Haemorheologic agent capable of reducing insuling resistance and restoring body tolerance to glucose and pharmaceutical composition based on said agent

FIELD: chemistry.

SUBSTANCE: present invention relates to use of dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidzo[1,2-a]benzimidazole as a compound which inhibits erythrocyte aggregation and reduces blood viscosity, and also reduces insulin resistance and restores tolerance of the body to glucose. The invention also relates to a pharmaceutical composition based on the said dihydrochloride.

EFFECT: new potential of the of the said compound has been studied.

3 cl, 4 dwg, 9 tbl, 7 ex

 

The invention relates to pharmacology, namely to biologically active substances and compositions possessing simultaneously hemorheological properties and properties to reduce insulin resistance and to restore the tolerance of the body to glucose, which can be used to create drugs that reduce insulin resistance and suppressing the aggregation of erythrocytes. This combination of two types of activity is extremely important, because diabetes at early stages of development there has been a violation of microcirculation, the syndrome of increased blood viscosity and development of sludge syndrome (Dedov I.I., Fadeev V.V. Introduction in diabetology. - M., 1998. - 199 C.).

It is known that diabetes type 2 is the main mechanism for the development of the disease is the reduced sensitivity of the body to insulin - the insulin resistance syndrome (Balabolkin M.I., Klebanov E.M., Kreminska V.M. Treatment of diabetes and its complications. A guide for physicians. - M.: Medicine, 2005, p.18-21). Thus there is a significant change thrombogenic potential of blood and hemorheological properties. So increased platelet aggregation, which determines a high capacity to thrombus formation (increased thrombogenic potential of blood). It also improves the ability of cells to agreg the tion with the development of the sludge syndrome, eventually manifested by an increase in blood viscosity and impaired microcirculation (Balabolkin M.I., Klebanov E.M., Kreminska V.M. Treatment of diabetes and its complications. A guide for physicians. - M.: Medicine, 2005, s).

There are a number of synthetic hypoglycemic drugs that reduce insulin resistance, reducing the tolerance of the organism to carbohydrates and intended for the treatment of diabetes with oral application. All these drugs are divided into two main groups: the biguanide and sulfonylurea derivatives.

The closest in performance and the achieved result is diabecon (gliclazide) 1-(3-azabicyclo[3,3,0]octyl-3)-3-(para-tamilselvan) urea (PPM Mashkovsky. - Drugs. - 15-ed., Rev., ISPI supplementary): New wave, 2006. - S.), developed by the firm Servier (France). It is connected mainly with the restoration of the physiological profile of the production of insulin, decreased insulin resistance and decrease platelet aggregation. This drug for a long time is used in diabetes mellitus type 2 is not only for the glucose-lowering effect, but also to stabilize the thrombogenic potential of blood and hemorheology. So gliclazide reduces platelet aggregation, normalizes impaired fibrinolytic sweat the capacity of the vascular wall and the process of fibrinolysis, slow diabetes. Gliclazide as a hypoglycemic agent begins to act within 1 hour after administration, the maximum effect is observed between the 4th and 8th hour, the duration of slightly less than 20 hours. Angioprotective effect is seen only after 3 months of treatment and even more clearly in 6-12 months.

Thus, currently used in clinical practice hypoglycemic drugs, combining glucose-lowering effect with microvascular action, are not perfect, as some of them angioprotective effect is seen only after 3-12 months after the beginning of reception (gliclazide) (Balabolkin M.N., Klebanov E.M., Kreminska VM - Treatment of diabetes and its complications. - M.: JSC "Publishing house "Medicine", 2005. - S-177). Therefore, the need for drugs, combining glucose-lowering effect with angioprotective action, but more effective than already applied in clinical practice, is very high, and the creation of medicines with such an original mechanism of action is relevant.

The technical result of the invention is to improve the efficiency of hemorheological effects (ability to lower elevated blood viscosity and erythrocyte aggregation), as well as the manifestation of the properties of reducing insulinresistance and restore tolerance of the body to glucose in diabetes mellitus, the prediabetes, insulin resistance syndrome and obesity.

The technical result is achieved by dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole (I):

The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole known as compounds having hypoglycemic (glucose-lowering and antiplatelet activity (ability to reduce thrombogenic potential of blood, i.e. to reduce the likelihood of blood clots in the bloodstream) (Anisimova V.A., Levchenko, M.V., Korochina T.B., A. A. Spasov, Kovalev S.G., Dudchenko G.P. Fr.Pat. 2691462 (1995), Bull., 95/23; EP 0571253. Kovalev, G.V., A. A. Spasov, Anisimov, VA, Vdovin G.P., Kovalev this YEAR, Balabolkin M.I., Mamaev,, Dudchenko G.P., Levchenko MV Pat. Of the Russian Federation No. 206148 (1996); bull. No. 20). The compounds identified additional hemorheological activity (the ability to reduce high blood viscosity, erythrocyte aggregation and ultimately lead to the restoration of microcirculation), and the activity that reduces insulin resistance and healing tolerance of the body to glucose in diabetes mellitus, prediabetes, insulin resistance syndrome and obesity.

The technical result is also achieved by pharmaceutical composition in the following ratio of ingredients, wt.%:

the dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole20-92
starch and/or polyvinylpyrrolidone, M. 7800-35000 (PVP),
and/or sodium carboxymethylcellulose (N)
or oksipropilmetiltselljuloza (OPMC)7-40
calcium and/or magnesium stearates0.3 to 1.0
microcrystalline cellulose (MCC) and/or lactosethe rest (up to 100)

Starch and/or polyvinylpyrrolidone, N, OPMC, MCC, lactose was used as filler and binder granules, calcium and/or magnesium stearate as a lubricating antifriction component (Chechev VI, Chernov N.E., L. Khokhlova. and other Industrial technology of drugs, Kharkov, Publisher of PAU MKT-book, 2002, Vol.2, s-334). At the same time, polyvinylpyrrolidone, NaK, OPMC and microcrystalline cellulose were used for prolonging the action of the substance (Chechev VI, Chernov N.E., L. Khokhlova. and other Industrial technology of drugs, Kharkov, Publisher of PAU MKT-book, 2002, Vol.2, s-355).

The pharmaceutical composition was prepared as follows: the La of this active substance dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole is mixed with the calculated amount of lactose to obtain a homogeneous mass, then moisturize with an aqueous solution of the binder of starch, and/or PVP, and/or (NAKM), and/or UPMC, granularit, receiving pellets up to 2 mm, dried at a temperature not exceeding 100 degrees, granularit, receiving granules not more than 1 mm, the Obtained granules optivault anti-friction substances: calcium and/or magnesium stearates and MCC. The resulting mixture was placed in a hard gelatin capsule with a lid or pressed tablets weighing from 0.1 to 0.5,

The method of obtaining the compound I consists in the condensation of 2-amino-1-diethylaminoethylmethacrylate II with an excess of dibromethane, the allocation of the resulting reaction dihydrobromide 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole III base Io the action of an alkaline agent and subsequent translation of the latter into the dihydrochloride I conventional techniques, for example by the action of HCl solution.

Below is an example of obtaining compounds I.

Example 1. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a] benzimidazole (I).

Stir the suspension to 69.6 g (0.3 mol) of 2-amino-1-diethylaminoethylmethacrylate (II) in 104 ml (1.2 mol) of dibromethane heated 30 min at 140-145°C. Add 80 ml of DMF and heated the mixture for 10-15 minutes to Cool to 20-25°C, the precipitate is filtered off, washed with DMF and acetone, getting 106 g dihydrobromide III (84%). The latter is dissolved in 230 ml of water spray alkalinized 40%sodium hydroxide solution to pH 10. Released on the surface of a light yellow oil (base) is extracted with toluene. Toluene extract is washed with water and dried. Toluene solution is acidified by addition of a saturated solution of hydrogen chloride in 2-propanol to a pH of 1. Released a heavy colorless precipitate the dihydrochloride I after 4-5 h, filtered off, washed with acetone and dried at 100-110°C to constant weight. Exit 75 g (90,9%, considering dihydrobromide III, and 75%, counting on the starting amine (II). Clear technical "debena" to the Pharmacopoeia purity by recrystallization from 2-propanol. TPL 258-259°C. Found, %: C To 54.4; H 7,2; Cl 21,2; N is 16.8. C15H22N4·2HCl. Calculated, %: C To 54.4; H 7,3; Cl 21,4; N 16,9. UV-spectrum (0,0025%solution of dihydrochloride of I in 95%EtOH), λmaxnm: 217±2, 279±2 and the shoulder at (282-286)±2. IR-spectrum (VAZ. oil) of compound I, cm-1: 1665 (C=N). An NMR spectrum1N (D2O, internal standard HMDS, ppm: 1,29 (6N, t, 2CH3), to 3.35 (4H, 2CH2), of 3.69 (2H, t, CH2N)to 4.41 (4H, s, nutrical. (CH2)2), to 4.62 (2H, t, NCH2), 7,41 (4H, m, aromatic. N).

Reaction with dibromethane can be carried out in other solvents, for example xylene, dioxane, diethylene glycol, diethoxyethane, benzonitrile, propylene carbonate, dimethyl sulfoxide, dimethylformamide, however, best results are still obtained when carrying out the reaction in excess of dibromethane.

Below is approx the market receiving the composition.

Example 2. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a] benzimidazole (0.1 g) moisturize 0.02 g NAKM in the form of a solution, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 1 mm, the resulting mass optivault 0.001 g of calcium stearate with a particle size of not more than 0.16 mm and pressed to tablets on a tablet press.

Example 3. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole (0.15 g) moisturize 0.04 g OPMC in the form of a solution, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 1 mm, the resulting mass optivault 0,007 g of calcium stearate with a particle size of not more than 0.16 mm and pressed to tablets on a tablet press.

Example 4. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]-benzimidazole (0.1 g) is mixed with 0,355 g lactose hydrate 0.04 g PVP in the form of a solution, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 1 mm, the resulting mass optivault 0.005 g of calcium stearate with a particle size of not more than 0.16 mm and pressed to tablets on a tablet press.

Example 5. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]-benzimidazole (0.1 g) moisturize 0.07 g of starch in the form of paste, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 2 mm, the resulting mass optivault 0,004 g magnetoroton with a particle size of not more than 0.16 mm and pressed to tablets on a tablet press.

Example 6. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]-benzimidazole (0.15 g) moisturize 0.06 g OPMC in the form of a solution, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 1 mm, the resulting mass optivault 0.004 g of magnesium stearate with a particle size of not more than 0.16 mm, pack up and Packed into gelatin capsules with a cap.

Example 7. The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]-benzimidazole (0.1 g) moisturize 0,009 g PVP in the form of a solution, granularit, dried, granularit and sieved through a sieve with the hole diameter is not more than 1 mm, mixed with 0.09 g MCC to obtain a homogeneous mixture. The resulting mass optivault 0,0017 g of magnesium stearate with a particle size of not more than 0.16 mm, pack up and Packed into gelatin capsules with a cap. All the tablets and capsules dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo-[1,2-a]benzimidazole satisfy the requirements of the global Fund XI edition. These data are presented in table 1.

Table 1
The quality indicators of granules, tablets and capsules of the drug on the basis dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole, prepared with various excipients
CompositionFlowability, g/sThe buoyancy force, NMechanical strengthRaspadaemost,
compression, N.abrasion, %
26,25±0,2313076,82±1,56of 99.1±0,4294±19
35,63±0,1728882,57±1,92of 99.3±0,7210±18
45,41±0,1517162,93±1,9798,7±0,5222±29
56,20±0,3419082,57±2,72of 99.1±0,6480±11
66,39±0,35---666±7
7 by 5.87±0,19-597±18

The proposed ratio of active substances and excipients is optimal, provided quality tablets and encapsulated drugs of the compounds I and the achievement of the desired therapeutic effect.

The study of the bioavailability of the pharmaceutical composition

A study of the bioavailability of the pharmaceutical composition in accordance with the "guidelines for the preclinical study of pharmacokinetics of drugs" (Firsov A.A. guidelines for conducting pre-clinical studies pharmacokinetics pharmacological substances and medicines / Air, Wpierdol etc. // Guidance on experimental (preclinical) study of new pharmacological substances: under the General Ed. Rugarama. - 2-ed., Rev. and supplementary): JSC "Publishing house "Medicine", 2005. - S-229).

Experiments to study the pharmacokinetics of the drug substance I and pharmaceutical compositions with PVP were performed on 100 outbred rats-males weighing 160-200 g Substance and the composition was injected probe intragastrically at a dose of 25 mg/kg (based on the substance). Sampling of blood was performed in 0.5; 1; 2; 3 and hours and urine after 1, 2, 3, 4, 6, 8, 12, 25, 36,48, 60 and 72 hours after administration of the studied compounds or compositions. The urine collection was carried out in the metabolic chambers "Termoplast" (Italy). Blood stabilized with 5% solution of sodium citrate.

The content of compound I was determined by HPLC on a liquid chromatograph HEWLETT PACKARD (USA) series 1050 with a column of the same firm size 100×2.1 mm, with a sorbent Hypersil MOS 5 μm, using a solvent containing 30% acetate buffer with pH 5.0 and 70% acetonitrile, flow rate 1 ml/min, pressure of 135 bar and sensitivity of 0.01 AU. Detection was performed by UV detector at a wavelength of 280 nm. Under these conditions, the retention time of the drug I - 5 minutes. The sensitivity was 100 ng/ml Extract of this drug was performed from whole blood by extraction with acetonitrile in the ratio of 1:1. Samples were centrifuged for 15 min at 3000 Rev/min the Concentration of the drug I was determined using the calibration graph.

Pharmacokinetic parameters were calculated by the method of statistical moments (Piotrovsky VK Method of statistical moments and the integral model independent pharmacokinetic parameters. - Pharmacology and toxicology. - 1986. No. 5. - v.49. - pp.118-127).

Pharmacokinetic curve (figure 1) in the study of the composition has a similar appearance compared with the kinetics curve with the introduction of the substance of the compound I with the only difference that reduced the f concentration is not to the 3 rd, and by the 5th hour. It should be noted that with the introduction of the substance of compound I somewhat faster than the maximum concentration in the blood.

Thus, with the introduction of the composition was observed an increase in the circulation of compound I in the blood of rats, accompanied by an increase in half-life, the residence time of the molecules of compound I in the body (MRT) and a decrease in the overall clearance by 21.4%. Pharmacokinetic parameters of substance I and composition of the drug are presented in table 2. The relative bioavailability of the composition in relation to the solution of the substance is 127,02%.

Thus, it is possible to conclude bioequivalence composition of the drug with respect to the substance of the compounds I and prolonging therapeutic effect of this connection is associated with a decrease in clearance and increase in the period of its half-life.

Table 2
Pharmacokinetic parameters substance compounds and compositions (when administered orally at a dose of 25 mg/kg)
AUC, (µg/ml) hourhourKel, h-1Cl, ml/HR MRT, h
The substance of compound I10,291,580,442,432,33
Track13,071,630,421,913,03

In the study of excretion of the compound I via the kidneys (figure 2), it was observed the increase of its concentration in urine from 2 to 5 hours up to a maximum, and then decrease in concentration by the 12th hour after administration of the substance I and 24 th hour after administration of the composition.

In the study of the excretion of compounds in urine was estimated renal clearance (ClR), determined by the ratio of cumulative excretion of the drug I from the urine to the AUC of the drug in the blood.

It is established that renal clearance of the composition of the drug I was following this indicator substance I 26.9% (ClR the subst.=2.91 in ml/HR, ClR Lek. form.=2,91 ml/hour).

Thus, speed of deducing of connection with urine it is possible to conclude that the prolongation of his detention in the body (when administered in the form of a composition) due to the decrease in the intensity of excretion via the kidney.

Pharmacological properties of the claimed compounds

This compound (I) is nijaat insulin resistance and, thus, restores the tolerance of the body to glucose, suppresses the aggregation of red blood cells and, thereby, reduces the viscosity of blood.

1. The effect of compounds on insulin resistance was determined from the change in the tolerance of animals to glucose (oral glucose load) (Functional methods of research in endocrinology / Shizune [and others]. - Kiev: Health, 1981. - 240 S.) at:

- latent form of streptozotocin diabetes (prediabetes);

experimental obesity;

- exogenous hyperinsulinemia (insulin resistance)

and interaction with exogenous insulin for dogs with remote pancreas.

2. The effect of compounds on hemorheological properties of blood were studied in experiments with streptozotocin diabetes:

changing the viscosity of the blood;

- suppression of aggregation of erythrocytes caused altianalis blue.

The effect of compound I on glucose tolerance in latent form of streptozotocin diabetes (prediabetes)

Effect of compound I on the glucose content in the blood of animals with the syndrome of altered glucose tolerance has been studied in animals with latent form of streptozotocin diabetes. Latent form of streptozotocin diabetes was reproduced by Kolesnik, Y.M. (Kolesnik, Y.M. State islet apparatus of the pancreas, with ek the pilot diabetes. - Archives of pathology. - 1992. - T.54. - 12. - c.24-27) in outbred rats weighing 160-220 g intraperitoneal injection of freshly prepared in citrate buffer streptozotocin (Sigma) at a dose of 30 mg/kg No sooner than three days were selected animals with impaired glucose tolerance. Oral glucose tolerance test was performed in the morning after a night (for 10-14 h) fasting animals at the intragastric glucose solution at a dose of 3 g/kg glucose in the blood of rats was determined by glucose oxydase method using a set of Bio-La-Test (Czech Republic, Lachema diagnostics). When studying antihyperglycemics effects on the model of disturbed carbohydrate tolerance in animals with latent form of streptozotocin diabetes was supposed to clarify the influence of the substances on the dynamics of secretion of the hormone (insulin). Study the connection I and the reference product with a combined mechanism of action - gliclazide (pronounced Pancreatinum action), the animals received intragastrically for 2 hours before the start of the experiment at doses of 25 and 50 mg/kg, respectively. After this time they orally injected with a solution of glucose (3 g/kg) and over the next 2 hours watching the dynamics of changes in blood glucose. For a more objective assessment of changes of parameters of glucose load were considered indicators of the area under the foi the ow dynamics of glucose in the blood Avireal (2005) (AV grewal The analysis of the results of oral glucose load test using a simple mathematical model / Avireal // lab. case. - 1985. No. 12. - S-741).

The activity of compounds was evaluated, taking into account their hypoglycemic activity in animals with latent form of streptozotocin diabetes and locking antihyperglycemics effect of the investigated substances in these same animals after oral glucose load. The results of the study are presented in figure 1 and in table 3. The initial concentration of glucose in rats treated with different analyte, ranged from 4,43±0,28 to 5.50±0.29 mmol/l

However, it should be noted that all animals that were taken in the experiment, have been pre-individual diagnosis (oral loading test glucose). According to the results of her study were used only rats with impaired tolerance to carbohydrates. Two hours after beginning of the experiment the animals of all groups, including control, there was a decrease of glucose, however in control rats, these changes were not statistically significant. The substance I, like drug comparison gliclazide, produced statistically significant (P<0,05) hypoglycemic effect. On the background of exogenous hyperglycemia in group of animals treated with gliclazide and compound I, it was noted accurately is at the absolute values compared with the control animals, lowering blood glucose levels. It should be noted that the reduction of the increase in blood glucose relative to the start of the glucose tolerance test were observed in animals that were administered gliclazide only one hour after a carbohydrate load. In the first 30 minutes of the percentage increase of glucose in animals of this group did not differ from control rats treated with the solvent substances. While the connection I already at 30 min was significantly (P<0,05) slowed the growth rate of glucose in the blood of Wistar rats. In terms of changes in the area under the curve glucose load connection I surpassed the preparation of comparison gliclazide.

Table 3
Influence gliklazida and compound I after intragastric administration on the glucose level in blood of rats with experimental diabetes (streptozotocin 30 mg/kg intraperitoneally) on the background of the oral load of glucose (3 g/kg) (M±m)
The treatment groupEd. MEAs.The time intervals (min)The area under the curve ($)
-120 0306090120
The content of glucose in the blood
Intact rats (CTR. 1)mm4,25±0,143.93±0,085,19±0,125,07±0,204,58±0,153,95±0,12504,61
%-7,5+32,1+29,0+16,5+0,5
Diabetes (contr)mm5,50±0,294,87±0,228,13±0,38of 7.93±0,437,31±0,406,09±0,26792,28
% K1+29,4 *+23,9*+56,6*+of 56.4*+59,6*+54,1*
%-11,4+66,9+62,8+50,1+25,1
Diabetes + Gliclazide (25 mg/kg)mm4,43±0,282,78±0,054,93±0,224,76±0,14or 4.31±0,073,40±0,04595,83
%-37,2**+77,34+71,22++55,04++22,25+
Diabetes + connection
tion I(25 mg/kg)
mmof 4.57+0,173,93±0,13by 5.87±0,29of 5.40±0,354,67±0,264,37±0,23543,75
%-14,1**+49,4++37,4 +18,8++11,2+
* changes were significant in comparison with control 1 (P<0,05)
+ - changes were significant in comparison with control 2 (P<0,05)
** changes were significant in comparison with the original data (P<0,05)

According to the results of the conducted research it can be argued that the connection I improves low glucose tolerance.

Studies on animals with experimental obesity

Obesity modeled in old rats males (age 2 years, up to the beginning of the experiment 290-350 g), which is more than three months on subcarinal diet with a high fat content (more than 80% of the total caloric content of the diet and carbohydrates with high glycemic insulin. During this period animals were not restricted in the diet. In the study were selected animals with impaired glucose tolerance and reduced insulin sensitivity (sample Hemsworth). Oral glucose tolerance test was performed in the morning after a night (for 10-14 h) fasting animals at the intragastric glucose solution at a dose of 3 g/kg glucose in the blood of rats was determined by glucose oxydase method using a set of Bio-La-Test (Czech Republic, Lachema the diagnosis is a).

Animals with obesity who were diagnosed with impaired carbohydrate tolerance and the syndrome of insulin resistance, were divided into two groups, one of which served as control, and other animals were administered the test substance and observed the changes in the glucose level two hours before the glucose load and two hours after it. The results of the study of Hypo - and antihyperglycemic action of the studied compounds I are presented in figure 2 and in table 4.

The connection I 2 hours after injection had a hypoglycemic effect within 10%. After glucose load a tendency to decrease glucose levels are preserved. It should be noted that antihyperglycemics effect observed throughout the experiment, was stable. Significant differences compared to control animals was observed after 30 minutes of oral ingested glucose.

Table 4
The effect of compound I (25 mg/kg) by intragastric administration on the glucose level in blood of rats with impaired tolerance to carbohydrates and insulin resistance on the background of the oral load of glucose (3 g/kg) (M±m)
The treatment group Ed. MEAs.The time intervals (min)
-1200306090120
The content of glucose in the blood
Intact rats (control 1)mm4,25±0,143,93±0,085,19±0,125,07±0,204,58±0,153,95±0,12
%-7,5+32,1+29,0+16,5+0,5
Rats with impaired tolerance to carbohydrates (control 2)mm4,15±0,11of 3.77±0,214,93±0,215,22±0,245,43±0,335,20±0,15
%to-9.2+30,8+38,5 +44,0+37,9
% K1-2,4-4,1-5,3+2,9+18,6*+31,6*
Rats with impaired tolerance to carbohydrates + compound I (25 mg/kg)mm4,30±0,17a 3.87±0,07and 5.30±0,154,63±0,19to 4.23±0,194,37±0,09
%-10,0+37,0+19,6+9,3++12,9+
* changes were significant in comparison with control 1 (P<0,05)
+ - changes were significant in comparison with control 2 (P<0,05)

Evaluation of the effectiveness of compound I in rats with exogenous hyperinsulinemia (model of insulin resistance)

The syndrome of insulin resistance reproduced by the method Gordienko PU with co-authors (Gordienko PU, Dead N.P., Salganik RI. Violation of glucose tolerance in rats with long-term insulin - About the problems of endocrinology. - 1973. - T. No. 6. - S-91) in outbred rats weighing 160-220, Animals for 27 days daily subcutaneously injected with a Protamine-zinc-insulin (Elli-Zilly, USA) at the rate of 2 UNITS/animal. For the study were selected animals with impaired glucose tolerance. Insulin resistance was determined using a sample of Hisword (Cuhna SI, Slavnov V., Panchenko NI and other Functional methods of research in endocrinology, Kiev: Health. - 1981. - 240 C.). Oral glucose tolerance test was performed in the morning after a night (for 10-14 h) fasting animals at the intragastric glucose solution at a dose of 3 g/kg glucose in the blood of rats was determined by glucose oxydase method using a set of Bio-La-Test (Czech Republic, Lachema diagnostics).

Animals with impaired tolerance to carbohydrates (based on results of the glucose tolerance test) and the syndrome of insulin resistance (diagnostics using samples Hemsworth) were divided into two groups: the first group was administered once orally investigated the connection, the second group - the solvent is the substance. The dynamics of change of the glucose level in the blood began to watch 2 hours after administration of the compounds, and then on the background of the oral glucose tolerance test glucose for a further two hours, taking blood samples every 30 minutes is.

The results of studying the influence of the compounds on the level of glucose in the blood of rats with impaired tolerance to carbohydrates after long-term administration of insulin are presented in figure 3 and in table 5.

The original glucose control animals and rats treated with the test substance, were practically identical (4,15±0.11 mmol/l, 4,30±0,17 mmol/l, respectively). In the analysis of blood samples, which were collected 2 hours after the start of the experiment and after 30 minutes after administration of glucose, significant differences from control animals (-9,16% +18,8%) and experimental groups (-10,0% and +23,26%) was not detected. However, after 30 minutes it was noted antihyperglycemic action of compound I, which were reliable (P<0,05). Increase glucose decreased in 2 times in comparison with control group of rats. Between 60 and 90 minutes to effect continued to grow and a half hours after modeling hyperglycemia was achieved all +of 9.30% against +44,03% in controls (P<0,05). To 120 minutes, which corresponded to 4 hours of the experiment, the glucose level was slightly increased, but the difference between the increase in glucose, in percentage terms, in the group of animals treated with the drug I, and the control rats remained in the range of 60% (P<0,05). Concentrations of glucose in animals treated with the substance, almost brought the ü to the source data, while the rats of the control group exceeded 25% glucose, marked the beginning of the experiment.

Thus, antihyperglycemics effect confirms the presence of the substance I in addition to pancreatology actions that cannot be implemented in this experimental model, extrapancreatic effects.

Table 5
The effect of compound I (25 mg/kg) by intragastric administration on the glucose level in blood of rats with impaired tolerance to carbohydrates (old animals with obesity) after oral glucose load (3 g/kg) (M±m)
The treatment groupEd. MEAs.The time intervals (min)
-1200306090120
The content of glucose in the blood
Intact rats (control 1)mm4,25±0,143,93±0,085,19±0,12 5,07±0,204,58±0,153,95±0,12
%-7,5+32,1+29,0+16,5+0,5
Rats with impaired tolerance to carbohydrates (control 2)mm4,27±0,224.26 deaths±0,29the 5.51±0,355,54±0,325,47±0,375,23±0,36
%-0,2+29,3+30,1+28,4+22,8
% K1+0,5+8,4+6,2+9,3+19,4*+32,4*
Rats with impaired tolerance to carbohydrates + compound I (25 mg/kg)mm4,75±0,154,30±0,124,75±0,254,70±0,10 4,60±0,104,65±0,25
%-9,5+10,5+9,3++7,0++8,1
* changes were significant in comparison with control 1 (P<0,05)
+ - changes were significant in comparison with control 2 (P<0,05)

The effect of compound I on the hypoglycemic action of exogenously injected insulin

One of the indirect indicators of increasing the sensitivity of tissues to insulin may be the influence of new substances on the severity of the hypoglycemic action of insulin in animal experiments with remote pancreas scheme .A.Houssay (1960).

Experiments were performed on 5 pancreatectomized dogs weight 8,6-11,5 kg Destruction of the pancreas was performed under geksenalovy anesthesia (50 mg/kg intraperitoneally) in aseptic conditions. The study was performed 3-4 days after surgery, when the concentration of glucose reached 23-26 mmol/L. By this time, the animals lost weight, they have developed polyuria, polydipsia, polyphagia, i.e. clinical signs of a severe form of diabetes, the main reason for the development of which is insulin deficiency. The effect of compounds is s I on glucose-lowering effect of insulin was performed in three stages.

1. Studied the effect of compound I on blood glucose in pancreatectomized dogs. Studied compound I was administered to the animals once intravenously at a dose of 5 mg/kg glucose-Lowering effect of the compounds were studied for 6 hours. Blood samples were taken every hour.

2. Studied the hypoglycemic effect of insulin injection (Minneapol, Moscow endocrine plant), entered repeatedly intravenously at a dose of 0.04 U/kg over 3 hours with 30-minute intervals.

3. We studied the effect of insulin in combination with compound I for the maintenance of blood glucose. Substance at a dose of 5 mg/kg was injected intravenously with the first dose of insulin. Monitoring of glucose in the blood of experimental animals continued until the disappearance of hypoglycemic effect. Blood samples were taken every hour throughout the experiment. Generalized data on the effects of insulin and substances I entered separately, and insulin, introduced in complex with compound I, on the concentration of glucose in the blood pancreatectomized dogs shown in figure 4.

The compound did not affect the glucose content in the blood in dogs with remote pancreas. Thus, changes in glucose concentrations ranged from 2.7 to 4.6% and were not statistically significant. After the introduction of insulin pancreatectomized dogs in an hour hormone decreased retained the e blood glucose by 23%. Hypoglycemic effect continued to grow and after 2 hours was the most pronounced, the glucose content in the blood of dogs by this time amounted to 16.6 mmol/l instead of the original 23.2 mmol/l, which corresponded to the reduction of glucose in the blood of experimental animals at 28%. On the 3rd hour of the experiment in 3 of 5 dogs blood glucose was maintained at this level, however (aggregated data) tended to stabilize, which was observed in the subsequent time. Between the 5th and the 6th hour of the experiment the concentration of glucose in the blood reached a baseline, and after 6 hours in 3 dogs even slightly exceeded the concentration of glucose, which was noted in the blood of animals before the start of the experiment. Under the joint administration of insulin for injection with compound I concentration of glucose in the blood of dogs after an hour decreased by 23%, which corresponded to the hypoglycemic effect of insulin. By the 2nd hour of the experiment, there has been increased hypoglycemic action of insulin, which by the 3rd hour after injection was statistically significant. The maximum reduction of glucose by 46% was observed for 4-5 hour surveillance. Hypoglycemic effect of insulin, introduced in combination with compound I in 2.7 times higher than the glucose-lowering effect, which was observed with the introduction of a single insulin. After 6 hours, the concentration of glucose in the blood start to rise and to th hour of the experiment, the glucose content in the blood is normalized.

Thus, lowering the level of glucose in the blood pancreatectomized dogs under the influence of insulin, put together with a connection that was more intense and longer than when using one of the insulin.

Studies give reason to conclude that the studied substance increases the sensitivity of tissues to insulin action.

Thus, on the basis of the conducted research it can be concluded that the studied compound I reduces insulin resistance of body tissues and restores the tolerance of the organism to carbohydrates in pathology of carbohydrate metabolism. Probably, the observed effect of compound I is associated with its ability to increase the sensitivity of body tissues to insulin.

Hemorheological properties of the claimed compound I

Hemorheological changes were assessed by two important parameters, the viscosity of blood and the ability of cells to aggregation induced altianalis blue in the conditions of experimental pathology - streptozotocin diabetes.

The Hyper viscosity syndrome caused by intraperitoneal injection of streptozotocin ("Serva, Germany) at a dose of 40 mg/kg (sheep V.G. Experimental diabetes. Leningrad: Nauka, 1983 - 216 C.). In the experience took animals that have developed persistent hyperglycemia (at least 17 mmol/l). IP is laguepie substances, dissolved in saline, was administered to rats intragastrically for seven days at a dose of 5 mg/kg Control animals received an equivalent volume of solvent. Blood samples for research hemorheological parameters were taken from the abdominal aorta of rats under hypentelium anesthesia (40 mg/kg), which according to the literature does not affect the rheological parameters of blood (Galenic VA, Gostynska E.V., Dicker VE Hemorheology disorders of carbohydrate metabolism - Novosibirsk: Nauka, 1987. - 342.).

Measurement of blood viscosity was carried out on rheological blood analyzer ACRE-2 (Russia) with seven shear rates, simulating different intensity of blood flow in the vessels (Analyzer blood viscosity / N. A. Dobrovolsky, Humopehy, Astafiev etc. // Rheological studies in medicine: Sat. scient. Tr. - M.: NCH Russian Academy of medical Sciences, 1998. - P.45-51). Was made to standardize blood samples to a single hematocrit 45% by the addition or removal of the necessary amount of plasma.

The index of aggregation of erythrocytes (IAE) has been calculated by the ratio of blood viscosity at 20°C to blood viscosity at 200-1(Dintenfass L. Modifications of blood rheology during aging and agerelated pathological conditions // Aging (Milano). - 1989. No. 1. - P.99-125). Erythrocyte aggregation was studied on two-channel laser aggregation analyzer (model 220LA) scientific-production firm is "Biola" (Russia) (Spasov AA, Ostrovsky O.V., Kucheryavenko, A.F., A. Degtyarev. The study of RBC aggregation on laser agricultutre // Clinical laboratory diagnostics. - 2000. No. 5. - P.21-23).

The study of the aggregation ability of erythrocytes was performed on washed red blood cells, using as an aggregating agent 50 μm aqueous solution ellenboro blue (Sigma, USA).

The results of the experiment are presented in table 6 and table 7.

Table 6
The effect of compound I and the comparison drug gliklazida on blood viscosity (CP) rats with streptozotocin diabetes at different shear rates (seven intragastric administration at a dose of 5 mg/kg) (M±m)
N p/pThe studied compounds and drugsBlood viscosity at different shear ratesIAE
200-1100-120-1
1.Control3,93±0,094,03±0,095,95±0,04 1,51
2.The connection I3,52±0,05*3,6±0,06*4,45±0,10*1,26
3.Gliclazide3,7±0,06*of 3.77±0,064,95±0,10*1,33
* data is significant in relation to control (p<0,05)
- reliable data in relation to gliclazide (p<0,05)
IAE - index aggregation of erythrocytes

Table 7
The effect of compound I and the comparison drug gliklazida on alcian-induced aggregation of red blood cells in rats with streptozotocin diabetes (seven intragastric administration at a dose of 5 mg/kg) (M±m)
№p/pThe studied compounds and drugsErythrocyte aggregation, Δ% compared to the control
1.The connection I-78,76±2,05*
2. Gliclazide-53,66±2,59*
* data is significant in relation to control (p<0,05)
- reliable data in relation to gliclazide (p<0,05)

So, as a result of the conducted research it was shown that the connection I reduces the viscosity of the blood of rats with streptozotocin diabetes, with activity exceeding the preparation of comparison gliclazide.

Thus, the claimed compound I has expressed hemorheological property that were not previously known (not shown), which is to reduce the aggregation of red blood cells and normalization of blood rheological properties (viscosity of blood) in rats with Hyper viscosity syndrome.

Study of acute toxicity of the compounds I and pharmaceutical compositions

Sredneseriynoe dose (LD50) substance and dosage form was determined by Arzamastseva E.V. with co-authors (Arzamastsev E.V., gouskova T.A., Berezovskaya IV and other guidance on the study obitoxitachi actions of pharmacological substances.- Manual on experimental (preclinical) study of new pharmacological substances / Under the General editorship corresponding member of RAMS, Professor Rugarama. - 2-ed., Rev. and supplementary): JSC "Publishing house "Medicine", 2005. - S-204). The experiments were performed on the be what's nonlinear rats of both sexes weighing 180-200 g The drug I was administered once orally to rats-males at doses of 1000, 1500, 3000, 4000, 5000 mg/kg, rats-females at doses of 1200, 1500, 3000, 5000, 6000 mg/kg Immediately after the introduction of the analyte animals were kept under constant observation for 4 hours in the following days, watched them twice a day: morning and evening. The duration of the experiment was 14 days. Assessment of the General condition and behavior of the animals was carried out according to the following criteria: the nature of physical activity, motor coordination, seizures and their nature, the presence of tremor, reflex responses to external stimuli - sound (tapping on the cage), tactile (touching the skin), assessed the condition of the coat (wool ruffled or smooth, shiny or dull). At the end of the observation period was estimated percentage of dead and surviving animals was calculated LD50method Litchfild and Wilcoxon (Belenky M. - IN the book: Elements of quantitative evaluation of the pharmacological effect. - L., 1968. - 151 S.).

According to the results of studies of acute toxicity of the substance I installed the levels of lethal doses are different for female rats and male and typical signs of intoxication.

The animals began to die already in use by them of compound I at a dose of 1500 mg/kg, However, the deaths were isolated, and the pattern of poisoning was not clear what iraena. Starting with a dose of 3000 mg/kg and ending with a dose of 6000 mg/kg, all animals showed signs of poisoning. Picture of the contamination and death of the animals was approximately the same in all groups of animals. The difference was the number of dead animals in a dose-dependent use of the drug, the rapidity of development symptom of poisoning and timing of death. After the injection there was a sharp sedation, decreased motor activity until complete immobility, and then there were clonic convulsions, and the animal was killed. Animals are alive, the next day was marked lethargy, decreased locomotor and feeding activity.

On the basis of the data obtained for the study of acute toxicity of the substance of the drug I was calculated sredneseriynoe dose (LD50). Also was determined sredneseriynoe dose for the drug form of the compounds I. General data acute intoxication caused in rats by oral administration of study drug, given in table 8.

According to the results of the research dihydrochloride I can be attributed to toxic substances. Compared with antidiabetic drugs (table), used in clinical practice for the treatment of non-insulin dependent diabetes mellitus, it is less toxic than derivatives of guanidine - ven the rata of Metformin, and almost equal for this indicator sulfonylurea derivatives I and II generation.

Table 8
The effect of compound I and pharmaceutical compositions in a single oral administration on the death of rats
Name of drugsSredneseriynoe dose (LD50) mg/kg
FemaleMales
The substance of compound I2321,0 (1646,27-3273,01)2740,91 (2017,54-3723,62)
Track3569,46 (2730,59-4666,05)3554,45 (2320,17-5445,33)
Table 9
Sredneseriynoe dose (LD50) antidiabetic drugs oral introduction (literature data)
Drug nameLD50mg/kgThe author
Tolbutamide250 Haller, and others, 1973°
Hlorpropamid2390Haller, and others, 1973°
Gliclazide3000Duhault J. et al.,1972°°
Metformin1000Haller, and others, 1973°
° - Haller G, Trautenberg C. Oral therapy of diabetes. - M.: Medicine, 1973. - 298 S.
°° - Duhault J., Baulanger M, Beregi L. The pharmacology of S 1702. A new highly effective oral antidiabetic drug with unusual properties. - Arzneim. Forsch. - 1972. - V.22. - P.1682-1685.

1. Application dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole of the formula I

as a compound that suppresses the aggregation of red blood cells and reduces blood viscosity and reduces insulin resistance and reducing the tolerance of the body to glucose.

2. Pharmaceutical composition for reducing the insulin resistance and healing tolerance of the body to glucose in diabetes mellitus, prediabetes, insulin resistance syndrome and obesity, as well as overwhelming the aggregation of erythrocytes and neausa blood viscosity, comprising as active principle an dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole of formula I:

taken in an effective amount.

3. The pharmaceutical composition according to claim 2, characterized in that it contains excipients in the following ratio of ingredients, wt.%:
The dihydrochloride 9-diethylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazole, 20-92

Starch, and/or polyvinylpyrrolidone Mm 7800-35000 (PVP),
and/or sodium carboxymethylcellulose (NAKM),
or oksipropilmetiltselljuloza (OPMC)7-40
Calcium and/or magnesium stearates0.3 to 1.0
Microcrystalline cellulose (MCC) and/or lactoseRest



 

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1 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns method for making solid oral pharmaceutical composition containing a hydrophilised form of 5-chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophencarboxaime (I), differing that at first by spraying granulation, a granulated material is prepared. It contains a hydrophilised form of active substance (I). Then said granulated material if necessary is transformed into a pharmaceutical composition with pharmaceutically acceptable additives added.

EFFECT: method allows improving biological availability of the active substance.

6 cl, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and concerns an agent expressing antithrombotic activity and containing an antagonist of purine R2U1-receptors, namely 2-(4-methoxyphenyl)-(9-morpholinoethyl)imidazo[1,2-a]benzimidazole dihydrochloride of formula .

EFFECT: there is described antithrombotic agent affecting regulation of thrombocyte capacity.

3 tbl

FIELD: pharmacology.

SUBSTANCE: there is produced synthetic derivative of phthalyl-glycyl-agginyl-piperidide peptide expressing anticoagulant activity estimated by inhibiting amidolytic thrombin activity in system in vitro and double prolongation of rats' blood plasma coagulation as compared with the control values in tests activated partial thromboplastin and thrombin time tests and having formula 1, including pharmaceutically acceptable salts.

EFFECT: new synthetic peptide derivative expressing anticoagulant activity.

1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for prevention of early postoperative thromboembolic complications in surgeries of pelvic organs. That is ensured by introduction of dissolved ozonised Perftoran in lateral pelvic fat prior to suturing up the incisional wound. In first three postoperative days, heparin is introduced in dose 1.5-2.0 thousand units twice a day in combination with intravenous drop-by-drop injection of Rheopolyglukin solution in a dose 7-8 ml per 1 kg of weight. For the 1st, 3rd, 5th postoperative days, Perftoran solution is introduced intravenously drop-by-drop in a dose 10-15 ml per 1 kg of weight.

EFFECT: higher preventive efficiency of early postoperative thromboembolic complications, three-time lower dosage of heparin.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a new glucitol derivative of formula (I): wherein m represents an integer chosen from 1-3; each R1, R2, R3 and R4 are independently choose from hydrogen atom and benzyl groups; Ar1 represents a naphthyl group which can be substituted by one or more substitutes chosen from the group, consisting of C1-C6alkyl group or halogen atom; A represents 5-7-members aromatic heterocyclic group containing one or more heteroatoms independently chosen from oxygen atom and sulphur atom which can form a condensed cycle with an aromatic carbocycle or an aromatic heterocycle where A can be substituted by one or more Rb provided when A is a benzocondensed cycle containing two or more rings, the group -(CH2)m- is connected with a heterocycle in A; Each Rb is independently chosen from C1-C6alkyl group, halogen atom and C1-C6-alkoxy group; or to their pharmaceutically acceptable salts. These compounds are used as a Na+ cotransport inhibitor and exhibits ability to reduce blood sugar level.

EFFECT: invention covers a pharmaceutical composition based on these compounds and to the method for treatment and prevention of such diseases associated with hyperglycemia, as diabetes, diabetes complications and obesity.

12 cl, 4 tbl, 5 ex

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