Hypotensive medication of 3-(3-[1,2,4]-triazolo)-oxatriazolium-5-olate with prolonged effect

FIELD: medicine.

SUBSTANCE: claimed is application of 3-(3-[1,2,4]-triazolo)-xatriazolium-5-olate (azasidnon-6), NO-independent hem-independent activator of soluble guanylate cyclase, as hypotensive medication with prolonged effect. In contrast to N0 donors, said medication causes lowering of arterial pressure during long time and does not cause increase of cardiac beat rate. Demonstrated is reduction of pressure under influence of medication both in normotensive and hypertensive rats, as well as vasodilating activity.

EFFECT: invention can be used in clinic for long reduction of arterial pressure and treatment of arterial hypertension.

6 ex

 

The invention relates to chemical-pharmaceutical industry, namely the creation of antihypertensives for long periods.

This invention can be used in biochemistry, physiology and medicine.

Nitric oxide (NO)synthesized by endothelial cells and other cell types and tissues, plays a key role in maintaining the normal tonus of smooth muscles of blood vessels, which determines the quantity peripheral vascular resistance and arterial blood pressure. In addition, nitric oxide has a spasmolytic effect on the smooth muscles of the gastrointestinal tract, biliary tract, ureter, uterus, bronchi and other organs, and also inhibits the processes of aggregation and adhesion of platelets and neutrophils. The molecular mechanism of action of NO is synthesized from the amino acid L-arginine by the enzyme NO-synthase, includes a stage of diffusion through the plasma membrane and binding to the heme group of the enzyme soluble guanylate cyclase (RGC). Guanilatziklazu /EC 4.6.1.2.; guanosin-5'-triphosphatases (ciclitira)/ is the enzyme that catalyzes the biosynthesis of guanosine-3',5'-cyclophosphate (cGMP) from GTP. Cyclic GMP is a secondary messenger that performs the universal role of the regulator of intracellular processes. Guanilatziklazu there are two forms - embrassing and soluble. Nitric oxide activates only one form of enzyme - RHC. At the moment it is known that in the result of the interaction of NO with iron atom of the heme that is part of the enzyme, the formation of the complex nitrosyl-heme. This raises a conformational change of the active centre of the enzyme, which lead to activation of the RHC and increased synthesis of cGMP in the cell. According to modern concepts dysfunction of vascular endothelium, accompanying diseases such as hypertension (Schiffrin et aL, 2000, Park et aL, 2001), diabetes (type I and II (Endemann et aL, 2004), disease of the coronary arteries (Monnink et aL, 2002), heart failure (Landmesser et aL, 2001), chronic renal failure, characterized by reduced endothelium-dependent dilation of the vessels (ESR) and a violation of the NO-RHC-cGMP-dependent pathway implementation expansion of the reaction vessels. Therefore, NO correction-RHC-cGMP-dependent relaxation of smooth muscle cells is of great importance for the normalization mechanism of regulation of vascular tone under different adaptive and pathophysiological reactions.

There are several ways of correcting NO-RHC-cGMP-dependent relaxation of blood vessels. It is shown that exogenous NO is formed in the bloodstream as a result of biotransformation of trinitroglycerine and other nitrates. However drugs-NO donators cannot be used for DL is positive correction of the expansion potential of vascular smooth muscle, because they operate within a short time, and they quickly develop a tolerance. In addition, large quantities of nitric oxide are dangerous to the tissues of the body, as it can react with active forms of oxygen and turn into peroxynitrite, which causes oxidative stress and damage to protein molecules in cells. In addition, there are allosteric regulators of activity RHC. Currently known allosteric regulators, as YC-1 and BAY 41-2272, manufactured by Bayer, is currently under development. In contrast to the NO-donor, they can cause a small reduction in HELL, but for a longer time (up to several hours).

In addition, in 1966, appeared for the first time data about the possibility of regulating blood pressure derivatives of oxadiazole (Kier LB et aL, 1966). The mechanism of action of compounds of this class for a long time remained unknown. In the present work an analysis of the actions of one of the derived oxadiazol - 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate (hereinafter assignon-6) on the magnitude of blood pressure in rats.

The task of the invention is to find a new NO-independent activator of RHC with long-term hypotensive effect.

This object is achieved by application of the chemical compound 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate formula

heme-dependent and NO-independent activator RHC.

The description of the present invention are illustrated by experimental data.

Examples 1-3 illustrate the physiological aspects of action 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate in vivo, namely, that the drug can cause long-term hypotensive effect when administered intravenously.

Example 4 demonstrates the vasodilator effect of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate.

Example 5 illustrates the biochemical effect 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate 0 activation of purified enzyme-RHC pigs.

Example 6 shows the chemical basis of molecular steps 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate, consisting in the absence of the generation of NO.

Example 1. Hypotensive activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate with normotensive animals.

Hypotensive activity of the compounds was determined in vivo in awake normotensive animals Wistar rats of average days of mass 300 g in a known manner. For measurement of mean arterial pressure and heart rate and for the introduction of the drug in the bloodstream for days before the experiment, animals were implanted polyethylene catheters (grades D-10, D-50) into the femoral artery and femoral vein. The free ends of the catheter taken out and fixed on the head. The operation of the por which were carried out under hypentelium anesthesia (40 mg/kg). The next day the rat was taken in the experiment. During the experiment were recorded blood pressure sensor company STATHAM (USA) followed by processing data using a computer program Bioshel, Faculty of Fundamental Medicine, Moscow state University. After M.V. Lomonosov). Compounds were injected bolus consistently doses to 0.011 mg/kg 0,11 mg/kg, 1.1 µg/kg, 11 mg/kg and 110 mg/kg in a volume of 20 µl. During the whole experiment the animals were awake and could move freely in the cage. Within 40 minutes the animals were adapted to the experimental conditions, and then began the registration of hemodynamic parameters, which were subsequently conducted continuously throughout the experience. The original values of mean arterial pressure and heart rate was 114 mm Hg and 322 blow/min, respectively.

A bolus of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate in doses to 0.011 mg/kg 0,11 mg/kg, 1.1 µg/kg had no effect on blood pressure within 30 minutes. A bolus of the drug at doses of 11 mg/kg and 110 mg/kg caused a statistically significant decrease in mean arterial pressure by 4.7% and 8.4%, respectively, without affecting the heart rate. The hypotensive effect of the drug was maintained for 30 minutes. Thus, a bolus of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-the lat awake normotensive rats Wistar causes a statistically significant reduction in the average blood pressure in doses of 11 mg/kg and 110 mg/kg

Example 2. Hypotensive activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate in hypertensive rats SHR.

Hypotensive activity of the compounds was determined in vivo in awake hypertensive animals line SHR average weight of 300 g in a known manner. For measurement of mean arterial pressure and heart rate and for the introduction of the drug in the bloodstream for days before the experiment, animals were implanted polyethylene catheters (grades D-10, D-50) into the femoral artery and femoral vein. The free ends of the catheter taken out and fixed on the head. The operation was conducted under hypentelium anesthesia (40 mg/kg). The next day the rat was taken in the experiment. During the experiment were recorded blood pressure sensor company STATHAM (USA) followed by processing data using a computer program Bioshel, Faculty of Fundamental Medicine, Moscow state University. After M.V. Lomonosov). Compounds were injected bolus consistently at doses of 110 mcg/kg and 550 mg/kg in a volume of 20 µl. During the whole experiment the animals were awake and could move freely in the cage. Within 40 minutes the animals were adapted to the experimental conditions, and then began the registration of hemodynamic parameters, which were subsequently conducted continuously throughout the experience. The original values of the average arter the social pressure and heart rate was 157 mm Hg and 311 blow/min, respectively.

Example 3. Hypotensive activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate in hypertensive rats SHR against the blocker synthesis of endogenous NO L-NAME.

Hypotensive activity of the compounds was determined in vivo in awake hypertensive animals line SHR weight 350 g in a known manner. For measurement of mean arterial pressure and heart rate and for the introduction of the drug in the bloodstream for days before the experiment, animals were implanted polyethylene catheters (PE-10, PE-50) into the femoral artery and femoral vein. The free ends of the catheter taken out and fixed on the head. The operation was conducted under hypentelium anesthesia (40 mg/kg). The next day the rat was taken in the experiment. During the experiment were recorded blood pressure sensor company STATHAM (USA) followed by processing data using a computer program Bioshel, Faculty of Fundamental Medicine, Moscow state University. After M.V. Lomonosov). First through the venous catheter was introduced nonselective blocker of NO-synthase L-NAME at a dose of 5 mg/kg, and after 60 minutes - 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate at a dose of 110 mg/kg Effects of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate was observed for 90 minutes. During the whole experiment the animals were awake and could move freely in the cage. Within 40 minutes the animals were adapted to the features of the experiment, and then began the registration of hemodynamic parameters, which were subsequently conducted continuously throughout the experience. The original values of mean arterial pressure and heart rate was 153 mm Hg and 315 beats/min, respectively.

A bolus of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate at a dose of 110 mg/kg on the background of the blocker of NO synthesis with L-NAME causes a statistically significant increase in the rate of reduction in blood pressure compared with control. By the end of the period of registration of the arterial pressure in the control relative reduction amounted to G mm Hg on the background of the action of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate - 27 mm Hg Thus identified long-term effects of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate with intravenous waking hypertensive animals line SHR against the backdrop of non-selective blocker of NO-synthase L-NAME.

Example 4. The vasodilator activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate.

The vasodilator activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate studied for its ability to change the tone perfuziruemah vessels. Activity 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate was determined in vitro on pulmonary vessels of Wistar rats of average weight 250 g Rats were decapotable, cut out the left lung and was isolated pulmonary artery is done with a small part of the preceding vessel of larger diameter. Other branches and smaller branches of the order were bandaged. The length of the isolated vessels was equal to 4 mm For experiment artery was fixed on a needle made of stainless steel with an inner diameter of 0.5 mm, so that the respective arteries of the lower order were free and kept the entire working surface of the endothelium. The distal end of the vessel remained loose. The external diameter of the artery is 300-400 microns. The vessels were perfesional with a constant flow, which amounted to 2 ml/min for the internal duct and 4 ml/min for the outer duct. Volume of the chamber for perfusion was equal to 10 ml For perfusion used the modified physiological R-R Krebs-Henseleit (the content of substances in mm: NaCl 118, KCl : 4.7, CaCl2- 3.3, MgSO4- 2.4, KH2PO4- 1.18, glucose - 5.05, NaHCO3- 24.9; pH 7.4), the solution was aeronavali with Carbogen (5% CO2, 95% O2within 20 minutes prior experience; the temperature of the solution was maintained at a level of 37.5°C (Nesterova M.A., A.A. Chuiko, et al., 1999). About the reaction of the vessel to be judged by the change in perfusion pressure recorded using a load cell (STATHAM, USA) and analog-to-digital Converter. The processed analog signal is recorded on a computer with a sample of 128 Hz. To create contractile tone, which is present in the body, the vessels were perfusionist 5-10-6M solution of serotonin. In our is xperimenta perfusion pressure in response to serotonin was increased to 20 mm Hg in the pulmonary vessels, which corresponds to normal values (Weir E.K. and J. T. Reeves, 1995; West J.B., 1990). Against this background, the contractile tone of the vessels was consistently perfesional solutions of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate with increasing concentrations: 1·109M, 1·10-8M, 1·10-7M, 1·10-6M and 1·10-5M

When perfusion pulmonary vascular solutions of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate in concentrations of 1·10-9M, 1·10-8M, 1·10-7M, 1·10-6M and 1·10-5M was dose-dependent decrease in perfusion pressure relative to control (perfusion serotonin 10-6M). A statistically significant increase relaxation was observed at concentrations of assignee-6 1·10-7M, 1·10-6M and 1·10-5and amounted to 10%, 13% and 25%, respectively. Thus, 3-(3-[1,2,4]-triazolo)-oxadiazole-5-Olathe has a relaxing effect on isolated perfoirmance drugs vessels.

Example 5. Activation of the soluble form of guanylate cyclase 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate.

The RHC activity was measured in preparations of the pig's lungs, obtained in a known manner. 1 kg pig lung was purified from cartilage, large vessels, fat, crushed in a grinder, homogenized in blendor of Moringa in one volume of buffer a containing 25 mm tea, 1 mm EDTA, 5 mm DTT, 40 mm NaCl, 1 mm PMSF, mm benzamidine, pH 7.5. The homogenate was centrifuged for 30 min at 18000g, the obtained supernatant was centrifuged at 100000 g for 40 min At a column DEE-Toyopearl volume of 300 ml, 5×15 cm, caused 1 l of protein solution and washed with 500 ml of buffer And with the speed of 320 ml/hour. RHC was suirable 1 l buffer And a linear gradient of NaCl concentration (0.04 To 0.05 M) at a rate of 90 ml/hour. According to the results of activity measurement RHC were combined fractions (130 ml). The concentration of NaCl in them amounted to about 150 mm. The resulting protein solution was diluted with 200 ml of buffer containing 25 mm tea, 7.5 mm DTT, pH 7.5. On a column of blue agarose (Sigma, Type 300, 0.5 mmol of dye in 1 ml of media) with a volume of 100 ml, 2.5×40 cm, caused 330 ml protein at a rate of 20 ml/hour and washed with 100 ml of buffer containing 25 mm tea, 5 mm DTT, 50 mm NaCl, 0.1 mm PMSF, 0.2 mm of benzamidine, pH 7.5. Almost all of the RHC activity was detected in the breakthrough, the volume of which amounted to 350 ml. of All the breakthrough inflicted on the same column (which washed before applying a buffer containing 1 mm NaCl for elution of sorbed proteins) and washed with 100 ml of buffer with rate of 24 ml/h. RHC was partially sarbievius on a column (about 40% of the total activity) and the enzyme was suirable a buffer containing 750 mm NaCl, with a rate of 80 ml/hour. Were combined fractions with the highest activity (20 ml). To the combined fractions was added a solution of DTT (+5 mm optional). 200 ml of breakthrough, the content is the future and the remaining 60% activity, struck on the same column at the rate of 13 ml/hour and suirable a buffer containing 750 mm NaCl, with a rate of 80 ml/hour. Were combined fractions with the highest activity (13 ml), and the active fractions from the previous chromatography, 33 ml. of this solution was added 1 μm leupeptin, 0.2 mm of benzamidine and DTT (+5 mm optional). The solution were dialyzed against 1 l of buffer containing 25 mm tea, 5 mm DTT, pH 7.5 to 2.5 hours On a column with a gap of 10 ml, 2.5×2 cm, struck a 20 ml solution after dialysis with a speed of 30 ml/hour. The column was washed with 10 ml of buffer containing 25 mm tea, 10 mm DTT, pH 7.4. RHC was suirable 50 ml of buffer with a linear concentration gradient of potassium phosphate (0-0,35 M). The chromatography was repeated under similar conditions with the remaining after dialysis 17 ml. After both chromatography combined fractions with the highest activity (13 ml). The resulting solution were dialyzed 14 hours versus 0.5 l of a buffer containing 25 mm tea, 5 mm DTT, 100 mm NaCl, pH 7.4. After dialysis, the solution was centrifuged at 18000g 25 minutes the Supernatant was fractionally using FPLS using chromatography installation ACT, Amersham Bioscience, Sweden, and the column QHyTrap volume of 5 ml Chromatography was carried out twice, each time dealing with 6.5 ml of protein solution at a speed of 5 ml/min the Column was washed with 10 ml of buffer D containing 25 mm tea, 5 mm DTT, 100 mm NaCl, pH 7.4. RHC was suirable 90 ml of buffer D with Lina is s ' concentration gradient of NaCl (0.1 To 1.0 M). After both chromatography fractions with the highest activity were combined total of 15 ml of the resulting solution was concentrated to 1.8 ml using membrane RM 30 (Amicon, the Netherlands) under nitrogen pressure. Subsequently, this stage is the selection of the enzyme was excluded. Was held FPLC-gelfiltration using chromatographic installation ACT, Amersham Bioscience, Sweden, and the column Sephacryl-300 capacity of 120 ml per column struck 1.8 ml of protein solution was suirable buffer D at a rate of 0.5 ml/min Fractions with the highest activity were pooled (5,2 ml) and concentrated to 1.1 ml using membrane 30 PM under nitrogen pressure. 1 ml of protein solution was diluted in 2 ml of buffer so that the final concentrations were: 30% glycerol, 1M NaCl, 10 mm DTT, 25 mm tea, pH 7.4. The solution was divided into aliquots and stored in liquid nitrogen.

Method for determining the activity of RHC based on catalytic conversion of GTP to cGMP, the subsequent allocation of cGMP from the reaction mixture and determining its concentration enzyme-linked immunosorbent assay. The volume of the sample was 100 μl. The reaction mixture consisted of 50 mm Tris-HCl (pH 7.4), 5 mm MgCl2, 4 mm creatine phosphate, 0.4 mg/ml creatine phosphokinase, 0.2 mm GTP, 5 mm dithiothreitol and deionized water (the final concentration in the sample). To obtain drug RHC was thawed aliquot of the enzyme, and before the introduction of the sample was diluted to the required concentration of the buffer, containing 50 mm Tris-HCl (pH 7.4) and 5 mm dithiothreitol. The reaction was started by adding to the reaction mixture an aqueous solution assignon-6 (100 μm), the NO-donor sodium nitroprusside (10 μm). To study the effect assignon-6 YC-1-induced activity in RHC part of the sample was added to 50 μm YC-1. Samples were incubated at 37°C for 15 minutes. The reaction was stopped by boiling in a water bath for 2 minutes. To the obtained samples was added 148 μl of 101.4 mm Zn(CH3Soo)2, 192 μl of 101.4 mm Na2CO310 μl of 100 mm califofnia buffer (pH 7.4) and 50 μl of 100 mm NH4HCO3were mixed and within 10 minutes was kept on ice. Next, the samples were tsentrifugirovanie 5 minutes at 8.8 thousand revolutions/min Thus, removal of excess GTP precipitated with carbonate of zinc, and denatured by boiling the protein. The supernatant was taken to investigate the content of cGMP enzyme-linked immunosorbent assay using antibody to cGMP. If necessary, the supernatant was diluted in a separate Eppendorf 50 μm kalyanamitra buffer (pH 6.8) for further investigation. The calibration curve constructed based on the known concentrations of cGMP, prepared 50 mm kalyanamitra buffer, pH 6.8. In this work we used a 3.2 nm to 6.4 nm, of 12.8 nm, of 25.6 nm of 0.05 ám, 0.1 ám, 0.2 μm solutions of cGMP. The calibration sample was besieged by the same way as the experimental samples. Kept the OS is in terms of calibration and test samples at a temperature of - 20°C. the concentration of cGMP in the supernatant was carried out by the method of competitive immunofermentnogo analysis using specific antibodies to cGMP on a tablet spectrophotometer at a wavelength of 492 nm.

In the above experiment, it was shown that 100 μm 3-(3-[1,2,4]-triazolo)-oxadiazole-5-Olathe activates RHC 30-fold compared to the basal activity of the enzyme (598,52±65,11 nmol/(min*mg HZ) - 100 μm 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate and to 20.52±3,44 nmol/(min*mg HZ), basal enzyme activity). It was found that 100 μm assignon-6 activates the RHC as 10 μm of the NO donor SNP (598,52±105,11 nmol/(min*mg HZ) and 686,46±106,56 nmol/(min*mg HZ), respectively). Activation RHC 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate, as well as SNP, was increased in the presence of 50 μm YC-1 to the same extent (1211,39±132,30 nmol/(min*mg HZ) and 1166,22±47,88 nmol/(min*mg HZ), respectively).

Example 6. The formation of NO from 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate.

To determine the NO-donor activity of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate used a spectrophotometric method for the determination of NO with oxyhemoglobin. As is known, NO can react with oxyhemoglobin to form methemoglobin and nitrate (Lancaster et al., 1994), thus there is the appearance of peaks at wavelengths of 577 and 401 nm the absorption spectrum. Knowing the cylinder is UNT extinction at these wavelengths, you can calculate the molar concentration of the resulting methemoglobin by the formula:

c=(l*d)/E

where l is the optical path length, d is the absorption at the wave of a wave, E is the molar extinction coefficient at this wavelength. Calculations were made considering the fact that oxyhemoglobin interacts with NO in equimolar ratio, respectively, the concentration of the resulting methemoglobin is equal to the concentration of NO.

The volume of the sample to spectrophotometrically amounted to 1 ml Final concentration of substances in the sample was 25 μm potassium phosphate buffer (pH 7.4), 5 μm oxyhemoglobin. The reaction was started by adding assignon-6 (100 µmol/l) in the experience of distilled water in the case of the control and NO-donor in the case of the positive control. In the experiments with positive control was used NO-donor Spermine NONOaT at a concentration of 5 µmol/L. the Measurement of the kinetics of the reaction was carried out using spectrophotometer Ultrospec 2000 (Pharmacia Biotech, USA). Data are presented as nmol NO/min per 1 mol of the substance.

The tool invokes a reliable long-term reduction of blood pressure when administered intravenously.

The invention can be used in the clinic for long-term decrease of blood pressure and treatment of hypertension. In contrast to the NO-donors this drug causes a reduction in blood pressure than is their long time and does not cause increase in heart rate.

The use of 3-(3-[1,2,4]-triazolo)-oxadiazole-5-olate (assignon 6), NO-independent heme-dependent activator of soluble guanylate cyclase, as antihypertensives for long periods.



 

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58 cl, 8 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims pellet with enterosoluble shell, including ixabepilone with structure (A). Also a capsule containing multiple pellets with enterosoluble shell is claimed. Pellet includes particle with coating, containing main particle and active component layer distributed completely or partially on or in the main particle. Active component layer includes ixabepilone of structure (A) and binding agent. In addition, versions of obtaining pellet with enterosoluble shell are claimed.

EFFECT: reduced or prevented ixabepilone powder flaking, possible oral administration of ixabepilone without combined acid-neutralising buffer administration.

14 cl, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly hematology, cardiology and endocrinology, and thrombin time normalisation for metabolic syndrome (MS) patients. Method involves complex 3 month therapy consisting of individual hypocaloric diet, sensibly graded physical exercise, and administration of 30 mg of pioglitazone once per day and 80 mg of valsartan once at the same day time. This complex of non-drug treatment and specified medicines combined with course duration selected empirically ensures normalisation of thrombin generation rate and volume leading to thrombin time normalisation due to therapeutical effect potentiation for single complex therapy components for MS patients.

EFFECT: normalisation of thrombin generation rate and volume.

1 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

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