Hexanone compounds and using them in medical applications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula I

which can be used for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis. In formula I A represents =S, -SR4 or =O, X represents F, Cl, Br or I, R1 represents phenyl, R2 and R3 are connected to form morpholine, and R4 represents C1-C6-alkyl.

EFFECT: invention refers to using the compound for producing the therapeutic agent for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis, and to the method for producing the above compounds.

8 cl, 2 tbl, 2 ex

 

The technical field to which the invention relates

The invention relates to the field of medicinal chemistry and, in particular, to gexanova compound and pharmaceutical composition. The present invention also relates to the use of compounds and pharmaceutical compositions for combating apoptosis, prevention or treatment of diseases or disorders associated with apoptosis, and, in particular, to protect the cells of the myocardium and for the prevention or treatment of diseases or disorders associated with apoptosis of myocardial cells.

The level of technology

Apoptosis usually refers to programmed cell death of cells of the body, occurring regulation of intracellular genes and their products in development, or under the influence of some factors. Apoptosis usually exists in the biosphere in the physiological condition and pathological state. It plays an important role in embryonic development and morphogenesis, stability of normal cells in tissues, protection and the immune response, the cell damage caused by disease or poisoning, aging, education and the development of tumors and is one of the hotspots in biomedical research.

Some studies show that the occurrence of many serious diseases refers to excessive apoptosis of cells, for example, reducci� CD4 +T cells in the development process ADIS; cell death mediated by cytotoxic T-cells in graft rejection; apoptosis of myocardial cells and nerve cells in ischemia-reperfusion injury, disease, degradation of the nervous system (such as Alzheimer's disease, Parkinson's disease, etc.); apoptosis induced by ionizing radiation in many tissues.

Some evidence indicate that apoptosis of cardiomyocytes is closely associated with the occurrence, development and prognosis of many diseases of the heart. In the study of apoptosis of cardiomyocytes was determined that the heart attack the heart muscle is not equivalent to myocardial necrosis and apoptosis is one of the mechanisms of myocardial infarction, and is the primary mechanism of death from heart attack early myocardial infarction and death from ischemia/reperfusion injury and apoptosis of cardiomyocytes in large quantities thus exacerbates myocardial injury. In 1989 Nepomniashchikh, etc. found when observing the ultrastructure of the atrophy of the myocardium that the synthesis of structural protein of cardiomyocytes is reduced and the number of cells decreases, but is not accompanied by a proportional decrease of cell nuclei, thus, tentatively suggested that atrophy of the myocardium caused by apoptosis. 1994 Gottlieb and Kawano, etc. received direct evidence of apopt�for cardiomyocytes with an electron microscope in combination with gel electrophoresis DNA in which first opened reperfusion injury induced apoptosis of cardiomyocytes rabbits, and the latter confirmed that patients with myocarditis had concomitant apoptosis of cardiomyocytes. Tanaka and others have also confirmed the existence of apoptosis of cardiomyocytes in mice-suckers. With the development of the methodology and the study of apoptosis, pathological features of apoptosis were installed in many diseases of the heart. Some research suggests that heart disease in spontaneously hypertensive rats (SHR) is related to apoptosis; the transition from pathological thickening of the heart to heart failure at a late stage due to apoptosis of cardiomyocytes; acute myocardial infarction also induces apoptosis in the early stage of infarction and reperfusion, except for necrosis; apoptosis of cardiomyocytes also detected in the transplanted heart and hypoplasia of the right ventricular myocardium and also oxygen deprivation induces apoptosis of cardiomyocytes.

Apoptosis to some extent can be recovered and apoptosis in myocardial infarction and ischemia/reperfusion has its own characteristics and laws, so that features can be used for the prevention and attenuation of apoptosis and may provide information for clinical prevention of ischemia/reperfusion, during reperfusion, apoptosis in about�lusty strip cut (around the location of the injury) is induced by some aggravating factors, so the inhibitors of apoptosis, such as medicines, can be used to prevent apoptosis and treatment of relevant diseases caused by apoptosis.

Currently, however, there are several types and many drugs that can be used clinically to combat apoptosis and protecting cells and their selectivity and focus are not satisfactory, and it is therefore important to the continuous development of new, safe and effective drugs for combating apoptosis and protection and, in particular, drugs with new mechanism of action.

Disclosure of the invention

For the development of new, safe and effective drugs to combat apoptosis and protecting cells, after carrying out extensive experimental studies over a long period of time, the inventors have discovered a group hexenuronic compounds that are effective in the suppression of apoptosis and protection of myocardial cells I. can be used for the prevention or. the treatment of diseases or disorders associated with apoptosis of cardiomyocytes. In particular, the first aspect of the present invention relates to a compound of formula I, or its isomer, pharmaceutically acceptable salt or solvate.

where A represents =S, -SR4or =O;

X represents F, Cl, Br or I;

R1represents phenyl, phenyl-C1-C6-alkyl-, where phenyl is unsubstituted or substituted with 1-4 (e.g., 1-2, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen, nitro, hydroxy, amino, cyano, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenoalkane, where alkyl, alkoxy and halogenated may be optionally substituted by hydroxyl, -O-(C1-C4)-alkyl, oxo, amino, -NH-(C1-C4)-alkyl or-N[(C1-C6)-alkyl]2or by alkyl, alkoxy and halogenation optionally including-O-,-S-, -NH-, -COO - or-CONH-; 5 - or 6-membered heterocyclic ring; or a substituted heterocyclic ring, which heterocyclic ring is unsubstituted or substituted with 1-3 (e.g., 1-2, 1, 2, or 3) substituents, independently selected from the group consisting of halogen, nitro, hydroxy, amino, cyano, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenoalkane, where alkyl, alkoxy and halogenated may be optionally substituted by hydroxyl, -O-(C1-C4)-alkyl, oxo, amino, -NH-(C1-C4)-alkyl or-N[(C1-C6)-alkyl]2or by alkyl, alkoxy and halogenation, optionally including-O-, -S-, -NH - or-COO-,and the heterocyclic ring may be a heterocycle with two nitrogen atoms in the ring, a heterocycle with the nitrogen atoms and oxygen, or heterocycle with the sulfur atoms and nitrogen;

R2and R3represent hydrogen, C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, C1-C6-alkoxy, C1-C6-alkyl, amino (C1-C6alkyl, mono-substituted or di-substituted amino (C1-C6alkyl, phenyl C1-C6alkyl, substituted phenyl C1-C6alkyl, heterocyclic C1-C6alkyl, substituted heterocyclic (C1-C6alkyl, phenyl, substituted phenyl, or C1-C6heterocyclic or substituted C1-C6heterocyclic group, in which R2and R3can be linked together to form a ring; and

R4represents C1-C6alkyl.

Preferably, the compound of the present invention is a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate, where:

And is =S, -SR4or =O;

X represents F, Cl, Br or I;

R1represents phenyl, phenyl-C1-C6alkyl-, where phenyl is unsubstituted or substituted with 1-4 (e.g., 1-2, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen, nitro, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1 -C6halogenoalkane, where alkyl, alkoxy and halogenated may be optionally substituted by hydroxyl, -O-(C1-C4)-alkyl, oxo, amino, -NH-(C1-C4)-alkyl or-N[(C1-C6)-alkyl]2or by alkyl, alkoxy and halogenation, optionally substituted-O-,-S-, -NH-, -COO - or-CONH-; thienyl, thiazolyl where thienyl, thiazolyl are unsubstituted or substituted with 1-3 (e.g., 1-2, 1, 2 or 3) substituents, independently selected from the group consisting of: halogen, nitro, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy and C1-C6halogenoalkane, where alkyl, alkoxy and halogenated may be optionally substituted by hydroxyl, -O-(C1-C4)-alkyl, oxo, amino, -NH-(C1-C4)-alkyl or-N[(C1-C6)-alkyl]2or by alkyl, alkoxy and halogenation, optionally including-O-, -S-, -NH - or-COO-;

R2and R3represent hydrogen, C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, C1-C6alkoxy (C1-C6alkyl, amino (C1-C6alkyl, mono-substituted or di-substituted amino (C1-C6alkyl, phenyl C1-C6alkyl, substituted phenyl C1-C6alkyl, heterocyclic C1-C6alkyl, phenyl, substituted phenyl, or heterocyclic �whether substituted heterocyclic group, where R2and R3can be linked together to form a saturated cycloalkyl, nitrogen - or oxygen containing heterocyclic ring; and

R4represents methyl, ethyl, propyl, isopropyl, butyl or pentyl.

In particular, the compound of the present invention is a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate, where:

And is =S, -SR4or =O;

X represents Cl;

R1represents phenyl or 2-thienyl;

R2and R3represent hydrogen, methyl, isopropyl, 2-methoxyethyl, 3-isopropoxyphenyl, 2-N,N-dimethylethyl, cyclohexyl, cycloheptyl, ortho-methoxyphenyl, ortho-fluorophenyl, ortho-chlorophenyl, para-chlorophenyl, benzyl, or 8 - chinolin, where R2and R3can be linked together with the formation of piperidine, morpholine or N-methylpiperazine; and

R4represents methyl or ethyl.

In particular, the compound of formula (I) is preferably the following link:

(1E)-1-phenyl-5-(1-morpholinylcarbonyl)-6,6,6-trichloro-1-ene-3-hexanone, or its isomer, pharmaceutically acceptable salt and solvate.

The compound of formula (I) of the present invention can be obtained in the following way:

Accepting connections (1) as an example, the compound of the present invention synthesized with use of benzaldehyde as a starting material by the interaction of benzaldehyde with acetone in a solution of sodium hydroxide in methanol to obtain (1E)-1-phenyl-1-ene-3-acetone, which then reacts with trichloroacetaldehyde during the catalysis of LDA to obtain intermediate 1, the chlorination of intermediate 1 thionylchloride and its interaction with potassium thiocyanate to obtain intermediate 2 and, finally, by boiling to reflux of intermediate 2 with morpholine in tetrahydrofuran to produce compound (1).

Another aspect of the present invention relates to pharmaceutical compositions containing a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate, and a filler or diluent.

The present invention also relates to the use of a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate in accordance with the first aspect of the present invention for the manufacture of a medicament for the suppression of apoptosis or for the prevention or treatment of a disease or disorder associated with apoptosis.

The present invention also relates to the use of a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate in accordance with the first aspect of the present invention for the manufacture of a medicament for the protection of cardiomyocytes and prevent or treat a disease or disorder associated with apoptosis of cardiomyocytes. The present invention relates to a method of combating � apoptosis or for the prevention or treatment of a disease or disorder, associated with apoptosis, the method includes the appointment if necessary, the patient, a therapeutically effective amount of a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate in accordance with the first aspect of the present invention.

The present invention also relates to a method for protection of cardiomyocytes or for the prevention or treatment of a disease or disorder associated with apoptosis of cardiomyocytes, the method includes the appointment if necessary, the patient a therapeutically effective amount of a compound of formula (I) or its isomer, pharmaceutically acceptable salt and solvate.

Diseases or disorders associated with apoptosis according to the present invention include: cardiovascular disease, degenerative nerve disease, multiple sclerosis, viral infections, etc.

Diseases or disorders associated with apoptosis of cardiomyocytes in accordance with the present invention include, but are not limited to: (i) atrophy of the myocardium, (ii) myocarditis, (iii) heart failure, (iv) damage to the myocardium caused by primary hypertension, (v) myocardial injury, due to the early stage of acute myocardial infarction, (vi), myocardial injury caused by reperfusion in acute myocardial infarction, (vii), pathological changes of cardiomyo�itow, caused by a heart transplant, or (viii) dysplastic myocardosis; or apoptosis of cardiomyocytes induced by hypoxia or sclerosis of the cardiovascular system.

In accordance with the present invention, the term "heterocyclic ring" includes, but is not limited to: pyridine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, oxazole, isoxazole, indole, benzofuran, benzimidazole, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, purine, phenothiazines and panasina.

Specialists in the art it is clear that in the compound of formula I has a chiral center. When you want one enantiomer of a compound of formula I, it can be obtained by using the reagents present in the form of a single enantiomer at all possible stages, or obtained by carrying out the reaction in the presence of a reagent or catalyst in the form of a single enantiomer or obtained by separation of the mixture of stereoisomers by conventional methods. Some preferred methods include separation using micro-organisms, chiral acids, such as any suitable acid, for example, mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc. in the form of a salt of the diastereoisomer, or separation with chiral base, such as bracine (brucine), an alkaloid hee�tion of wood or derivatives thereof in the form of a salt of diastereoisomer. With commonly used methods can be found in "Enantiomers, Racemates and Resolution" (Enantiomers, racemate and division) as edited by Jaques et al (Wiley Interscience, 1981).

Specialists in the art it is clear that the compounds of the present invention can also be used in the form of its pharmaceutically acceptable salt or solvate. Physiologically acceptable salts of the compounds of formula I include conventional salts formed from pharmaceutically acceptable inorganic acid or organic acid or an inorganic base or organic base or acid-additive salt of Quaternary ammonium. More specific examples of suitable salts of acids include salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pambou acid, malonic acid, hydroxymaleimide acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, the base, methylsulfonic acid, naphthalene-2-sulfonic, benzolsulfonat, hydroxynaphthoic acid, itestosterone acid, malic acids�, steroic (stearic), tannic acid, etc. as with other acids such as oxalic acid, although they are not themselves pharmaceutically acceptable, they can be used to obtain salts as intermediates for obtaining the compounds of the present invention and its pharmaceutically acceptable salts. More specific suitable alkaline salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, N-methylglucamine and novocaine. Compounds of the present invention, the following include the compound of formula I and its pharmaceutically acceptable salt and solvate.

The present invention additionally includes the prodrug compounds of the present invention and after administration of a prodrug, it is chemically transformed by metabolic active drug.In General, this kind of prodrugs are functional derivatives of the compounds of the present invention, which can be easily converted into the desired compound of formula (I). For example, in "Design Of Prodrugs" (Design of prodrug), edited by N. Bund Saard, Elsevier, 1985, describes the conventional methods of selection and obtaining of suitable prodrug derivatives.

The present invention also includes any active metabolites of the compounds of the present from�retenu.

Another aspect of the present invention relates to pharmaceutical compositions containing the racemate or optical isomer of the compound of the present invention, and at least one pharmaceutically acceptable carrier, and which is suitable for treatment in the body and possessing biocompatibility. Pharmaceutical composition can be manufactured in various forms for various routes of administration. The compound of the present invention can also be manufactured in the form of various pharmaceutically acceptable salts.

Pharmaceutical composition of the present invention contains an effective amount of a compound of formula I of the present invention or its pharmaceutically acceptable salt or hydrate and one or more suitable pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum protein such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, hydrogen phosphate, denetria, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances�VA, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax and lanolin.

Pharmaceutical composition compounds of the present invention may be introduced by any of the following ways: by oral administration, by inhalation of nebulized solution, rectal administration nazalnam the introduction, buccal administration local administration, parenteral administration, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intramammary, intracranial injection or perfusion, or by introduction through explantions depot, preferably by oral administration, intraperitoneal or intravenous injection.

For oral administration the compound of the present invention can be obtained in any suitable form for oral administration, including but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Tablets use the media, which typically include lactose and corn starch, further comprising a lubricant such as magnesium stearate. Capsules use thinner, which typically include lactose and corn starch. Aqueous suspensions typically use a mixture of active ingredients and a suitable emulsifier and fluidizer means. If necessary, the above-mentioned oral Lek�stennie forms may additionally include a number of sweeteners, fragrances or dyes.

For topical use, especially in the treatment of local external application of neurogenic diseases are easily available surface area or organ, such as eyes, skin, or the lower part of the gastrointestinal tract, the compound of the present invention can be manufactured in different dosage forms for topical application for various relevant affected surfaces or bodies, which are illustrated as follows:

For local application to the eyes of a compound of the present invention can be manufactured in the dosage form in the form of a fine suspension or solution, which uses the carrier is an isotonic sterile saline solution with a specific pH, which can be added or not added preservative, such as salt chlorobenzylamino. To use for the eyes, the connection may be made in the form of ointments, such as vaseline ointment.

For local application on the skin, the compound of the present invention can be manufactured in appropriate dosage forms such as ointments, lotions or creams, in which the active component suspended or dissolved in one or more carriers. Carriers suitable for ointments, include, but are not limited to: mineral oil, fluid�m paraffin white petrolatum, propylene glycol, polyethylene oxide, polypropyleneoxide, emulsified wax and water; carriers used in lotions or creams include, but are not limited to: mineral oil, sorbitol monostearate, Tween 60, wax ester hexadecane, aromatic hexadecanoyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compound of the present invention can also be administered in the dosage form of sterile injections, including aqueous or oily suspension for injection or sterile sterile solutions for injection. Used carriers and solvents include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oil can also be used as solvent or suspension medium, such as monoglycerides or diglycerides.

It should also be noted that the doses and methods of using the compounds of the present invention depend on many factors, including age, body weight, gender, natural health status, nutrition, activity, connections, time of administration, rate of metabolism, the severity of disease and subjective evaluation of the physician in the diagnosis. Advantageous effects of invention

The present invention relates to a group hexenuronic compounds, and it has been shown that such compounds EF�objective in the suppression of apoptosis and in cell protection and thus offer a new method and approach in the treatment of diseases or disorders, caused by apoptosis and, in particular, in the treatment of diseases or disorders associated with apoptosis of cardiomyocytes.

The implementation of the invention

The implementation of the present invention is illustrated as follows in conjunction with the following examples, but the specialists in the art it is clear that the following examples serve only to illustrate the present invention and should not be construed as limiting the invention. Methods in the examples which are not detailed is carried out under normal conditions or conditions suggested by the manufacturers. All reagents or devices, manufacturers are not listed, are conventional commercially-available products.

The melting point of the compounds is measured by a device for measuring the melting temperature of RY-1 and thermometers not calibrated. Mass spectra are recorded using a Micromass ZabSpec mass spectrometer high resolution (resolution: 1000).1H NMR was measured using JNM-ECA-400 superconducting NMR spectrometer, operating frequency:1H NMR (400 MHz,13With NMR 100 MHz.

Example 1. (1E)-1-phenyl-5-(1-morpholinylcarbonyl)-6,6,6-trichloro-1-ene-3-hexanone

3 ml of acetone was added to 4,80 g of 10% aqueous NaOH, and the mixture was stirred at 30°C for 5 minutes, add dropwise 1 ml of benzo�of legida, and stirred at room temperature for 3 hours. Then the reaction solution was separated and the organic layer is eluted in petroleum ether:ethyl acetate=20:1 as the displacing solvent to obtain 1.00 g (1E)-1-phenyl-1-ene-3-butanone in the form of yellow crystals. 0.64 g of Diisopropylamine was dissolved in 10 ml of THF under nitrogen gas and the solution was cooled to -40°C, was added dropwise 0.40 g n-utillity, stirred for 30 minutes and then cooled to -78°C. 0.84 g (1E)-1 - phenyl - 1-ene-3-butanone dissolved in 15 ml of THF and the solution was added dropwise to a solution of LDA, and then subjected to the reaction at -78°C for 40 min 1.19 g of trichloroacetaldehyde dissolved in 15 ml of THF and the solution was added dropwise to the above reaction solution, and then subjected to the reaction at -78°C for 12 hours. After the temperature is raised to -40°C, the reaction mixture is added 20 ml of a saturated aqueous solution of NH4Cl, stirred for 30 min, warmed to room temperature and then added 20 ml of ethyl acetate for extraction. The organic layer is eluted in petroleum ether: ethyl acetate=6:1 as the displacing solvent to obtain 1,49 g of (1E)-1-phenyl-5-hydroxy-6,6,6-trichloro-1-ene-3-hexanone in the form of pale yellow crystals. This was dissolved in 20 ml of THF and to the solution was added 1.1 ml of thionylchloride and boiled for 6 hours. Rast�oritel distilled off and the residue dissolved in 20 ml of acetone, then add 0.74 g KSCN and stirred at 40°C for 1.5 hours. Petroleum ether-ethyl acetate=30:1 is used as the displacing solvent for elution after the reaction, to obtain 1.2 g of (1E)-1-phenyl-5-isothiocyanate-6,6,6-trichloro-1-ene-3-hexanone in the form of light yellow solids. 0.33 g of a solid substance and 0.06 ml of morpholine are boiled to reflux in THF for 1 h to precipitate a white solid which was recrystallized from THF to obtain 0.10 g of pure product.1P-NMR (400 MHz, DMSO-d6) δ for 3.28-3.43 points (m, 4H); δ 3.46 in-3,58 (m, 4H); δ 3,68-3,74 (m, 2H); δ 3,81-a 3.87 (m, 2H); δ 6,27-6,29 (m, 1H); δ 7,02-7,06 (d, 1H); δ 7,43-of 7.46 (t, 3H); δ 7,60-of 7.64 (d, 1H); δ 7,21-7,74 (m, 2H); δ 8,03-with 8.05 (d, 1H). MS (TOF) 421,7 (M+).

Example 2. Experimental determination of the activity of compounds in the protection of cardiomyocytes

Primary culture of cardiomyocytes

The isolation and culture of cardiomyocytes is carried out by differential adhesion (Kreider, A. Messing, N. Doan, S. U. Kim, R. P. Lisak, and D. E. Pleasure, Enrichment of Schwann cell cultures from neonatal rat sciatic nerve by differential adhesion (Enrichment cultures of Schwann cells of the sciatic nerve of newborn rats by differential adhesion), Brain Res 2 (1981), pp.433-444). Used breast newborn mice Wistar within 24 hours, sterilized the skin of the abdomen with tincture of iodine and ethanol, spend a thoracotomy with scissors on a subxiphoid midline with variation�the group left, heart extract inclined after thoracotomy and placed in PBS, pre-cooled with ice; in the heart gently pumped and removed with 0.01 M PBS to remove blood cells and other tissues, and then cut into pieces of 0.5 mm3, washed with 0.01 M PBS 2-3 times; the parts are placed in a conical flask, add 4 ml of 0.125% of Pancreatin, 1 ml of 0.1% collagenase II (final concentration respectively of 0.1% and 0.02%), shaken in a water bath at 37°C for 10 minutes, the liquor drop; then 4 ml of 0.125% of Pancreatin and 1 ml of 0.1% collagenase II is shaken in a water bath at 37°C for cleavage within 10 minutes, the liquor is separated and transferred to a centrifuge tube and to the liquor add DMEM containing 10% FBS to complete cleavage; stage shaking and splitting in a water bath, repeat 3-4 times to complete the splitting parts of the fabric, the collected cell suspension was centrifuged at 1000 rpm for 10 minutes, the liquor is removed, then culture medium was added for resuspension; resuspendable cells are sown in a flask for cell culture, are placed in CO2incubator at 37°C for incubation for 1.5 h, then the culture medium is separated, counting under a microscope, then DMEM culture medium containing 10% FBS, are used to adjust the density of cells seeded in an amount of 1×1042at 37°C for 24 h, then half of the medium replaced, further added culture medium containing 0.1% Brdu, then the medium was replaced once per 48 hours, and primary cardiomyocytes obtained after 4 days of cultivation.

Measuring the degree of suppression of the cells (MTT)

Isolated primary culture of cardiomyocytes seeded in an amount of 104cells to a cell in the tablet with 96 cells and the volume of each cell is 100 ál (marginal cell is filled with sterile PBS). After cultivation in an incubator with 5% CO2and 37°C for 4 days, they add the compound of formula I of example 1 at different concentrations (0.3 µm, 1 µm, 3 µm, 10 µm, 30 µm, 100 µm), 3 double cells used for each concentration, while also using zero cell (the culture medium, MTT, DMSO), and control cells (culture medium, DMSO). After continuous cultivation for 48 hours in each cell add 20 ál of MTT solution (5 mg/ml, mixed with PBS (pH=7,4), i.e. 0.5% MTT) and cultivation was continued for 4 hours. After the cultivation, the culture medium of the cells was carefully removed. In each cell, add 150 ál DMSO, shaken at low speed on a flat shaker for 10 minutes, so that the crystals are sufficiently dissolved. Ve�ichino optical density (OD) of each cell is measured at a wavelength of 550 nm device for enzyme-linked immunosorbent assay, and each cell is measured 5 times and the results recorded. The results are presented in table 1.

Table 1
The effect of the compounds at different concentrations on the survival rate of cardiomyocytes by definition by the method of MTT
GroupThe degree of suppression of cardiomyocytes (%)
Control group100
The compound of example 1A group of 100 µm2,91±1,88
A group of 300 µm0,76±0,42

The results show that the compound of example 1 at a concentration of 300 µm no effect on the survival rate of normal cardiomyocytes

Determination of the activity in the protection of cardiomyocytes: activity in the protection against apoptosis induced TG

Cardiomyocytes subjected to primary culture above method and add thapsigargin (TG) to induce apoptosis. The compound of the present invention is added for pretreatment for 30 minutes before inducere�ing apoptosis. Cells divide randomly into 5 groups: (1) control group solvent (DMSO); (2) TG intermediate group (0.4 µm); (3) TG (0.4 mm)+intermediate connection group (0.3 µm); (4) TG (0.4 mm)+intermediate group of compounds (1 μm); TG (0.4 mm)+intermediate group of compound (3 μm). TG is mixed with the DMSO content in the liquor is 4 mm; and the compound of the present invention is mixed with DMSO and content in the liquor is 150 mm. The survival rate of the cells is determined by the above method of MTT to test the protective effect of the compounds of the present invention from TG-induced apoptosis of cardiomyocytes and the results are presented in table 2.

Table 2
The effect of compounds at various concentrations on TG-induced apoptosis of cardiomyocytes by definition by the method of MTT
GroupThe survival rate of cardiomyocytes (%)
Control group100
TG intermediate group59±1.1
The compound of example 1 The group of 0.3 µm76,3±7,6
Group 1 µm83,3±7,1
A group of 10 µm92,2±5,6

Note: the survival rate of cells=1 - degree of suppression of cells

Experimental results: compared with the group with addition of TG survival rate of cardiomyocytes significantly increased when TG and the compound of example added together, indicating that the compound of example, as shown in table 2, can significantly normalize TG-induced apoptosis and has a protective effect against cardiac myocytes.

Although specific embodiments of the invention are described in detail, specialists in the art it is clear that in accordance with the revealed essence of the invention these details can be modified and replaced and all of these changes are included in the scope of claims of the present invention. The scope of the claims of the present invention defined by the attached claims and any equivalents.

1. The compound of the formula I

or its pharmaceutically acceptable salt or solvate, where
And is =S, -SR4or =O;
X represents F, Cl, Br or I;
R1represents phenyl;
R2and R3 linked together to form a morpholine;
and R4represents C1-C6-alkyl.

2. The compound according to claim 1, where
R4represents methyl, ethyl, propyl, isopropyl, butyl or pentyl.

3. The compound according to claim 1, where
X represents Cl;
R4represents methyl or ethyl.

4. The compound according to claim 1, which is (1) to (1E)-1-phenyl-5-(1-morpholinylcarbonyl)-6,6,6-trichloro-1-ene-3-hexanone,
or its pharmaceutically acceptable salt or solvate.

5. Pharmaceutical composition for protection of cardiomyocytes or for the prevention or treatment of a disease or disorder associated with apoptosis of cardiomyocytes containing an effective amount of a compound according to any one of claims. 1-4 and a pharmaceutically acceptable carrier, excipient or diluent.

6. Use of a compound according to any one of claims. 1-4 for the manufacture of a medicament for the protection of cardiomyocytes or for the prevention or treatment of a disease or disorder associated with apoptosis of cardiomyocytes.

7. The compound according to any one of claims. 1-4 for use for protection of cardiomyocytes or prevention, or treatment of a disease or disorder associated with apoptosis of cardiomyocytes.

8. A method of obtaining a compound according to any one of claims. 1-4 of benzaldehyde as a starting material, including the interaction of benzaldehyde with acetone in �aStore of sodium hydroxide in methanol to obtain (1E)-1-phenyl-1-ene-3-acetone, then the interaction (1E)-1-phenyl-1-ene-3-acetone with trichloroacetaldehyde during the catalysis of LDA to obtain intermediate 1, which is chlorinated by thionylchloride, and then interaction with potassium thiocyanate to obtain the intermediate 2 and finally boiling to reflux intermediate 2 with morpholine in tetrahydrofuran to obtain the target compound.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to a method for producing N-substituted thiomorpholines of formula (I) wherein divinylsulphide is reacted with an amine substrate (propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide) in the presence of the catalyst PdCl2-CF3COOH-PPh3 in the molar ratio of divinylsulphide : amine substrate : PdCl2 : CF3COOH : PPh3 = 10 : 10: (0.3-0.7) : (1.5-3.5) : (0.3-0.7), at a temperature of 55-65°C and an atmospheric pressure for 38-42 h in toluene. In general formula (I), R=CH3(CH2)2, C6H5, o-, p-CH3C6H4, C2H4OH, CH3CO.

EFFECT: one-stage high-yield production of the divinylsulhide compounds.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to a method for producing N-substituted thiomorpholines of formula (I) wherein divinylsulphide is reacted with an amine substrate (propylamine, aniline, o-, p-toluidine, monoethanolamine, acetamide) in the presence of the catalyst PdCl2-CF3COOH-PPh3 in the molar ratio of divinylsulphide : amine substrate : PdCl2 : CF3COOH : PPh3 = 10 : 10: (0.3-0.7) : (1.5-3.5) : (0.3-0.7), at a temperature of 55-65°C and an atmospheric pressure for 38-42 h in toluene. In general formula (I), R=CH3(CH2)2, C6H5, o-, p-CH3C6H4, C2H4OH, CH3CO.

EFFECT: one-stage high-yield production of the divinylsulhide compounds.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: method includes reacting anilines of general formula R-C6H4NH2 (where R=H, o-, m-, n-CH3, o-C2H5, o-, m-, n-Cl, n-F) and α,ω-diols (1,4-butanediol, 1,5-pentanediol) in the presence of a catalyst FeCl3·6H2O in the medium of tetrachloromethane at 180°C for 4-8 hours with molar ratio [FeCl3·6H2O]:[RC6H4NH2]:[diol]:[CCl4]=0.2-0.5:100:100-400:20-100. At 180°C and reaction duration of 6 hours, output of N-arylpyrrolidines reaches 45-88%, and output of N-arylpiperidines reaches 33-85%. Synthesis is carried out in an argon atmosphere.

EFFECT: method reduces reaction time and enables to use more affordable catalyst.

1 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: device refers to new styrene derivatives with the structure formula A in the form of geometrical isomers or tautomers and their pharmaceutical acceptable salts. In structural formula (A) R1 represents hydrogen; R2 represents hydrogen or C1-C6alkyl; R3, R4, R5 and R6 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12; R7 represents hydrogen or C1-C6alkyl; R8 represents hydrogen; R9 represents hydrogen, C1-C6alkyl, or -C(=O)R13; R10 represents hydrogen or C1-C6alkyl; Z represents W-Y, wherein W represents -C(R14)(R15)-; Y represents -C(R16)(R17)-; each R12 independently represents hydrogen or C1-C6alkyl; each R13 independently represents C1-C6alkyl; R14 and R15 are identical or different, and independently specified in hydrogen, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OCH3 or -NH2; or R14 and R15 together form oxo; R16 and R17 are identical or different and independently represent hydrogen, halogen, C1-C6alkyl or -OR12. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.

17 cl, 14 tbl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing cyclohexane and derivatives thereof of general formula R=H, . The method involves producing saturated hydrocarbons and derivatives thereof, which can be used as semi-products in organic synthesis. The method involves hydrogenation of cyclohexene or a derivative thereof, which is selected from 1-(N-piperidino)cyclohexene-1,1-(N-morpholino)cyclohexene-1 or 1,4-dicyclohex-1-enylpiperazine with hydrogen gas at atmospheric pressure of hydrogen in the presence of a nanocatalyst in tetrahydrofuran medium at temperature of 50-70°C for 5-6 hours, followed by extraction of the end product. The nanocatalyst used is nickel nanoparticles which are obtained by reducing nickel (II) chloride with lithium aluminium hydride in situ. The method can also be used to obtain a wider range of cyclohexane derivatives which contain heterocyclic groups.

EFFECT: method enables to conduct the process at atmospheric pressure using a catalyst obtained using a simpler technique, which simplifies the method overall.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a heterocyclic compound, involving: reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in a first solvent and at a first temperature ranging from approximately 90°C to approximately 110°C to obtain a compound of formula where the first solvent contains alcohol; cooling the mixture containing the compound of formula VIH to a second temperature ranging from approximately 85°C to approximately 95°C; adding a volume of a second solvent which is different from the first solvent to the mixture, where the second solvent contains water; and forming a suspension of the compound of formula VIH; where the second solvent is heated to the second temperature. The invention also relates to methods of producing a compound of formula VIH using other solvents such as heptane and HO-(CH2)q-OH or HO-CH2CH2OCH2CH2-OH, where q is selected from 2, 3 or 4.

EFFECT: novel method of producing a compound of formula VIH, which enables to obtain a highly pure product which does not require additional purification and is more suitable for use on a large scale owing to the solvents used.

74 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing cycloalkylamines of general formula Alk-R, where

, , , , , , , , , . The method is realised by reacting a cyclic ketone with an amine derivative and formic acid in the presence of a catalyst. The cyclic ketones used include cyclopentanone, cyclohexanone and 2-adamantanone, and the amine derivative used is formamide, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-ethylenediamine, and the catalyst used is copper nanoparticles. The process is carried out in molar ratio ketone: amine derivative: HCOOH equal to 1:3-4:5-10, at temperature 100°C for 3-9 hours. The copper nanoparticles can be obtained in situ, as well as beforehand.

EFFECT: high output of cycloalkylamines under milder conditions for carrying out the process.

3 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new chemical compound - N-1-[(4-fluorophenyl)-2-(1-ethyl-4-piperidyl)-ethyl]-4-nitrobenzamide hydrochloride of formula Also, the invention refers to drugs.

EFFECT: preparation of a new biologically active compound which exhibits antiarhythmic and antifibrillatory activity.

2 cl, 1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 1-aminomethyl-2-phenylacetylenes of formula (1), where is characterised by that, phenylacetylene (Ph-C≡CH) is reacted with gem-diamines R2NCH2NR2, where R2N is as defined above, in the presence of a Sm(NO3)2*6H2O catalyst in molar ratio phenylacetylene: gem-diamine: Sm(NO3)2*6H2O=10:(8-12):(0.2-0.6) at 80°C and atmospheric pressure for 3-5 hours.

EFFECT: new method is designed for synthesis of 1-aminomethyl-2-phenylacetylenes, which can be used in fine organic synthesis, particularly for synthesis of scarce polycyclic compounds.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

The invention relates to organic chemistry, in particular to new compounds of the formula (I)

in which U represents O or a lone pair of electrons; V represents O, S, - CH2-, - CH=CH - or - C-; W represents CO, COO, CONR1CSO , CSNR1, SO2or SO2NR1; m and n independently of one another each represents a number from 0 to 7, and the sum of m+n is from 0 to 7, provided that m represents 0, if V denotes O or S; AND1represents H, lower alkyl, hydroxy(ness.)alkyl or (ness.)alkenyl; AND2means (ness.)alkyl, cycloalkyl, cycloalkyl(lower)alkyl or (ness.)alkenyl, optionally substituted by a group R2;3and4each denotes a hydrogen atom or (ness.)alkyl; AND5denotes H, (ness.)alkyl, (ness.)alkenyl or aryl(ness.)alkyl; AND6means (ness.)alkyl, cycloalkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl; R2denotes hydroxy, hydroxy(ness.)alkyl, (ness.)alkoxy, (ness.)alkoxycarbonyl, N(R4,R5) or thio(ness.)alkoxy; R1, R3, R4and R5each independent is asepticheski acceptable esters

The invention relates to methods for new di-aromatic compounds useful in the prevention of atherosclerosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

FIELD: food industry.

SUBSTANCE: invention relates to a polyphenol grape extract, a compound for oral administration, a food product, beverage, a taste additive, a nutraceutical product, a revitalising composition and therapeutic remedy including the said grape extract. According to the invention, the grape extract contains nearly 5-15 wt % of monomers, nearly 5-20 wt % of dimers, nearly 3-10 wt % of trimers, nearly 2-10 wt % of tetramers and nearly 2-10 wt % of pentamers.

EFFECT: grape extract reduces blood pressure with patients suffering from prehypertonic condition or metabolic syndrome.

27 cl, 4 dwg, 8 tbl, 7 ex

Vasopressor agent // 2552529

FIELD: chemistry.

SUBSTANCE: invention refers to N, S-substituted isothiourea derivatives of the general formula (1) in the form of salts with pharmacologically acceptable acids as a NOS-inhibitory and vasopressor agent wherein: n=1, 3, i.e. an acyl substitute represents cyclobutanoyl or cyclohexanoyl; R represents an alkyl group: C2H5, i-C3H7; HX represents a pharmacologically acceptable inorganic or organic acid: HCl, HBr, HI, hydrogen methyl sulphate, oxalic, succinic acids, etc.

EFFECT: extending the range of products of the vasopressor action.

6 cl, 7 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to implanted medical devices. A device for drug delivery includes an implanted intra-lumen framework, which has a luminal surface and abluminal surface; a multitude of through hollows in the intra-lumen framework, where each of the multiple through holes contains a composition, selected from the following groups. Compositions of a mTOR inhibitor and base structure, which has the configuration, which will make it possible for the mTOR inhibitor in the composition of the mTOR inhibitor to elute, mainly in the abluminal direction for seven (7) to one hundred and twenty (120) days, with the composition of the mTOR inhibitor containing a polymer in a combination with the mTOR inhibitor and the base structure containing a multitude of polymer layers with the absence of mTOR inhibitors; compositions of a phosphodiesterase III inhibitor and an upper covering structure, which has the configuration, making it possible for the phosphodiesterase III inhibitor in the composition of the phosphodiesterase III inhibitor to elute, mainly in the luminal direction for five (5) to sixty-one (61) day, with the composition of the phosphodiesterase III inhibitor containing the polymer in a combination with the phosphodiesterase III inhibitor, and the upper covering structure containing a multitude of polymer layers in the absence of the phosphodiesterase III inhibitor.

EFFECT: invention makes it possible to provide independent on each other rates of sirolimus and cistazol release, simultaneously providing the targeted delivery of each of the medications.

6 cl, 30 dwg, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to application of composition for preparation of medications aimed at secondary prevention of cardiac infarction. Application of composition based on substances, applied in Chinese medicine, for preparation of medications aimed at secondary prevention of cardiac infarction, with composition, based on substances, applied in Chinese medicine, is prepared from composition, which contains Radix Astragali, Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae, taken in specified ratio.

EFFECT: composition makes it possible to prepare medication, which is effective for secondary prevention of cardiac infarction, prevents stenocardia, improves coronary blood flow.

14 cl, 8 dwg, 74 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with a crystalloid cardioplegic solution, which contains salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and a structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=CH3, Y=H, Z=OH. The group of inventions also deals with the crystalloid cardioplegic solution, containing salt solution, including sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydrogen carbonate, water for injections and structural analogue of natural apelin X-Arg(NGY)-Pro-Arg-Leu-Ser-His-Lys-Cly-Pro-Nle-Pro-Phe-Z, where X=H, Y=NO2, Z=NH2.

EFFECT: group of inventions provides the recovery of the coronary flow, cardiac contractile and pump function in case of the reperfusion and the reduction of injury to membranes of cardiomyocytes.

2 cl, 2 dwg, 8 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiac surgery, and represents cardioplegic solution, which contains sodium chloride - 3.41-3.62, potassium chloride - 1.092-1.156 g, magnesium chloride - 3.190-3.485 g, calcium gluconate - 0.0105-0.0130 g, mannite - 4.365-4.520 g, L-carnosine - 20.1504-24.1650 g, N-acetylcarnosine - 8.056-11.032 g, L-histidine - 0.705-0.820 g, water for injections to 1000 ml.

EFFECT: invention ensures prevention of reduction of amplitude, speed of front and speed of pulse-wave reduction, as well as increase of diastolic pressure in left heart ventricle during reperfusion with preservation of buffer capacity and osmolarity of cardioplegic solution with physiological pH parameters.

4 tbl, 2 ex

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