-Dipropyl-8-(1,4-benzodioxan-6-yl)xanthine.

Mix of 2.18 g (0,013 mol) of 1,4-benzodioxan-6-aldehyde, 80 ml of ethanol and 2.4 ml of glacial acetic acid and mixed with 2.8 g (0.012 mol) of 5,6-diamino-1,3-dipropionate. The clear solution is refluxed for 2 1/4 hours and then cooled to 60aboutC. At this temperature, add drops of 2.1 ml (0,013 mol) diethyl ether complex of azodicarboxylic acid obtained viscous suspension is mixed with 80 ml of ethanol and refluxed for 2 hours after a further 20 h at room temperature the mixture is cooled to 5aboutWith that solid is sucked off and washed with ethanol and simple ether. Obtain 4.1 g (92% of theory) of the specified compound as a grey solid, so pl. 280-282aboutC.

P R I m m e R 2. 1,3-Dipropyl-8-(tetrahydropyran-4-yl)xanthine.

3.2 g (0,025 mol) tetrahydrofurane 30 min at room temperature. After you have added 5.7 g (0,025 mol) of 5,6-diamino-1,3-dipropionate the mixture is stirred for 4 h at room temperature and then concentrated in vacuum. The residue is mixed with 130 ml of water and 11.6 g of calcium hydroxide, stirred for 30 min at 80aboutFrom and after cooling, under cooling with ice, acidified with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and the organic phase is dried and concentrated. Chromatography crystalline residue on silica gel using as elution solvent of methylene chloride and methanol in the ratio of 99:1 to obtain 1.7 g (15% of theory) of the compounds in the form of white crystals, so pl. 171-172aboutC.

P R I m e R 3. 1,3-Dipropyl-8-(3-oxocyclopent)-xanthine.

2.4 g (0.014 mol) of 1,4-dioxaspiro[4,4]nonan-7-carboxylic acid are dissolved in 56 ml of methylene chloride and after the addition of 2.2 g (0.014 mol) of carbonyldiimidazole stirred for one hour at room temperature. Then add 3.2 g (0.014 mol) of 5,6-diamino-1,3-dipropionate and stirred further for 4 h at room temperature. The solution is concentrated in vacuum, the oily residue is mixed with 70 ml of water and 4.5 g of calcium hydroxide and stirred for one hour at 60aboutC. Add 100 ml of 50% hydroxide ndadaye ice solution is brought to pH 6 with hydrochloric acid and extracted with methylene chloride. From the combined organic phase after drying and concentrating under vacuum to obtain a crystalline residue, which is recrystallized from ethanol in the presence of activated carbon. Obtain 0.8 g (16%) of white crystals with so pl. 147-148aboutC.

Used as a protective group dioxolane hydrolyzing acid is known in the literature follows and receives the connection.

P R I m e R 4. 1,3-Dipropyl-8-(3-oxocyclopent)-xanthine.

a) Obtaining 3-oxo-cyclopentanecarboxylic acid. 100.0 g (0.7 mol) of a compound methyl ester 3-oxocyclopentanecarboxylate acid is mixed with 1000 ml of 2-molar hydrochloric acid and stirred for 10 h at boiling temperature. The solution is cooled and fully condensed in a vacuum. The remaining amount of water removed in three stages, each time with 50 ml of toluene (toluene added to the residue and distilled off by evaporator with a full water jet vacuum and the temperature of the water bath 60-70aboutC). The resulting crude product is subjected to fractional distillation in a high vacuum.

1. Faction: because0,0220-110about(Get: 1.2 g oil);

2. Faction: because0,02110-116aboutC.

Get: 4-7 g semi-crystalline mekkatorque later forming.

8.8 g (0,072 mol) 3-oxocyclopentanecarboxylate acid served in 240 ml of absolute methylene chloride and stirring is served at 20-25aboutWith 11.6 g of carbonyldiimidazole and stirred for 2 h at room temperature. Then add at 20-25aboutWith 16.0 g (0,072 mol) 1,6-diamino-1,3-di-n-propyl-uracil and stirred further for 3 h at room temperature. The reaction mixture is concentrated to dryness in vacuo. The oily residue is mixed with 3200 ml of distilled water and 35 g of calcium hydroxide and stirred for 0.5 h at 80aboutC. Then cooled to 5aboutC, pH adjusted to 1-2 with concentrated hydrochloric acid and extracted three times, each time with 100 ml of methylene chloride. The combined organic phases are washed once with 100 ml water, dried with magnesium sulfate, filtered and concentrated to dryness. The resulting crude product is purified on 350 g of silica gel brand S160 using as eluent about 4 l of methylene chloride and methanol in the ratio of 99:1. Pure fractions concentrated to dryness. The crystalline residue is mixed with 100 ml of simple ether and sucked off. Output: 11.5g gray crystals (50.2% of theory). So pl. 164-168aboutC.

P R I m e R 5. 1,3-Dipropyl-8-(4,7,7-trimethyl-2-oxa-bicyclo[2,2,1]-heptane-3-one-1-yl)Xanthi N.

aboutC. the Cooled suspension is acidified under cooling with ice and extracted with methylene chloride. The combined organic phases are dried and concentrated and the residue purified by chromatography on silica gel using as elution solvent of methylene chloride and methanol in the ratio of 99:1. Receive 200 mg (10% of theory) of the above compound in the form of white crystals with so pl. 200-201aboutC.

P R I m e R 6. 1,3-Dipropyl-8-(2-formylfuran-5-yl)xanthine.

To 400 ml of absolute dimethylformamide at 0-10aboutWith drops add to 16.4 g (0.11 mol) of phosphorus oxychloride. When 5-15aboutTo add a solution of 15.6 g (0.05 mol) of 1,3-dipropyl-8-paraxanthine in 330 ml of dimethylformamide. The reaction mixture is stirred for one hour at room temperature and for 7 hours at 85aboutC. the Mixture is poured onto 500 ml of ice and extracted with methylene chloride. The combined organic extracts dried and concentrated in vacuum, the residue is crystallized from simple diethyl ether. Get 12,1 g (73% of theory) indicated imuran-5-yl)xanthine.

A solution of 0.26 g (1.5 mmol) of silver nitrate in 2 ml of water is shaken with a solution of 0.4 of sodium hydroxide in 1 ml of water within 5 min. Grey-black precipitate of silver oxide is sucked off and washed with water, then served in 5 ml of water and mixed with 1,3-dipropyl-8-[5-formyl-(2-furanyl)]xanthine. The mixture is heated to 50aboutWith, and drops slowly add a solution of 0.1 g of sodium hydroxide in 2 ml of water. Then stirred for 15 min at 50aboutWith and for one hour at room temperature, and then filtered. The filtrate is acidified and mixed with methylene chloride, precipitated precipitate is sucked off and washed with methylene chloride and easy diethyl ether. Obtain 0.4 g (77% of theory) of the compounds in the form of light brown crystals with so pl. 201-203aboutC.

P R I m e R 8. 1,3-Dipropyl-8-[2-(2,2'-bis(etoxycarbonyl)vinyl)-furan-5-yl] xanthine.

A mixture of 2.5 g (7.6 mmol) of 1,3-dipropyl-8-[5-formyl-(2-furanyl)]-xanthine, 1.2 g (7.6 mmol) of a compound diethyl ester of malonic acid, 0.03 g (0.3 mmol) of piperidine, 0.09 g (1.5 mmol) of glacial acetic acid and 5 ml of benzene is boiled for 6 hours on a water separator. After cooling, the reaction mixture is diluted with 10 ml of toluene, the solid is sucked off and dissolved in 100 ml of warm chloride met the 1.0 g (28% of theory) of the above compound in the form of yellow crystals with so pl. 220-222aboutC.

P R I m e R 9. 1,3-Dipropyl-8-[2-(N,N-diethylaminoethyl)furan-5-yl]-xanthine.

1.0 g (2.9 mmol) of 1,3-dipropyl-8-[2-carboxyphenyl-5-yl)]xanthine are dissolved in absolute dimethylformamide and mixed at 0-5aboutWith from 0.38 g of triethylamine and 0.45 g (3.3 mmol) of isobutylacetate. The mixture is stirred for 2 h at 0-5aboutWith, then added 0.34 g (2.9 mmol) of N,N-diethylamino-ethylamine, and continue stirring the mixture for 12 h on a melting ice bath. The mixture is concentrated under high vacuum, mixed with methylene chloride and water, alkalinized and extracted with methylene chloride. The organic phase is removed, the aqueous phase is acidified and again extracted. The combined organic extracts are dried, filtered, concentrated and the residue crystallized from ethyl acetate. Obtain 0.25 g of the above mentioned compounds in the form of yellowish crystals with so pl. 247-250aboutC.

P R I m e R 10. 1,3-Dipropyl-8-(1-oxocyclopent-3-yl)xanthine.

0.5 g (1.6 mmol) of 1,3-dipropyl-8-(1-oxo-3-cyclopentyl)xanthine, 10 ml of ethanol and 0.1 g (2.6 mmol) tetrahydridoborate sodium stirred for 2 1/2 days at room temperature. The reaction mixture was concentrated in vacuo and mixed with water and methylene chloride, the aqueous phase podcaster chromatography on silica gel using as elution solvent of methylene chloride and methanol in the ratio 95:5. From the first fraction receive 0.4 g (39% of theory) of the above compound in the form of white crystals (39% of theory), so pl. 174-176aboutAnd from the second faction gets 0.4 g (39% of theory) of the above compound in the form of white crystals with so pl. 191-193aboutC.

P R I m e R 11. 1,3-Dipropyl-8-[1-((4,7,7-trimethyl-2-oxa-bicyclo[2,2,1] -heptane-3 - one-1-yl)carbonyloxy)cyclopentane-3-yl] xanthine.

0.2 g (0.6 mmol) of 1,3-dipropyl-8-(1-hydroxy-3-cyclopentyl)xanthine and 0.24 g (3 mmol)of pyridine is stirred in 10 ml of absolute methylene chloride and after the addition of 0.2 g (0.9 mmol) of the acid chloride campanulas acid is stirred for 4 h at room temperature. The reaction mixture is mixed with water and separating the aqueous phase. The organic phase is dried and concentrated in vacuum, the residue is purified by chromatography on silica gel using as elution solvent of methylene chloride and methanol in the ratio 95:5. Receive 50 mg of the above compound in the form of a yellowish oil.

P R I m e R 12. 1,3-Dipropyl-8-(1-cyanomethylene-3-yl)xanthine.

0.28 g (1.6 mmol) diethyl ether complex cyanomethylphosphonate acid was dissolved in 20 ml of absolute benzene, type of 0.13 g (3.2 mmol) of a 60% dispersion of sodium hydride and boiled with a reflux the s phase is extracted, dried and the combined organic extracts concentrated. Subsequent chromatography of the residue on silica gel using as elution solvent of methylene chloride and methanol in the ratio of 97: 3 receive 0.1 g (18% of theory) of the above compound as a colourless oil.

P R I m e p 13. 1,3-Dipropyl-8-(norbornane-2-yl)xanthine.

1.0 g (3.1 mmol) of (1,3-dipropyl-8-(5-norbornene-2-yl)xanthine in the environment of 30 ml of ethanol is subjected to hydrogenation under pressure in the presence of palladium on coal up until there is no longer the absorption of hydrogen. The catalyst was filtered, the filtrate concentrated and the residue chromatographic on silica gel using as elution solvent of methylene chloride and methanol in the ratio of 99:1. Obtain 0.4 g (39% of theory) of the above compound in the form of white crystals with so pl. 136-138aboutC.

P R I m e R 14. 1,3-Dipropyl-8-(2-(2'-etoxycarbonyl-2'-carboxyvinyl)-furan-5-yl)xanthine.

To a solution of 0.8 g (1.4 mmol) of potassium hydroxide in 20 ml of ethanol is added 3.2 g (6.8 mmol) of 1,3-dipropyl-8-[2-(2',2'-bis(etoxycarbonyl)vinyl)-furan-5-yl] xanthine and the mixture is refluxed for 4 hours, After cooling, diluted with 50 ml of water and extracted with methylene chloride. The aqueous phase is acidified while cooling liltih crystals with so pl. 252-253aboutC.

P R I m e R 15.1,3-Dipropyl-8-(1-(2-oxyethyl)-cyclopent-3-yl)xanthine.

1.7 mmol 1,3-dipropyl-8-(1-methoxycarbonylmethylene-3-yl)xanthine are dissolved in 5 ml of tetrahydrofuran and added in drops to a suspension of 0.04 (1.1 mmol) of alanate lithium in 5 ml of tetrahydrofuran. The mixture is stirred for 35 h at room temperature and mixed with a saturated solution of diammonium tartrate. The aqueous phase is extracted with ethyl acetate, the combined organic extracts dried and concentrated in vacuum. The product was then purified by crystallization from a mixture of methylene chloride and methanol. Receive 1,3-dipropyl-8-(1-(2-oxyethyl)-cyclopent-3-yl)Xan-tin with so pl. 164-165aboutC. Yield: 80% theory.

P R I m e R 16. (+)1,3-Dipropyl-8-(3-oxocyclopent)xanthine.

a) 2.0 g (6.2 mmol) of racemic 1,3-dipropyl-8-(3-oxocyclopent)xanthine suspended in 2 l of absolute toluene and under vigorous stirring mixed with 640 mg of acetanhydride and 2.0 g of lipase from Candida cylindracea. After 6 h at room temperature the enzyme is filtered and washed with methanol. The combined filtrates concentrated to dryness in vacuo and the residue chromatographic on silica gel using as elution solvent of methylene chloride and methanol in the ratio 95:5.

D20+12o(c= 0.4, methanol).

C) Optically enriched alcohol dissolved in 490 ml of absolute methylene chloride and mixed with 490 mg acetanhydride and 1.5 g of lipase "Amano P". The mixture is stirred for 24 h at room temperature, the enzyme is removed by filtration and the filtrate concentrated to dryness in vacuo. The result chromatography on silica gel using as elution solvent of methylene chloride and methanol in a ratio of 95:5 to obtain 480 mg of the above compound with the rate of rotation [D20+18,2o(c=0.5, methanol); according to high performance liquid chromatography optical purity is >99%

P R I m e R 17. (-)-1,3-Dipropyl-8-(3-hydroxy-cyclopentyl)xanthine.

a) 1.0 g of racemic 1,3-dipropyl-8-(3-oxocyclopent)xanthine suspended in 1 l of absolute toluene and together with 320 g of acetanhydride and 1.0 g of lipase from Candida cylindracea stirred tacosa in vacuum. The remainder chromatographic on silica gel using as elution solvent of methylene chloride and methanol in the ratio 95:5. Obtain 0.45 g of crystalline residue that was mixed with simple diethyl ether and sucked off. Thus obtain 350 mg of the crystals with the rate of rotation [D20-13,7o(c=0.4, methanol).

b) Optically enriched alcohol in the environment of toluene again stirred with 110 mg of acetanhydride and 350 mg of lipase from Candida cylindracea for 16 h at room temperature. The mixture is processed in the manner described above. Receive 200 mg of colorless crystals with a rate of rotation [D20-20,2o(c=0.5, methanol). According to high performance liquid chromatographic enantiomer has a purity of >99%

P R I m e R 18. (+) and (-) 1,3-Dipropyl-8-(3-oxocyclopent)xanthine.

1.0 g of optically pure alcohol 1,3-dipropyl-8-(3-oxocyclopent)xanthine are dissolved in 30 ml of absolute methylene chloride and after the addition of 1.1 g Harrogate pyridinium stirred for 2.5 h at room temperature. The mixture is washed twice with water, the aqueous phase is extracted with methylene chloride and the combined organic phases are dried and evaporated in vacuum. Cleaning implement chromium is 3, respectively. Depending on the optically pure alcohol produced the following compounds.

From (+)spirit receive (-)1,3-dipropyl-8-(3-oxocyclopent)xanthine (example 18a) [D20-8,3o(c=0.5, methanol).

From (-)of the alcohol produced (+)1,3-dipropyl-8-(3-oxocyclopent)xanthine (example 18b). [ D20+8,0o(c=0.5, methanol). According to the accepted nomenclature this compound has the following name: 8-(3-oxocyclopent)-1,3-dipropyl-7H-purine-2,6-dione.

Similarly, as shown in the examples can be obtained are given in table.1 the compounds of formula I. In the table.1 used the following abbreviations:

Me methyl

Et ethyl

Ks Campanula acid.

Pharmacological data.

The cerebral cortex of the rhesus was gomogenizirovannykh in 10-fold volume of ice-cold sucrose (0.32 mol/l) in 50 mmol/l buffer Tris Hcl (pH 7.4), after which the mixture was centrifugals at 4aboutC and 3000 rpm for 10 min. the Supernatant was again centrifugals at 20,000 rpm for 15 min and the residue was re-suspendible in 50 mmol/l Tris buffer x xl containing 10 mmol/l magnesium chloride. The obtained suspension was centrifugals and twice gomogenizirovannykh th for the receptor binding of adenosine (a value of Ki). Incubation was conducted at 25aboutC for 60 minutes as radioligand used was 0.5 nmol/l [3H]-1,3-dipropyl-8-cyclopentyl-adenosine. In addition, encubierta mixture contained 1 μg/ml deaminase adenosine (to remove residual adenosine), 10 mmol/l magnesium chloride and 200 μl of the product homogenization of the membrane. To determine nonspecific binding was used 10-5mol/l (-)-N6-phenylisopropylamine. After incubation, the mixture was filtered. Determining values of Kiwas carried out using a computer program.

The compounds and the results of the experiment are given in table.2. As a comparison we used a well-known antagonist of adenosine theophylline.

Comparison of the data table.2 shows the best activity of new compounds in comparison with the known.

The compounds of formula I belong to the category of low-toxic substances.

1. Xantina derivatives of General formula

< / BR>
where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by group

< / BR>
where Alk1WITH4-alkyl,drofuran, optionally substituted lower alkyl or a group

< / BR>
or furan, or thiophene, substituted lower alkyl or nitro-group or the unsubstituted cycloalkyl with 6 to 8 carbon atoms, cycloalkane or cycloalkyl with 5 to 6 carbon atoms, an unsubstituted cycloalkyl with 4 to 6 carbon atoms or cycloalkane4WITH6replaced Gruppman2N NH-phenyl, whereby phenyl may be substituted, NON, -OCONH-phenyl, and phenyl may be somesense of SOON3, -CH2COOCH3, -CH2CH2NH2, -OS(C6H5)3, OAlk, where Alk has the specified value, R4where R4the remainder campanulas acid, lower alkyl, phenyl, substituted lower alkoxyl, phenyl, methoxymethyl, six-membered nitrogen-containing heterocycle; cyclohexane, substituted cyanomethylene, or oxyalkyl1WITH4or hydroxy-group, or cyclopentane, substituted lower alkyl or phenyl, which may have as a second Deputy in genialnom position relative to the first hydroxyl group, or ketal formula

< / BR>
or R3residue selected from the group

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
in the form of mixtures of isomers or individual isomers, obladaushi the properties of antagonists of adenosine.

 

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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

FIELD: medicine, gerontology.

SUBSTANCE: the present innovation deals with rehabilitation therapy of cerebrovascular diseases. One should introduce microcirculators and nootropic preparations to conduct training neuropsychological procedures. Moreover, microcirculatory and nootropic preparations should be introduced as intravenous infusions for 10 d, ten during 1 mo it is necessary to introduce tableted forms of the same preparations at simultaneous neuropsychological training directed to improving household skills valuable for a patient that deal with memorizing different names, important dates, names of medicinal preparations and location of domestic articles. On achieving a success the tasks should be complicated. Training should last for 30 min carried out thrice weekly: therapy course includes 12 trainings. The innovation widens the number of preparations for treating elderly and senile patients at discirculatory encephalopathy stage III and coarse cognitive deficiency.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

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