Compound possessing inhibitory action on phosphodiesterase type 5, and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

 

Field of the invention

The present invention relates to a compound having inhibitory activity against phosphodiesterase type 5, its salts, methods for its preparation and pharmaceutical compositions containing the specified connection or its salts.

Prior art

Cyclic adenosine monophosphate (camp) and cyclic guanosine monophosphate (cGMP) are important secondary messengers in the cell and the level of camp and cGMP in the cell is important for the regulation of various cellular functions.

The enzymes involved in the regulation of cellular levels of camp and cGMP, include adenylyl cyclase (AC), guanylyl cyclases (HZ) and phosphodiesterase (PDE). The balance of these enzymes supports the level of camp and cGMP in the cell in the normal range. Certain medical conditions (such as hypertension, stenocardia, etc.) discovered that the level of camp and cGMP in the cell falls. To increase the level of camp and cGMP in the cell can be used two options: 1) activate the AC and GC, and 2) to inhibit PDE from which the second possibility has the best effect. In recent years there has been great interest in the research and development of PDE inhibitors, and clinical use of selective in respect of the isoenzymes of PDE inhibitors have achieved revolutionary progress. At present the results of experiments on Cloner�of cDNA molecules proved because there are at least 10 of the PDE gene families in mammals. For each PDE gene family there are many subtypes of PDE isoenzymes (splice variants), of which phosphodiesterase type 5 (PDE-5) can selectively hydrolyze cGMP and widespread in some organs of the body.

The PDE-5 inhibitor has the following pharmacological functions and clinical use:

(1) Inhibition of platelet aggregation and suppression of thrombosis:

the ideal antithrombotic drugs must suppress platelet aggregation without relaxation of smooth muscles of blood vessels to avoid the area of ischemia with subsequent development of ischemia. As inhibitors of PDE-3 and PDE-5 inhibitors inhibit platelet aggregation. However, given that the PDE-5 inhibitor to a lesser extent relaxes vascular smooth muscle, it has a significant advantage in the treatment of arterial thrombotic diseases. Typical PDE-5 inhibitor, representing dipiridamol, have good antithrombotic effect.

(2) Reduction of pulmonary hypertension and treatment of cardiovascular disease: abnormality of the pulmonary vascular resistance is often an important factor in causing cardiovascular disease. In experiments on animal models selective PDE-5 inhibitor, predstavlyalsya zaprinast, can significantly increase the effective time and the intensity of nitric oxide and has a relatively strong effect on the reduction of pulmonary hypertension. Clinically it is used to treat angina, hypertension and myocardial infarction. In the latest report of the PDE-5 inhibitor, which is an E-4010, may increase the survival rate of rats with hypertension induced by monocrotaline.

(3) anti-asthmatic action: it is Reported that experiments using pigs as an animal model show that the PDE-5 inhibitor, representing the SR-265579, has a therapeutic effect for vitaminization bronchiectasis;

(4) Treatment of diabetic gastroparesis: it is Reported that in rats with diabetes, the PDE-5 inhibitor, representing sildenafil citrate, can eliminate the delay of gastric emptying and has certain therapeutic and positive effects on the autonomic neuropathy of the digestive system, complicated by diabetes.

(5) Treatment of erectile dysfunction: Because PDE5 is widely distributed in the corpora cavernosa of the penis, PDE5 inhibitor can cause increased levels of cGMP in the corpora cavernosa of the penis. Due to a number of physiological and biochemical reactions of smooth muscles of the blood vessels of the penis relaxes and get erections penalties�and. Unlike prostaglandin E1, a PDE-5 inhibitor will not cause pathological erection; its function is still going to need a sexual stimulus.

In light of the above pharmacological functions of PDE5 inhibitor, the inventors have modified the chemical structure of sildenafil chemical method molecular modification and got new compounds and their citrates, i.e. 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-ketone and citrate (ZTH). It is established that ZTH can effectively suppress the activity of the enzyme PDE-5. These are the prerequisites of the invention.

Brief description of the invention

The first object of the present invention is to provide new compounds that can inhibit the activity of phosphodiesterase type 5 and its salts, such as citrate. The second object of the present invention is to provide a method of obtaining a new connection and its citrate. The third objective of the present invention is the provision of a pharmaceutical composition, which contains a new compound or its salt, such as citrate.

The present invention provides a compound of formula I and pharmaceutical citrate formula II:

Chemical compound name, predstavlennog� formula I is 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-D]pyrimidine-7-he. To illustrate its structure is used the method of nuclear magnetic resonance and to calculate the molecular mass used mass spectrometry:

[013]1H-NMR (400MHz, MeOD) δ 8,180-8,185 (d, J=2Hz, 1H), 7,880-7,908 (dd, J1=2,4 Hz, J2=8,8 Hz, 1H), 7,356 - 7,379 (d, J=9,2 Hz, 1H), 4,284 - 4,337 (q, J=14Hz, 2H), 4,234 (s, 3H), 3,575-3,603 (d, J=11,2 Hz, 2H), 2,865-2,902 (t, J=7,2 Hz, 2H), 2,377 (br, 2H), 2,261 (s, 3H), 2,112-2,168 (t, J=11,2 Hz, 2H), 1,795-1,851 (m, 2H), 1,465-1,500 (t, J=7,2 Hz, 3H), 1,090-1,105 (d, J=6Hz, 6H), 0,978-1,015 (t, J=7,2 Hz, 3H). MS 503 [M+H]+

Citrate formula II is obtained by reaction of a compound of formula I and citric acid. Chemical name of citrate represented by formula II: 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-D]pyrimidine-7-UNCITRAL. The analysis is performed using nuclear magnetic resonance:1H-NMR (400MHz, CDCl3) δ8,164-8,170 (d, J=2,4 Hz, 1H), 7,914-7,942 (dd, J1=the 2.4 Hz, J2=8,8 Hz, 1H), 7,363-7,385 (d, J=8,8 Hz, 1H), UAH 4,276-4,329 (q, J=14Hz, 2H), 4,231 (s, 3H), 3,746-3,776 (d, J=11,2 Hz, 2H), 2,986 (br, 2H), 2,858-2,895 (t, J=7,2 Hz, 2H), 2,792 (s, 2H), 2,739 (s, 2H), 2,590 (s, 3H), 2,406-2,464 (t, J=11,6 Hz, 2H), 1,784-1,839 (m, 2H), 1,448-1,483 (t, J=7,2 Hz, 3H), 1,253-1,269 (d, J=6,4 Hz, 6H), 0,972-with 1.009 (t, J=7,2 Hz, 3H).

The compound of formula I is mainly produced using CIS-2, 6-dimethylpiperazine and 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-e]pyrimidine-7-ketone as starting materials and synthesized in several stages. The path of synthesis is as follows:

2.6-dimethyle�Razin and di-tert-BUTYLCARBAMATE add tetrahydrofuran, the reaction at room temperature and then concentrated tetrahydrofuran and get 3,5-dimethyl-1-tert-butoxycarbonyl-piperazine (ZTH-1). According to nuclear magnetic resonance and mass spectrometry:1H-NMR (400 MHz, CDCl3) δ3,8-4,1 (br, 2H), of 2,75 2,80 (m, 2H), of 2.2-2.5 (br, 2H), 1,45 (s, 9H), 1,052-1,067 (d, J=6 Hz, 6H). MS 215 [M+H]+.

To ZTH-1 sequentially added tetrahydrofuran, potassium carbonate and methyl iodide, and the reaction at room temperature overnight; then filtered and concentrated, add water and dichloro methane in the sediment and washed with dichloromethane, combine organic layers washed with saturated salt solution and dried over anhydrous sodium sulfate, concentrated and the residue purified column chromatography (methanol:dichloro methane = 1:20) and get 3,4,5-trimethyl-1-tert-butyl-carbonitriding (ZTH-2). According to spectrometry nuclear magnetic resonance and mass spectrometry:1H-NMR (400MHz, MeOD), 54,505-4,533 (m, 2H), 4,110-4,134 (m, 2H), 2,943 (s, 3H), 2,779 (br, 2H), of 2.196 (s, 9H), 1,782-1,797 (d, J=6Hz, 6H). MS 229 [M+H]+.

ZTH-2 was dissolved in dioxane, cooled and slowly added dropwise concentrated hydrochloric acid solution in dioxane, stirred at room temperature and then the solvent evaporated under reduced pressure and get 1,2,6-trimethylpyrazine (ZTH-3). According to spectrometry nuclear magnetic resonan�and mass spectrometry: 1H - NMR (400MHz, MeOD) δ4,505-4,533 (m, 2H), 3,722 (br, 2H), 3,611-3,644 (m, 2H), 3,310-3,423 (m, 2H), 2,937 (s, 3H), 1,493-1,506 (d, J=5,2 Hz, 6H). MS 129 [M+H]+.

Added dropwise 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazol[4,3-D]pyrimidine-7-he's in chlorosulfonic acid while maintaining the temperature of the reaction solution does not exceed 25°C, the reaction is carried out at room temperature and then the reaction solution is poured into crushed ice, mechanically stirred at room temperature, keeping the temperature no higher than 25°C, and then filtered and dried, yielding 5-(2-ethoxyphenyl-5-chlorosulfonyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (ZTH-4). According to spectrometry nuclear magnetic resonance and mass spectrometry:1H-NMR (400MHz, DMS0) δ 7,871-7,876 (s, 1Η), 7,700-7,727 (dd, J1=2Hz, J2=8,4 Hz, 1H), 7,098-is 7,119 (d, J=8,4 Hz, 1H), of 4.125-4,161 (m, 5H), is at 2,778-2,816 (t, J=7,6 Hz, 2H), 1,700-1,756 (m, 2H), 1,303 - 1,337 (t, J=6,8 Hz, 3H), 0,919-0,956 (t, J=7,6 Hz, 3H). MS 411 [M+H]+.

In tetrahydrofuran is added ZTH-4, ZTH-3 and triethylamine was stirred at room temperature overnight, then the solvent evaporated, to the residue was added water and methylene chloride, separated and sequentially washed with a layer of methylene chloride saturated solution of sodium bicarbonate in water, saturated brine, and then dried and concentrated and recrystallization of the resulting residue from ethanol the compound of formula I (ZTH-5).

In ZTH-5 added�Ute anhydrous methanol, stir, heating until dissolved, add citric acid after clarification of the solution; after the reaction, dissolution, cooled to room temperature, filtered, washed with methanol and dried, yielding the compound of formula II (ZTH).

ZTH-5, salt ZTH-5, such as ZTH are pyrazolo-pyrimidine-ketone compounds, the chemical structure of which is similar to the chemical structure of cGMP and they can compete with cGMP for binding to the catalytic domain of PDE-5 and, thus, to inhibit the degradation of cGMP in PDE-5, to increase the concentration of cGMP and maintain cGMP concentration within the normal range. ZTH-5, salt ZTH-5, such as ZTH, can effectively inhibit the activity of phosphodiesterase type 5 and thus, can be used as inhibitors of phosphodiesterase type 5, or as an effective component of depressant phosphodiesterase type 5. ZTH-5, salt ZTH-5, such as ZTH, can potentially be the basis for the development of a new generation of drugs for the treatment of erectile dysfunction, inhibition of platelet aggregation and treatment of thrombosis, to reduce pulmonary hypertension and treatment of cardiovascular diseases, for the treatment of asthma and treatment of diabetic gastroparesis.

Detailed description of the invention

(1) Obtaining ZTH-5(5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-ol�MPI-1,6-dihydro-7H-pyrazolo[4,3-D]pyrimidine-7-he):

1. Obtaining 3,5-dimethyl-1-tert-butoxycarbonyl-piperazine (ZTH-1):

In a 250 ml flask is added 2,6-dimethylpiperazine (11.4 g, 100 mmol, 1 EQ) and ditretbutilfenol (21.8 g, 100 mmol, 1 EQ), was then added 100 ml of tetrahydrofuran, the reaction is carried out at room temperature for 4 hours and concentrated tetrahydrofuran (until the tetrahydrofuran is not consumed completely and 21.4 g ZTH-1 in the form of an orange oily substance, in which the yield of the target substances is 100%.

2. Getting 3,4,5-trimethyl-1-tert-butyl-carbonyl piperidine (ZTH-2):

In a 250 ml flask add ZTH-1 (10.7 g, 50 mmol, 1 equiv); sequentially added 100 ml of tetrahydrofuran (THF), potassium carbonate (of 10.35 g, 75 mmol, 1.5 EQ.) and methyl iodide (8,52 g, 60 mmol, 1.2 EQ.), the reaction at room temperature over night; filtered and concentrated, to the residue was added 100 ml of water and 100 ml of dichloromethane and washed with dichloromethane (50 ml×twice), combined organic layers washed with saturated salt solution, dried over anhydrous sodium sulfate, concentrated and the residue purified column chromatography (methanol: dichloro methane=1:20) and get 5.7 g ZTH-2 in the form of an orange oily substance, in which the yield of the target substances is 50%.

3. Getting 1,2,6-trimethylpyrazine (ZTH-3):

ZTH-2 (11.4 g, 50 mmol, 1 EQ) was dissolved in 100 ml of dioxane, cooled �about 0°C and slowly added dropwise a saturated solution of hydrochloric acid in dioxane (4M, 25 ml, 2 EQ.), was stirred at room temperature for 2 hours and the solvent evaporated under reduced pressure and get ZTH-3 in the form of a crude solid product is white, which is directly used without purification in the next step.

4. Getting 5-(2-ethoxyphenyl-5-chlorosulfonyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4, 3-e]pyrimidine-7-she(ZTH-4):

At a temperature of -10°C to 100 ml of chlorosulfonic acid are added dropwise 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazol[4,3-D]pyrimidine-7-he(50 g, 160 mmol), in the process of dripping the temperature of the reaction solution is maintained up to 25°C, after dripping the reaction at room temperature for 3 hours; then the reaction solution is poured into crushed ice, mechanically stirred, keeping the temperature no higher than 25°C, and then stirred at room temperature for 1 hour, filtered and dried, yielding 50 g ZTH-4 in the form of white solids, in which the yield of the target product is 75.9%.

5. Getting 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-D]pyrimidine-7-she(ZTH-5):

In 500 ml of tetrahydrofuran is added ZTH-4 (36 g, 10 mmol, 1 EQ), ZTH-3 (17.6 g, 10 mmol, 1 EQ), and triethylamine (60.6 g, 60 mmol, 6 EQ.), was stirred at room temperature overnight; evaporated dissolve�ü, add 200 ml of water and 200 ml of methylene chloride, separated and sequentially washed with a layer of methylene chloride saturated solution of sodium bicarbonate in water and then saturated brine, and then dried and concentrated, after recrystallization from 10-fold amount of ethanol get 32 g ZTH-5 as a white crystalline residue, after recrystallization from 50 - fold amount of ethanol and 16.5 g of a white crystalline ZTH-5, while the yield of the target substances is 37%.

(2) Obtaining ZTH (5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-D]pyrimidine-7-UNCITRAL):

In a 500 ml reaction vessel (bottle) add 15 g connection ZTH-5, 270 ml of anhydrous methanol, stirred, warming to dissolve, add 12.5 g of citric acid after clarification of the solution; in the reaction, dissolved in approximately 1.5 hours, cooled to room temperature, filtered, washed with methanol (three times×5 ml) and dried to obtain 15 g ΖΤΗ in the form of a white solid.

(1) and (2) the above options are receiving and (3) given below is an experimental implementation.

(3) study of the inhibitory effects ΖΤΗ on PDE-5

1. Inhibitory effect ΖΤΗ to the action of PDE5 on cGMP: Experimental method:

To detect in vitro inhibition tion�following the effects of different concentrations ZTH to degradation under the action of cGMP PDE-5 using enzyme-linked immunosorbent assay. The concentration of cGMP is determined in accordance with the procedure provided for kit enzyme immunoassay for the biotransformation of cGMP (ELISA kit) (also called: cGMP biotrack enzymeimmuoassy system, EIA), manufactured by Amersham (the company). As a positive control, use of sildenafil citrate.

Obtaining reagent:

Getting ZTH and sildenafil citrate with different concentrations of the drug:

Make a batch of ZTH for dissolution in distilled demineralized water, respectively, was added DMSO for dissolution (drug: DMSO=1 mol:1 liter) to microwells 100 µl, final concentration: 10-4mol/liter, 10-5mol/liter, 10-6mol/liter, 10-7mol/liter, 10-8mol/liter, 10-9mol/liter, 10-10mol/liter, 10-11mol/liter, 10-12mol/liter.

A drug comparison that represents sildenafil citrate, is prepared in the same manner as described above.

Obtain a working solution of the PDE-5 are:

Take a certain amount of PDE-5, diluted in an appropriate volume of buffer solution for ELISA, where the final concentration is 1 U/μl, and the solution is stored at low temperature -80°C for later use.

Obtaining cGMP:

Make a batch of cGMP (cGMP, Na), dissolved in an appropriate volume of buffer solution�and for ELISA, the final concentration of cGMP is 3200 femtomole/50 μl, and the solution is kept at a low temperature of -20°C for later use.

Experiment:

Degrading action of PDE5 on cGMP:

PDE-5 and cGMP mix, 100 ál of the well contains 3200 fmol cGMP, degrading action of PDE5 on cGMP is detected during the reaction at 30°C for 20 minutes.

Inhibitory effect on ZTH PDE5:

ZTH and sildenafil citrate, which represents a positive control, was mixed with cGMP, respectively and stirred well (assuming the use of a solution of DMSO in distilled demineralized water as a negative control) and 3 PDE-5 is added and the reaction is carried out at 30°C for 20 min In 100 ál of the well contains 3200 fmol cGMP. The concentration of the drug can be 10-4mol/liter, 10-5mol/liter, 10-6mol/liter, 10-7mol/liter, 10-8mol/liter, 10-9mol/liter, 10-10mol/liter, 10-11mol/liter, 10-12mol/liter to identify inhibitory effect of various concentrations of ZTH and positive control in called PDE-5, the degradation of cGMP. The above samples are added to microwells coated with antibody, and then 100 µl of antiserum is added, respectively, to suspend the reaction, which is carried out at 4°C for 15-18 h, and then added�Ute 50 ál of cGMP, conjugated with peroxidase to suspend the reaction, which proceeded for 3 hours and then washed, add 200 ál of TMB for the development of colouring and using BIORAD 450 ELISA reader for reading absorbance at a wavelength of 630 nm. On the basis of the measured values of absorption of cGMP expect the ratio TO/IN % by the formula absorption ELISA [(OD of standard or sample OP NSB)×100/(OD Of standard OP NSB)] (NSB - background characterizing nonspecific binding). IC50 for ZTH, sildenafil citrate, representing a positive control test drug PDE-5, calculated using linear regression for approximation of S-curve regression and curve constructed by the probit method.

The results of the experiment:

Degrading action of PDE5 on cGMP

PDE-5 is reacted with cGMP at 30°C for 20 minutes and then PDE-5 could ruin 3200 fmol cGMP to 1600 fmol.

Inhibitory effect on ZTH called PDE-5 degradation of cGMP:

Compare the inhibitory effect of different concentrations (10-4mol/liter, 10-5mol/liter, 10-6mol/liter, 10-7mol/liter, 10-8mol/liter, 10-9mol/liter, 10-10mol/liter, 10-11mol/liter, 10-12mol/liter) of the respective groups ZTH, control, test drug and a solution of DMSO in distilled demineralized water on a drying action FD�-5 on cGMP.

The IC50 value of the drug is calculated based on the difference in absorption (OD value) at different concentrations of the drug ZTH, overwhelming the ability of PDE5 to degrade cGMP, using the formula absorption ELISA to calculate % IN/IN [(OD of standard or sample OP NSB)×100/(OP 0 standard OP NSB)]. Data can be approximated by S curve (p<0,05) using linear regression; IC50 is calculated using the regression method built broken. The IC50 value for ZTH is 2.12×10-9and sildenafil citrate, which represents a positive control test drug is 6,958×10-9M.

2. Action on ZTH called PDE-5 cGMP decay:

Experimental method:

To detect in vitro effects of different concentrations ZTH to degradation under the action of cGMP PDE-5 using enzyme-linked immunosorbent assay. The concentration of cGMP is determined in accordance with the procedure provided for kit enzyme immunoassay for the biotransformation of cGMP (ELISA kit) (also called: cGMP biotrack enzymeimmuoassy system, EIA), made by Amersham. As a control use sildenafil citrate.

Obtaining reagent:

Getting camp:

A certain amount of cyclic amp (camp), sodium (Na) is weighed and dissolved in appropriate volume of buffer solution for ELISA, respectively. The final concentration of cyclic amp is 1600 fmol/5 ál. The product is stored at a low temperature of -20°C for later use.

Getting ZTH and sildenafil citrate and obtain a working solution of PDE-5 are the same as described above.

Experiment:

Degrading action of PDE5 on cyclic amp:

PDE5 and camp mix, 100 ál of the well contains 1600 fmol of camp. Degrading action of PDE5 on cyclic amp is detected during the reaction at 30°C for 20 minutes.

The effect of ZTH to the action of PDE-5 to of camp:

ZTH and positive control test drug connect with camp and mix thoroughly (as a negative control, a solution of DMSO in distilled demineralized water), and add 3 Ed PDE-5 and the reaction at 30°C for 20 min, 100 ál of the well contains 1600 fmol of camp. The concentration of the drug can be 10-4mol/liter, 10-5mol/liter, 10-6mol/liter, 10-7mol/liter, 10-8mol/liter, 10-9mol/liter, 10-10mol/liter, 10-11mol/liter, 10-12mol/liter. The above samples are added to test wells coated with antibodies, then add 100 ál of antiserum to suspend the reaction, which lasted at 4°C for 2 hours and then add 50 μl of camp, conjugated with peroxidase to pause the reaction carried out for 1 h and then washed�, add 150 µl of TMB for the development of color and the results spectrophotometric at a wavelength of 630 nm on an ELISA plate-reader. Based on the measured absorption value of camp attitude %IN/IN is calculated, using the formula absorption ELISA [(OD of standard or sample OP NSB)×100/(OP 0 standard OP NSB)]. The IC50 value for ZTH, sildenafil citrate, which is the positive control test drug relative to PDE-5 calculated using linear regression for approximation of S curve and regression, built by the probit method.

The results of the experiment:

Degrading action of PDE5 on cyclic amp:

PDE-5 does not destroy the camp.

The effect of ZTH to the action of PDE-5 to of camp:

No significant differences in values between OP ZTH group, medical control group and negative control group, which is distilled demineralized water (p>0,05), and the data cannot be approximated by S curve (p>0,05).

Conclusions:

ZTH is pyrazolo-pyrimidine-ketone compound, the chemical structure of which is similar to that of cGMP and which can compete with cGMP for binding to the catalytic domain of PDE-5 and thus to suppress the degrading action of PDE5 on cGMP and increase the concentration of cGMP.

In examining the inhibitory effects on ZTH vyzyvaem� PDE-5 degradation of cGMP, IC50 for ZTH (concentration ZTH required for the inhibition of PDE5 by 50%) determined as of 2.12 x 10-9mol, and for the positive control test drug IC50 is defined as 6,958 x 10-9mol. The result shows that ZTH can suppress the degrading action of PDE5 on cGMP, has dose-effect and is a very good inhibitor of PDE5. Its inhibitory activity towards the enzyme PDE-5 is significantly better than inhibiting activity of sildenafil citrate. Thus, ZTH can potentially be the basis for the development of a new generation of drugs for the treatment of erectile dysfunction, inhibition of platelet aggregation and suppression of thrombosis, to reduce pulmonary hypertension and combat cardiovascular disease, to combat asthma and the treatment of diabetic gastroparesis.

In the above experimental embodiments of the invention, although disclosed only experimental data on ZTH, due to the fact that ZTH is citrate ZTH-5 and ZTH-5 has a similar structure with ZTH (i.e. ZTH-5 and salt ZTH-5, except for citrate, have a structure similar ZTH, and have a common pyrazolo-pyrimidine-ketone structure), from experimental effects ZTH can be concluded that ZTH-5, salt ZTH-5, except for citrate, have inhibitory effect on the called PDE-5 degradation of cGMP and are in�ibition PDE-5 and could potentially be the basis for the development of a new generation of drugs for the treatment of erectile dysfunction, for inhibition of platelet aggregation and treatment of thrombosis, to reduce pulmonary hypertension and treatment of cardiovascular diseases, for the treatment of asthma and treatment of diabetic gastroparesis.

1. The Union, representing 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he is the citrate of the formula II:

2. Pharmaceutical composition for inhibiting phosphodiesterase type 5, comprising 5-[2-ethoxyphenyl-5-(3,4,5-trimethylpyrazine)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he citrate according to claim 1 as an effective component and a well-known carrier of drugs and/or excipient.



 

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EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula , fragment A is specified in a group consisting of , or , R1, R3, R4 and R5 mean hydrogen or alkyl; each of R4a and R5a represents hydrogen; G1 represents aryl or heteroaryl, which can by unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl, halogen, cyano, -OR1b, -S(O)R2b, -C(O)R1b, -C(O)OR1b, -OC(O)N(Rb)(R3b), -(CR4bR5b)m-OR1b, -C(OH)[(CR4bR5b)m-R4b]2, and halogenalkyl; G2 means cycloalkyl, cycloalkenyl or heterocycle unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl; Rb represents hydrogen or alkyl; R1b and R3b represents hydrogen, alkyl or halogenalkyl; R2b represents alkyl; R4b and R5b represents hydrogen, halogen, alkyl or halogenalkyl; m represents 1, 2, 3, 4 or 5; R2 is specified in a group consisting of hydrogen, alkyl, -(CR4aR5a)m-G1 and -S(O)2R6, R6 represents G1, X1 means N or CR9; X2 means N or CR10; X3 means CR11; X4 means N or CR12; provided one fragment of X1, X2 or X4 can represent N; each of R9, R10, R11, R12, R13 and R14 independently represents hydrogen, alkyl, alkenyl, halogen, -G1, -G2, -OR1a, -C(O)G3, -C(O)OR1a, -C(O)N(Rb)(R3a), -N(Rb)(R3a), -(CR4aR5a)m-G1, -CR4a=CR5a-G1, -(CR4aR5a)m-G2, -CR6a=C(R7a)2, halogenalkyl and fragment ; R1a and R3a represents hydrogen, alkyl, haloalkyl, G1, -(CR4aR5a)m-G1, G2 or -(CR4aR5a)m-G2; R6a is alkyl or halogenalkyl; R7a represents hydrogen, alkyl or helogenalkyl; G3 represents heterocycle attached to an adjoining carbonyl fragment through a nitrogen atom being a part of heterocycle; or R10 and R11 or R13 and R14 together with carbon atoms which they are attached to, form unsubstituted phenyl or cycloalkyl; Y1 means NR17, CR18R19, C(O), S(O)n or O; Y2 means NR20, CR18R19 or C(O); Y3 means NR17, CR18R19 or C(O); or Y1 and Y2 together represent CR18=CR19, n means 2; R17 represents hydrogen; R18 and R19 represents hydrogen; and R20 is specified in a group consisting of hydrogen, alkyl and -S(O)n-G1.

EFFECT: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a 5-HT2C and/or 5-HT6 receptor modulator, to a based pharmaceutical composition and to methods for preparing them.

33 cl, 7 tbl, 20 dwg, 278 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to field of therapy and/or prevention of diseases in mammals, in particular humans. Group of inventions includes medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood, representing dairy product of ruminants with reduced cholesterol content, where cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, as well as application of dairy product of ruminants with reduced cholesterol content, in which cholesterol content constitutes from 10 mg/100 g of fat to 150 mg/100 g of fat, for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis by increasing content of polyunsaturated fatty acids in mammal's blood.

EFFECT: obtaining medication for treatment and/or prevention of cardiovascular disease, and/or inflammatory disease, and/or liver disease, and/or neurological disease, and/or steatosis.

18 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, wherein R1 and R2 are identical or different and specified in an alkyl or alkenyl hydrocarbon chain; the R3 group values split by lipase are specified in the patient claim. R4 and R5 are independently hydrogen or C1-C7alkyl; R6 represents hydrogen or C1-C7alkyl; and R7 and R8 are independently hydrogen or C1-C7alkyl. The invention also refers to using compounds of formulas ,

which are introduced into the mammalian biological system and increase the cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens.

EFFECT: compounds are applicable in treating or preventing the age-related disorders associated with high membrane cholesterol, high amyloids and low plasmalogens, such as neurodegeneration, cognitive disorder, dementia, cancer, osteoporosis, bipolar disorder and vascular diseases.

11 cl, 18 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to cardiology, and represents a method of the drug treatment of patients in late rehabilitation period after aortocoronary bypass surgery, consisting in the combined administration to the patient of medications thrombo ASS 100 mg, atorvastatin 20 mg and additionally amlodipine in a daily dose from 5 to 10 mg and losartan in a daily dose from 25 to 100 mg.

EFFECT: invention ensures the long-term preservation of results of surgical myocardium revascularisation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine.

SUBSTANCE: method involves taking general baths and prescribing mud applications on lower extremities with underlying standard drug therapy. The patient takes prepared silicate-carbonate baths with the concentration of sodium salt of metasilicic acid of 100-150 mg/l and the content of carbon dioxide of 1.2 g/l. The bath water temperature is 36°-37°C. The length of the procedure is 10-15 minutes. Taking the baths is followed by having a 30-40-minute rest. Sulphide silt mud sock- or boot-like applications are performed. The mud temperature is 32°-36°C; the length of procedure is 8-20 minutes. The procedures are performed 2 days running, with a pause on the 3rd day. The therapeutic course makes 6-10 procedures.

EFFECT: method provides the further development of the symptom-free involvement of target organs: heart, kidneys, vessels by taking the antihypertensive, antianginal and antiarrhythmic effects, promotes the energetic and adaptation possibilities of the body.

5 ex

FIELD: medicine.

SUBSTANCE: invention refers to biotechnology and concerns a method for producing progenitor cells from mammalian myocardial samples. A presented method involves milling the samples, implanting them on culture dishes coated so that to provide adhesion; culturing the samples in the hypoxic environment so that to provide the sample adhesion to form a cell culture; recovering cells from the cell culture by enzymatic treatment; culturing the recovered cells until forming cell aggregates, and processing the cell aggregates with an enzyme solution to produce the progenitor cells of myocardium.

EFFECT: presented invention can be used in medicine and veterinary science for studying the myocardium regeneration mechanisms and stem cell biology, as well as for treating cardiac diseases.

10 cl, 2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: herbal tea has the hypolipidemic, antiaggregant, vasoprotective and adaptogenic action. The herbal tea contains common liquorice roots, blood-red hawthorn fruit, wild camomile blossom, blood-red hawthorn blossom, elevated part of meadow crane, elevated part of clump speedwell, clove tree flower buds, sweet flag rhizome, turmeric rhizome, anomalous peony root, common valerian rhizomes, elevated part of common sweet clover, common willow leaves, field caraway fruit, elevated part of tripartite bur-marigold, elevated part of common St. John's wort, elevated part of garden sage, meadowsweet blossom, elevated part of field mint, elevated part of cudweed in certain proportions. The above herbal tea extends the range of products for preventing primary ischemic stroke in the patients suffering cerebrovascular disease. It promotes mobilising all links of self-protection: immune protective, antioxidant and detoxification, neuroendocrine system.

EFFECT: more effective prevention.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, specifically to compositions for inducing angiogenesis in tissues, and can be used in medicine. The method provides transforming the strain E. coli TOP10 by the pCMV-VEGF165 plasmid, culturing the strain in an environment acceptable for the biomass collection followed by separating the superhelical pCMV-VEGF165 plasmid that is followed by the pCMV-VEGF165 plasmid lyophilisation, which is conducted in the necessary presence in the lyophilised solution of a cryoprotectant, a pH stabiliser, an antioxidant and other substances enabling producing normal saline for injections with the pure plasmid concentration of 0.1 to 10 mg/ml and pH 7.0 to 9.0 and providing t the superhelical form of the pCMV-VEGF165 plasmid storage retention. The method of treating an individual's tissue and/or organ ischemia consists in administering an effective amount of the prepared pharmaceutical composition intramuscularly into the individual.

EFFECT: invention enables preparing the therapeutically applicable pharmaceutical composition of the pCMV-VEGF165 plasmid DNA with preserving properties of the main substance at long-term storage at +2-+8°C.

3 cl, 2 dwg, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and immunology.

EFFECT: bispecific anti-human vascular endothelial growth factor VEGF and human angiopoietin-2 ANG-2 antibodies, methods for producing them, pharmaceutical compositions containing the above antibodies, and using them are described.

13 cl, 26 dwg, 15 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine.

SUBSTANCE: invention concerns preparing systemic and topical solid and soft dosage forms for external application in the form of a 1.5% hydrophilic gel and rectal capsules containing a 7.5% hydrophilic gel 1.9 g (in terms of the amount of the active substance of 0.14 g/capsule), for preventing and treating chronic venous insufficiency possessing anticoagulant, antithrombotic, anti-inflammatory, antiexudative and antitranssudative, capillary protective activities and improving haemorheology. An active pharmacologically active substance is presented by a substance of a potassium salt of sulphated arabinogalactan; a hydrophilic base is Aerosil, glycerol and pure water; the ingredients of the agent are taken in certain proportions, wt %.

EFFECT: invention provides the effective prevention and treatment of chronic venous insufficiency, has a broad spectrum of therapeutic action, improves haemorheology, tones the vessels and can be used in particular for treating varicose veins, thrombosis and posttraumatic oedema.

5 cl, 7 ex, 8 dwg

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