Antihypoxic and hypolipidemic pharmaceutical agent improving coronary and cerebral blood flow

FIELD: medicine.

SUBSTANCE: therapeutically effective amount of ethyl methyl hydroxypyridine succinate and calcium atorvastatin, as well as additives in the form of lactose and magnesium stearate are encapsulated in gelatine. Ethyl methyl hydroxypyridine succinate and magnesium stearate is placed into an inner smaller gelatine capsule inside a main outer gelatine capsule containing atorvastatin, lactose and magnesium strearate. The ingredient ratio in the inner capsule makes, wt %: Ethyl methyl hydroxypyridine succinate 96.2-98.6; magnesium stearate 1.4-3.8, and the ingredient ratio in the outer capsule makes, wt %: calcium atorvastatin 10.0-45.0; lactose 52.0-89.0; magnesium stearate 1.0-3.8.

EFFECT: method enables providing the higher pharmaceutical effectiveness of the preparation and prolonging the shelf-life by preventing atorvastatin degradation.

3 cl, 3 tbl

 

The invention relates to medicine, more precisely to the pharmacy, and can be used for the preparation of medicinal antihypoxic and lipid-lowering agents, improving coronary and cerebral blood flow. Known use as antihypoxic funds, improve blood flow, such pharmaceutical preparations as Mexidol and Mexicor (Mashkovsky M. D. Medicines. 1997, T. 2). Preparations on their basis or on the basis of salts of succinic acid is protected by patents of the Russian Federation 2205640, 2002; 2205640, 2003; 2366426, 2007, 2410094, 2005; 2410094, 2009 However, these known products do not contain lipid-lowering substances, which in combination with salts of succinic acid could provide a pronounced antihypoxic and lipid-lowering effect, which is necessary in the treatment of atherosclerosis.

Preparation on the basis of salts of succinic acid and lipid-lowering means atorvastatin described in the patent No. 2445091 as antihypoxic and hypolipidemic agent, improves coronary and cerebral blood flow. This technical solution is chosen as the prototype of the claimed invention. Known means contains in wt.%:

1,0-5,0
2-ethyl-6-methyl-3-oksipiridina succinate65,0 to 90.0
atorvastatin
the filler(s) and provide(s) strength
substance(a)from 0.5 to 25.0
binder0,05-3,0
the substance(s) that provide(s) sufficient fluidity
and prevent the build-up0,5-2,0

However, this tool has the following disadvantages.

Studies have shown that a well-known tool storage loses its pharmacological activity due to degradation of atorvastatin. As the most likely causes chemical damage to the structure of atorvastatin calcium it is possible to allocate the reduction in pH of the medium, the presence of oxidants, increasing temperatures and atmospheric oxygen. The reaction of cyclization of atorvastatin lactone can be represented as follows.

One of the main factors acidification of the environment in the studied combinations are the chemical properties of the substance etilmetilgidroksipiridina succinate. Due to the acidic properties etilmetilgidroksipiridina succinate pH environment, which is the substance that is reduced, which leads to the stabilnosti of atorvastatin calcium. Presumably, the proton of the hydrogen molecule dissociates from etilmetilgidroksipiridina succinate, reacts with atorvastatin, which leads to cyclization of atorvastatin lactone (1). This reaction proceeds under normal conditions, the temperature rise can be a catalyst process. Studied literature recommended for solving problems like this to use as a secondary raw material substances with basic properties such as calcium carbonate, magnesium oxide, sodium lauryl sulfate, and D. R.

To prevent destruction of atorvastatin calcium to exclude the influence on the quality of the dosage form itself, methods of sample preparation (partly, perhaps, through education nitrilase salts undergoes hydration of acetonitrile, participating in the analysis in an acidic environment to amides and further hydrolysis to carboxylic acids, which shifts the pH):

The present invention prevents this negative effect.

The technical result of the invention is to increase the pharmacological effect of the drug and increase its shelf life by preventing degradation of atorvastatin in pharmaceutical form.

This technical result is achieved by the fact that in the known antigipoksicski the m and hypolipidemic pharmaceutical means, improves coronary and cerebral blood flow, comprising a therapeutically effective amount etilmetilgidroksipiridina succinate and atorvastatin calcium, as well as excipients as lactose and magnesium stearate, enclosed in gelatin capsules of etilmetilgidroksipiridina succinate, magnesium stearate, placed in the inner lower gelatin capsule placed inside the main outer gelatin capsules containing atorvastatin, lactose, magnesium stearate, while in the internal capsule, the ratio of ingredients in wt.% is:

Ethylmethylketone-DIN succinate96,2-98,6
Magnesium stearateof 1.4 to 3.8

and in the external capsule, the ratio of ingredients is in the mass. %:

Atorvastatin calcium10,0-45,0
Lactose52,0-89,0
Magnesium stearateof 1.0 to 3.8

A therapeutically effective dose etilmetilgidroksipiridina succinate may be 100-250 mg

A therapeutically effective dose of atorvastatin may makes the 10-40 mg.

The proposed pharmacological tool is made as follows.

For the production of equipment was used, allowing the packaging of the product technology capsule in the capsule". Was used capsulearava machine ACG Pam AF-40T (capacity 40,000 capsules per hour, the production of India).

stage 1 TA - cooking process mixture for capsules No. 3 - composition 1.

stage 2 TP - cooking process mixture for capsules No. 0 part 2.

stage 3 TP - packing process a mixture of composition 1 in capsules No. 3. On capsuleers machine sets the format No. 3 for powder filling of capsules. Download the capsule 3 and the technological mix - part 1. After receiving the required number of capsules perform the cleaning procedure. Remove format No. 3, set the format of # 0 with the group for powder filling and packing of capsules in the capsule.

stage 4 TS - packing process mixture composition 2 and capsules No. 3 in capsules No. 0. In the hopper load an empty capsules capsule format No. 0. Into the hopper of the powder module load process mixture - composition 2, and into the hopper module packaging of capsules in a capsule loaded capsules No. 3, containing etilmetilgidroksipiridina succinate. Get a medicinal product is manufactured in a capsule in which pale", that allows you to separate the two active substances, and to exclude their influence on each other.

Examples of implementation funds

As described above were prepared 7 sample means of the following composition:

Composition No. 1

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate250 mg/capsule
Magnesium stearate5 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calcium10 mg/capsule
Lactose88 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 2

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate175 mg/capsule
Magnesium stearate5 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calciumLactose88 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 3

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate175 mg/capsule
Magnesium stearate3 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calcium20 mg/capsule
Lactose73 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 4

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate250 mg/capsule
Magnesium stearate3 mg/capsule

The composition of the mixture in the external capsule:

/tr>
Atorvastatin calcium20 mg/capsule
Lactose78 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 5

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate100 mg/capsule
Magnesium stearate2 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calcium40 mg/capsule
Lactose58 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 6

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate250 mg/capsule
Magnesium stearate2 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calcium40 mg/capsule
Lactose58 mg/capsule
Magnesium stearate2 mg/capsule

Composition No. 7

The composition of the mixture in the internal capsule:

Etilmetilgidroksipiridina succinate175 mg/capsule
Magnesium stearate2 mg/capsule

The composition of the mixture in the external capsule:

Atorvastatin calcium40 mg/capsule
Lactose58 mg/capsule
Magnesium stearate2 mg/capsule

The obtained capsules were deposited at normal and elevated temperatures of 60°C for 80 days, and then subjected to chemical analysis.

Research methods

Authentication

HPLC atorvastatin. The retention time of the principal peak in the chromatogram of the test solution should correspond to the retention time of the principal peak in the chromatogram of a standard solution of atorvastatin calcium of three-hydrate (Sigma 134523-03-08).

UV-spectrophotometry of atorvastatin. About 12 mg of drug was placed the t in a volumetric flask with a capacity of 50 ml, dissolve in methanol to bring the volume of solution of methanol to the mark and stirred for 12 ág/ml UV-absorption spectrum of the resulting solution, shot on the spectrophotometer in the field of 220-300 nm in a cell with a layer thickness of 1 cm relative to the methanol must have a maximum absorption at a wavelength of 246±2 nm.

UV spectrophotometry etilmetilgidroksipiridina succinate. Ultraviolet absorption spectra of the solutions of the drug and the standard solution sample etilmetilgidroksipiridina succinate prepared to quantify in the field of 250-350 nm, must have a maximum at the same wavelength.

TLC etilmetilgidroksipiridina succinate. In the chromatogram of solution B (2 μg) obtained in the determination of impurities, the main spot must match the parameter holding R1the spot in the chromatogram of standard solution sample witness etilmetilgidroksipiridina succinate.

Quantitative determination of substances in each mixture were carried out separately.

1. The HPLC method for atorvastatin.

About 0.10 g (accurately weighed) of the pulverized powder of the outer capsule is placed in a volumetric flask with a capacity of 100 ml, was added 70 ml of a mixture for dissolution, stirred for 30 min, the volume was adjusted suspension of the same mixture to the mark, mix and filter through a membrane filter with diametral pores of 0.45 μm, discarding the first portion of the filtrate (test solution).

Chromatographic conditions:

column - 4.6 mm ×25 cm Hypersil ODS (5 μm) or similar;

the mobile phase - acetonitrile - tetrahydrofuran - 0.05 M solution of citric acid(27:20:53);

flow rate - 1.0 ml/min;

detector - spectrophotometric, 244 nm.

Consistently chromatographic 20 µl of the test solution and the solution RNO atorvastatin calcium.

The content of atorvastatin in the capsule in milligrams (X) is calculated by the formula:

where S1the peak area of atorvastatin on the chromatogram of the test solution;

S0the peak area of atorvastatin on the chromatogram of solution RNO;

a1- weighed powder capsules, in grams;

a0- hanging RDF atorvastatin calcium, in milligrams;

W - water content in RDF atorvastatin calcium, percent;

b - the average weight of the contents of the capsules, in milligrams;

0,96705 - the conversion factor of atorvastatin calcium on anhydrous atorvastatin.

The contents of C33H35FN2O5(atorvastatin) in the capsule must meet the requirements of the global Fund XI, vol.2, considering the average weight of the contents of the capsule.

The results of analysis are considered reliable if the requirements of the test "to test the suitability of the chromatographic system is.

1. Preparation of 0.05 M solution of citric acid. 9.6 g of citric acid, calculated on the anhydrous dissolved in 800 ml of water, adjusted the pH to 4.0±0,1 a concentrated ammonia solution to bring the volume of solution with water to 1000 ml, and mix.

2. Preparation of the mobile phase. Mixed acetonitrile - tetrahydrofuran - 0.05 M solution of citric acid in the ratio 27:20:53.

3. Preparation of a solution of atorvastatin calcium. About 0,054 g (accurately weighed) of atorvastatin calcium is placed in a volumetric flask with a capacity of 50 ml, dissolved in a mixture of acetonitrile - citrate buffer solution with a pH of 7.4 (1:1) to bring the volume of solution of the same mixture to the mark and mix. 5 ml of the resulting solution is transferred into a volumetric flask with a capacity of 50 ml, the volume was adjusted solution of the same mixture to the mark and mix.

Solution use freshly prepared.

4. To test the suitability of the chromatographic system. Chromatographic solution of atorvastatin calcium. The column efficiency (N) calculated at the peak of atorvastatin should be not less than 3000 theoretical plates, asymmetry factor (T) of the peak of atorvastatin should not be more than 2.0. The relative standard deviation of the peak area of atorvastatin with five sequential injection should be not more than 2.0%.

2. The method of UV spectrophotometry for etilmetilgidroksipiridina

1 ml of the filtrate is transferred into a measuring flask of 100 ml capacity, bring the volume of the solution up to the mark with 0.1 M solution of hydrochloric acid and stirred (test solution).

Measure the optical density of the test solution on the spectrophotometer at the maximum absorption at a wavelength of 297 nm in a cell with a layer thickness of 10 mm as the reference solution using 0.1 M solution of hydrochloric acid.

Simultaneously measure the optical density of the solution nor etilmetilgidroksipiridina succinate.

Content etilmetilgidroksipiridina succinate in one pill in milligrams (X) is calculated by the formula:

where a is the optical density of the test solution;

A0- the optical density of the solution WITH etilmetilgidroksipiridina succinate;

a0- the mass of a sample WITH etilmetilgidroksipiridina succinate, in milligrams;

A1- the weight of the portion pounded granulate, in milligrams;

P - the actual content of the basic substance in etilmetilgidroksipiridina succinate, calculated on the anhydrous substance, percent;

M is the average mass of the contents of one capsule in milligrams.

The contents of C12H17NO5(etilmetilgidroksipiridina succinate) in one capsule, considering the average weight of the contents of the capsules must comply with the requirements of the global Fund XI, vol.2.

Preparation of the solution WITH etilmetilgidroksipiridina succinate

About 100 mg (accurately weighed) etilmetilgidroksipiridina succinate (mm 42-8455-07, the Fund 42-06502066-06) is placed in a volumetric flask 100 ml capacity, add 60 ml of 0.1 M solution of hydrochloric acid, stirred until dissolved, bring the volume of the resulting solution in the same solvent up to the mark and mix. 1 ml of the resulting solution is placed in a volumetric flask with a capacity of 100 ml, bring the volume of solution in the same solvent up to the mark and mix.

Evaluation of the effect of auxiliary substances and determination of impurity compounds in the mixtures was also conducted separately:

- HPLC method for atorvastatin.

To 0.10 g pulverized powder from the external capsule was added 20 ml of a mixture for dissolution (see "quantification"), stirred for 30 min and filtered through a membrane filter with a pore diameter of 0.45 μm, discarding the first since the AI filtrate (test solution). 0.5 ml of the test solution is placed in a volumetric flask with a capacity of 100 ml, bring the volume of the solution mixture to dissolve up to the mark and mix (solution comparison).

Consistently chromatographic 20 µl of the reference solution and the test solution under the conditions described in "quantification". Check the test solution should not less than 3 times the retention time of the principal peak.

The peak area of any extraneous impurity in the chromatogram of the test solution should not exceed the peak area of atorvastatin on the chromatogram of the reference solution (not more than 0.5%); the sum of the areas of all peaks of impurities should not be more than 4 times the peak area of atorvastatin on the chromatogram of the reference solution (not more than 2.0%).

- TLC method for etilmetilgidroksipiridina succinate. About 200 mg of powder pounded the contents of the internal capsules are placed in a test tube with a glass stopper with a capacity of 20 ml, add 10 ml of ethanol 96%, shaken for 2 min and filtered through a filter paper of "blue ribbon", discarding the first portion of the filtrate, or centrifuged at 3000 rpm/min (solution A).

0.5 ml of the solution And placed in a volumetric flask with a capacity of 50 ml, the volume was adjusted solution of ethyl alcohol 96% up to the mark and mix (solution B).

The start line of chromatographic the Russian plate attached to an aluminum substrate with a layer of silica gel 60 F254 (Merck type) of size 10×20 cm applied separately to 0.01 ml of solution A (200 µg), solution B (2 µg), a solution of 1 (2 g) and solution 2 (0.5 μg) much of etilmetilgidroksipiridina.

The vinyl coated samples dried in air for 10 min, placed in an unsaturated chamber with a mixture of acetone-ethyl acetate-ammonia solution concentrated (50:50:1) and chromatographic ascending method. When the front of the mobile phase will be held 10 cm from the start line, it is removed from the chamber, air-dried for 10 min and viewed under ultraviolet light at a wavelength of 254 nm.

The chromatogram of the solution And spot one single impurities should not exceed in the aggregate size and the absorption intensity of the spots on the chromatogram of a solution of 1 (not more than 1.0%). Pets spot on the start line.

The results of analysis are considered reliable if the requirements of the test "to test the suitability of the chromatographic system.

1. Preparation of solutions 1 and 2 much etilmetilgidroksipiridina succinate. 20 mg etilmetilgidroksipiridina succinate (mm 42-8455-07, the Fund 42-06502066-06) is placed in a volumetric flask with a capacity of 100 ml, dissolve in 50 ml of ethyl alcohol 96%, bring the volume of solution in the same solvent up to the mark and mix (solution 1).

To 1 ml of solution 1 was added 3 ml of ethyl alcohol 96% and mix (solution 2).

2. To test the suitability of the chromatographic system. Chromatographic system is and are considered suitable, if the chromatogram of solution 2 (0.5 μg), there is a clear spot.

The pH of the medium was carried out by an automatic apparatus pH meter Sartorius PB-11.

The results are presented in tables 1, 2 and 3.

Table 1 presents the results of a study of newly manufactured devices No. 1 to No. 7.

Table 2 presents the results of the study after storage devices No. 1 to No. 7 at 25°C for 3 years and 6 months.

Table 3 presents the results of the study after storage devices No. 1 to No. 7 at an elevated temperature of 60°C for 80 days, which is equivalent to 3 years and 6 months normal storage.

As can be seen from tables 1-3 and on the basis of the received data samples, we can conclude that in a mixture of atorvastatin calcium, lactose and magnesium stearate, and the mixture etilmetilgidroksipiridina succinate and magnesium stearate does not decrease the concentration of the main active substances.

At the same time, under the joint custody of a mixture of atorvastatin, etilmetilgidroksipiridina succinate, lactose and magnesium stearate was increased impurity compounds. At elevated temperature (accelerated stored in a thermostat at 40°C) in these samples was observed that the impurities are higher than in normal storage conditions in vivo. Thus, it is possible in order to draw a conclusion about the lack of stability of atorvastatin calcium and etilmetilgidroksipiridina succinate in the sample, made the prototype, and maintenance of the chemical structure of active substances in the product is manufactured according to the invention. Maintenance of the chemical structure of the compounds in the present samples provides improved pharmacological activity of these drugs compared with samples of the prototype.

Table 1
CompositionHPLC atorvastatinUV-spectrophotometry of atorvastatinUV spectrophotometry etilmetilgidroksipiridina succinateTLC etilmetilgidroksipiridina succinate
Composition No. 110,16246,0 nm248,30,55
Composition No. 29,95245,5 nm175,30,54
Composition No. 319,92245,5 nm174,80,55
Composition No. 420,21246,6 nm250,70,55
Composition No. 539,84245,8 nmof 101.50,56
Composition No. 640,13246,3 nmof 249.60,55
Composition No. 7245,8 nm176,10,56

Table 2
CompositionHPLC atorvastatinUV-spectrophotometry of atorvastatinUV spectrophotometry etilmetilgidroksipiridina succinateTLC etilmetilgidroksipiridina succinate
Composition No. 110,00246,2 nm248,30,56
Composition No. 29,92246,1 nm175,30,55
Composition No. 319,78245,8 nm174,80,54
Composition No. 420,16246,4 nm250,70,56
Composition No. 539,43245,8 nmof 101.50,56
Composition No. 639,88246,2 nmof 249.60,55
Composition No. 739,35245,9 nm176,10,54

Table is CA 3
CompositionHPLC atorvastatinUV-spectrophotometry of atorvastatinUV spectrophotometry etilmetilgidroksipiridina succinateTLC etilmetilgidroksipiridina succinate
Composition No. 19,96246,0 nm246,20,56
Composition No. 2to 9.91245,5 nm173,80,55
Composition No. 3to 19.74245,5 nm173,20,56
Composition No. 4grade of 20.06 246,6 nm258,40,55
Composition No. 539,38245,8 nm100,10,55
Composition No. 639,85246,3 nm248,80,56
Composition No. 739,35245,8 nmof 174.50,54

1. Antihypoxic and hypolipidemic pharmaceutical agent that improves coronary and cerebral blood flow, comprising a therapeutically effective amount etilmetilgidroksipiridina succinate and atorvastatin calcium, as well as excipients as lactose and magnesium stearate, which concluded in gelatin capsules, characterized in that etilmetilgidroksipiridina succinate and magnesium stearate placed in the inner lower gelatin capsule placed inside the main outer gelatin capsules containing atorvastatin, lactose, magnesium stearate, while in the internal capsule, the ratio of ingredients in wt.% is

Etilmetilgidroksipiridina succinate96,2-98,6
Magnesium stearateof 1.4 to 3.8

and in the external capsule, the ratio of ingredients is in the mass. %
Atorvastatin calcium10,0-45,0
Lactose52,0-89,0
Magnesium stearateof 1.0 to 3.8

2. Pharmaceutical facility under item 1, characterized in that therapeutically effective amount etilmetilgidroksipiridina succinate is 100-250 mg

3. Pharmaceutical facility under item 1, characterized in that a therapeutically effective amount of atorvastatin calcium is 10-40 mg



 

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FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to treatment of cardiovascular disease, and deals with the reduction of cholesterol level in blood plasma. The method includes introduction of an efficient quantity of the first composition, which contains quercetin, vitamin C and vitamin B3, and an efficient quantity of the second composition, containing statin, to a patient in need. In the first composition the weight ratio of quercetin, vitamin C and vitamin B3 equals to 1:0.2-2.5:0.02-1. The efficient quantity of the first composition represents the quantity which provides 1000 mg of quercetin per day.

EFFECT: method provides substantial reduction of cholesterol level, including patients, who have already received therapy by statins.

30 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology and cardiology, and deals with treatment or prevention of thrombosis. For this purpose dabigatran etexilate is introduced in a dose from 150 to 300 mg twice per day.

EFFECT: method provides prevention of thromboembolic complications and development of stroke in patients with atrial fibrillation, who have creatinine clearance less than 80 ml/min with an absence of additional factors of risk of massive bleeding.

7 cl, 7 tbl, 4 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: composition containing an activated-potentiated form of antibodies to the brain-specific S-100 protein, and an activated-potentiated form of antibodies to endothelial NO-synthase as an additional exalting component is administered.

EFFECT: effective treatment of organic diseases of the nervous system by the synergetic neurotropic action of the components.

18 cl, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: therapeutic agent containing an activated-potentiated form of antibodies to the brain-specific S-100 protein, and an activated-potentiated form of antibodies to endothelial NO-synthase as an additional exalting component is administered.

EFFECT: effective treatment of Alzheimer's disease by the synergetic action of the components.

11 cl, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to treating neurological behaviour development disorders, including attention deficit syndrome (ADS), attention deficit/hyperactivity syndrome (ADHS). A therapeutic agent presented in the form of a pharmaceutical composition containing an activated-potentiated form of antibodies to the brain-specific S-100 protein, and an activated-potentiated form of antibodies to endothelial NO-synthase as an additional exalting component is administered.

EFFECT: effective treatment of the above pathology by the synergetic neurotropic action of the components of the therapeutic agent.

14 cl, 2 ex, 4 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of N-phenyl(pyperazinyl or homopyperazinyl)benzenesulphonamide or benzenesulphonylphenyl(pyperazine or homopyperazine), or to their physiologically acceptable acid addition salts, described by general formulas (I) and (I'), where X is a chemical bond or a group N-R4; R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is hydrogen, C1-C3alkyl, fluorine, C1-C2alkoxy or fluorinated C1-C2alkoxy; R4 is hydrogen, C1-C4alkyl or C3-C4cycloalkyl-CH2-; R5 is hydrogen, fluorine, chlorine, C1-C2alkyl, C1-C2alkoxy or fluorinated C1-C2alkoxy; R6 is hydrogen and n is 1 or 2. The invention also relates to a pharmaceutical composition based on the compound of formula

or

.

EFFECT: novel compounds, modulating activity of the 5HT6 receptor are obtained.

35 cl, 2 tbl, 105 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel macrocyclic alkylammonium derivatives of 6-methyluracil of formula (1). The compounds have anticholinesterase activity and can be used for pharmacological correction of synaptic defects which cause Alzheimer's disease, myasthenia gravis and other forms of pathological muscle weakness. The compounds can be used when treating glaucoma, intestinal atony, alcoholism, schizophrenia, manic-depressive psychosis, traumatic brain injury, sleep disorders, etc. In formula (1) X=NO2, Y=(CH2)4 (1a); X=CN, Y=(CH2)4 (1b); X=NO2, Y=C6H4 (1c); X=CN, Y=C6H4 (1d).

EFFECT: improved properties of compounds.

2 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of biotechnology, namely to the application of a conjugate of an immunogenic peptide and can be used in medicine. The said conjugate, containing 1÷93 of immunogenic peptides Aβ(35-42) (SEQ ID NO: 2), or 1÷93 of immunogenic peptides Aβ(33-42) (SEQ ID NO: 3), or 1÷93 of immunogenic peptides Aβ(33-40) (SEQ ID NO: 4), connected with a native albumin by means of a linker region, containing cysteine and a bifunctional linker, on condition that the linker region is connected by means of cysteine to the N-end of not more than one immunogenic peptide, can be used for the application in treatment or prevention of a disease, associated with the deposit of amyloid proteins. The invention also relates to the application of a pharmaceutical composition, containing the said conjugate, for the treatment or prevention of the disease, associated with the deposit of the amyloid proteins.

EFFECT: invention makes it possible to efficiently reduce levels of the amyloid peptide with the application of a simple in obtaining structure of the immunogenic peptide conjugate.

9 cl, 8 dwg, 7 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

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