N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3- carboxyimidoyl chloride, pharmaceutical composition containing the same and treatment method

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

 

Derived gelegenheid-3-piperidino-2-hydroxy-1-propyl)hydroximino acid, its use in the treatment of immunity to insulin and pharmaceutical preparation containing this derivative as an effective agent.

The technical field to which the invention relates.

This invention relates to a derivative of gelegenheid O-(3-piperidino-2-hydroxy-1-propyl)-hydroximino acid, its pharmaceutical use and pharmaceutical products containing this derivative as the active ingredient. The invention relates to N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino, its stereoisomers, as well as their acid additive salts. In addition, the invention also relates to the use of these compounds in the treatment of immunity to insulin and pharmaceutical products containing these derivative as an active ingredient.

Background of invention

Derivatives gelegenheid O-(3-piperidino-2-hydroxy-1-propyl)hydroximino acid is already known from the description of European patent No. 0417210 B1. According to the description of this patent, these compounds possess selective beta-blocking effect and are therefore suitable for the treatment of diabetic angiopathy (abnormal blood vessels), more to the specific diabetic retinopathy (disease of the retina) and nephropathy.

According to PCT publication WO 98/06400 derivatives gelegenheid O-(3-piperidino-2-hydroxy-1-propyl)-hydroximino acid and other compounds of similar structure is effective for protecting and regenerating endothelial cells of blood vessels, and thus they are suitable active agents for treating diseases caused by endothelial dysfunction.

The increase in actions related to the expression of a number of derivatives of hydroxylamine, among them halides O-(3-piperidino-2-hydroxy-1-propyl)hydroximino acid, and the use of these compounds in the treatment of diseases related to the operation of the associated system known from WO 97/16439. In this patent application N-oxide derivatives of the acid chloride O-(3-piperidino-2-hydroxy-1-propyl)-3-pyridylcarboxylato acid (among others) are defined and claimed in the claims as new compounds, however, describes a method for only the piperidine-N-oxide and compounds containing N-oxide group in piperidinium and the pyridine ring. Compounds of the present invention is not noted in the above-identified application.

Insulin resistance is a pathological disease state, which blocks the action of insulin. Usually it is associated with diabetes, although it is also possible independent education. the consequence of immunity to insulin the body requires larger and larger concentrations of insulin for carbohydrate, fat and protein metabolism, which leads to extremely high concentrations of insulin. It is proved that prolonged high insulin concentration is independent cardio-cerebral-vascular risk factor.

Reducing resistance to insulin is essential for diabetes of both types: in the case of type 2 diabetes is the main etiological factor, whereas in the case of type 1 diabetes insulin resistance is caused by glucose toxicity, and excessive amounts of insulin used exogenous therapeutic purposes.

To reduce resistance to insulin was developed several active agents. Among them the most significant are insulin-sensitizing products, among them the best known agent is troglitazone, representative group of thiazolidine-diones (A.R.Saltiel et al., Diabetes 45/12/1996, pp. 1661-1669 and S.Kumar et al., Diabetologia 1996/39/6, pp.701-709). The main action of this compound is to reduce resistance to insulin by decreasing peripheral concentrations of insulin in the ground state and after glucose stimulation. As a result of this improved carbohydrate metabolism, and also corrected a number of abnormalities that appear as a secondary action of high levels of insulin, such as hyperlipidemia and etologicheskie hemostasis. The final positive action is to reduce the risk of cardiovascular disease. The disadvantage, however, is that can be caused by heavy, mainly hepatotoxic side effects, resulting in the use of these compounds is limited and requires proper precautions.

Summary of the invention

When conducting research in the field of halides O-(3-piperidino-2-hydroxy-1-propyl)hydroxypoly acids was carried out thorough study maleate acid chloride of O-(3-piperidino-2-hydroxy-3-propyl)-3-pyridin-hydroximino acid, known as vimolmal, and found that the most noticeable effect it has on the pathological effects of chronic neuropathy; it significantly improves the lack of speed of motor and sensory nerve conduction in diabetes and also a favorable effect on pathological deviations resulting from autonomic neuropathy. In addition, as in experiments on animals and in testing in phase II on the person he lowered pathological secretion of albumin in the urine in diabetes, and in animals it reduced the pathological histological and electrophysiological changes resulting from diabetic retinopathy. However, for red eye reduction is of immunity to insulin bioklima was ineffective.

At the present time there is no medicinal products, which could reduce insulin resistance and at the same time effectively treat deviations resulting from all three chronic complications of diabetes.

In the search for active substances was investigated biological activity of N-oxide derivatives of bioclave. In the preliminary test was investigated the effectiveness of three N-oxide derivatives of bioclave motor and sensory neuropathy in STZ diabetic Wistar rats. The effectiveness of three N-oxide derivatives of bioclave to improve the lack of speed of motor and sensory nerve conduction caused by streptozotocin-induced diabetes was determined using the method described in experiment 2. The results are presented in the following table 1.

Table 1
GroupnImproving the speed of nerve conduction
motor (MSNP)touch (/MOP)
bioklima 20 mg/kg772,466,9
pyridine-N-oxide derivative of bioclave 5 mg/kg8 66,563,4
the piperidine-N-oxide derivative of bioclave 5 mg/kg834,7*27,3**
dual N-oxide derivative of bioclave 5 mg/kg825,9*29,1**
*p<0,05 relative bioclave

**p<0,01 relative bioclave

From the above results it is obvious that the pyridine-N-oxide derivatives of bioclave equivalent to vimolmal, while the other two N-oxide derivatives have significantly weaker effect on motor and sensory neuropathy. Based on the results of this experiment were continued research pyridine-N-oxide derivatives of bioclave, in particular N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino.

The authors of the present invention obtained the unexpected result that N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridine-1-oxide-3-carboxymethylated reduces peripheral insulin resistance in addition to the presence of steps equal to or in some cases exceeding the action of bioclave in the treatment of three of the above complications in diabetes. Thanks to these characteristics the connection can be used for the treatment of chronic complications when d is Abete, especially retinopathy, neuropathy and nephropathy, and for the simultaneous reduction of peripheral resistance to insulin, and it is also suitable for the treatment of nediabeticescoy abnormal resistance to insulin and any associated pathological disease conditions.

The favorable biological properties of N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino were confirmed in the following experiments. For test data as the study of compounds used maleate of N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino or maleate suitable optically active compounds. In the description of the experiments maleate racemic compounds referred to as a connection, Whereas maleate optically active stereoisomer is always mentioned specifically.

Experiment 1

The treatment effect of the compound a and bipolaron on carbohydrate metabolism, obesity, immune to insulin, hyperinsulinemia rats Zucker fa/fa with impaired glucose tolerance after 2-month treatment

Materials and methods:

In our experiments we used the so-called Zucker fa/fa rats (Charles River Laboratories Inc.). In monozygotic animal obesity, insulin resistance, high levels of insulin in the blood, impaired t is lerotholi to glucose and hyperglyceridemia were the result of mutations hypothalamic latinoware receptor. Due to these characteristics they are adopted model of early type 2 diabetes.

Animals were placed in individual metabolic cages for 24 hours at baseline and after 1 or 2 months of treatment at 24 hours for urine collection.

Animals were given either the compounds or saline using a gastric probe for monitoring once per day between 14-22 weeks.

Biochemical parameters of blood and urine were measured using an automatic analyzer Kodak Ectachem 700. The total level of protein in the urine was determined spectrophotometrically at 595 nm using a staining according to Bradford (Hitachi U-3200). The insulin concentration in serum was determined by radioimmunoassay method (RIA) using rat antiinsulin antibodies.

Systolic, diastolic blood pressure and rate of heart contractions was measured weekly on the tails of rats (the so-called tail-cuff method using an automatic analyzer Letica 200. After two months of treatment to determine the level of tolerance of glucose using intraperitoneal tolerance test glucose (2 g/kg intraperitoneally).

The results:

Bioklima entered in a daily dose of 20 mg/kg orally, significantly reduced the steady level of glucose in the blood, however, he h is impacted on a stable insulin concentration.

In comparison with previous data was obtained an unexpected result, namely, that the compound a, administered in a daily dose of 20 mg/kg orally, significantly reduced steady concentrations of both glucose and insulin, the latter by approximately 50%. The results are presented in table 2.

Table 2

The effect of compounds a and bioclave on a steady concentration in the blood glucose and insulin
Stable blood glucose (mmol/l) value ±Stable insulin in the blood (ng/ml) value ±
Control (skinny)7,197±0,315***3/727±0,302***
Control (obese)9,774±0,34222,882±3,790
Connection8,267±0,436**11,176 what does it change±1,955**
Bioklima8,179±0,316***29,362±9,211
** p<0,001,

***p<0,0001 compared with control for obese

In the process intraperitoneal test glucose tolerance nor vimolmal, no connection And did not affect the area under the curve of blood glucose (AUC). However, in the case of AUC for insulin there is a difference m is waiting for two compounds: bioglobal no effect while the connection And significantly reduces it to the same level, which was observed to control for skinny. The results are presented in table 3.

The table contains values of area under curve (AUC) between 0 to 60 minutes.

Table 3

The treatment effect using bioclave and connections And glucose tolerance in obese immune to insulin, hyperinsulinemia rats Zucker fa/fa with impaired glucose tolerance after treatment for 2 months
Blood glucose (AUC) value±Insulin (AUC) value±
Control (skinny)823,69±60,66***599,49±86,76***
Control (obese)1417,00±159,881986,34±213,84
Connection1418,40±194,57790,35±66,08***
Bioklima1286,86±131,592337,71±590,49
***p<0,0001 compared with control for obese

Summary:

Connection And significantly reduces peripheral insulin resistance, whereas bioklima not decrease.

Experiment 2

The effect of treatments is key connection And and bipolaron on pathological deviations, resulting from peripheral neuropathy, STZ-diabetic Wistar rats after treatment for 1 month

Materials and methods:

In our experiments we used male Wistar rats (Charles River Laboratories Inc.). In the beginning of the experiment they weighed 340-370, Diabetes was induced by the intravenous injection of a single dose of 45 mg/kg streptozotocin (STZ, Sigma, St.Louis, MO), dissolved in physiological saline. Development of diabetes was monitored after 1 day using test glucose in the blood, considering a value greater than 15 mmol/L.

The analyzed and reference compounds were administered to the animals orally once daily.

To determine the speed of nerve conduction (SNP) used the method of Stanly (Stanley), a modified De Konyom (De Konig) and Hispano (Gispen). Animals were anestesiologi simultaneous introduction giorgina (1 mg/kg intraperitoneally, Janssen, Tiburg, Denmark), fluanisone (10 mg/ml) and ventanilla (0.2 mg/ml). Subsequently, the left sciatic and tibial nerves were stimulated at standard points. Used supramaximal stimulus (a square pulse of 0.03 MS) via the stimulator Nihon-Kohden (model SEN-1104, Japan) using a platinum needle electrode. Electromyogram (EMG), transferred from a single muscle, and strengthens the myograph (Elema-Schönander, Stockholm, Sweden), was further analyzed using p is Grammy Matlab for Windows (Mathwork Inc. UK). The degree SNP damage caused by diabetes, expressed in m/s With it compared the efficacy of treatment in terms of percent. Statistical calculations were performed using unpaired t-test or ANOVA test of a single criterion (along with the test Newman-Keuls after that) (Graphpad Instat, San Diego, CA).

The results:

Vimolmal, administered once daily at a dose of 20 mg/kg, and compound a, administered once daily at a dose of 5 mg/kg significantly improved the diabetic animals motor (SNP) and sensory (/MOP) the speed of nerve conduction to the same significant degree. Increasing doses of compounds And more than 10 mg/kg did not increase this effect. The results are presented in table 4.

Experiment 3

The treatment effect of the compound a and bipolaron on pathological deviations resulting from diabetic autonomic neuropathy, in STZ-diabetic Wistar rats after treatment for 1 month

Materials and methods:

In our experiments we used male Wistar rats (Charles River Laboratories Inc.). In the beginning of the experiment they weighed 340-370, Diabetes was induced by intravenous administration of a single dose of 45 mg/kg streptozotocin (STZ, Sigma, St.Louis, MO), dissolved in physiological saline. Development of diabetes was monitored after 1 day with a test for glucose is blood, considering a value greater than 15 mmol/L.

The analyzed and reference compounds were administered to the animals orally once daily.

The experiments were carried out under anesthesia, conducted by the administration of a 60 mg/kg pentobarbital sodium intraperitoneally (Nembutal, Sar ofi, Phylaxia). Then in the femoral artery or vein was injected vnutritraheinogo tube or a polyethylene cannula. The arterial catheter was connected to a voltage Converter for simultaneous measurement of systolic and diastolic blood pressure (operational automatic measuring and transmitting system with a computer program Haemosys). After 20 minute period of equilibration was intravenously injected following chemicals: norepinephrine, 5 µg/kg centuries - isoproterenol of 0.4 µg/kg centuries - stimulation of the vagus nerve (2B, the duration of 500 μs, delay 1 msec). The action of the substances controlled within 10 minutes.

The results:

Autonomic neuropathy is one of the main causes of sudden cardiac death as in case of diabetes, and other diseases (e.g., liver disease). Therefore, all products that could effectively reduce pathological deviations resulting from autonomic neuropathy, are of great importance.

In the experiments a single daily dose of 20 mg/kg or bioclave, whether is about connection And considerably reduces some pathological abnormalities resulting from autonomic neuropathy.

A summary and comparison of results obtained by the authors of the results are shown in table 5.

The double arrow in the table indicates that the test substance is statistically more effective than another connection.

Table 5
Deviations due to diabetesBioklimaConnection
Systemic arterial hypotension↑↑
Weight loss↑↑
Hypertrophy of the left ventricle of the heart↑↑
Reduced NA-induced response in systemic arterial pressure↑↑
Reduced IS-induced systemic arterial hypotension-
Low IS-induced positive chronotropic effect↑↑
Increased negative chronotropic effect on the stimulation of the vagus nerve
Reduced hypotension stimulation bluedude the nerve

NA: noradrenaline ↑: adjusts

IS: isoproterenol -: ineffective

Experiment 4

The treatment effect of the compound a and bipolaron on pathological histological changes caused by early diabetic retinopathy, in STZ-diabetic Wistar rats after treatment for 1 month

Materials and methods:

In our experiments we used male Wistar rats (Charles River Laboratories Inc.), in the beginning of the experiment they weighed 340-370, Diabetes was induced by intravenous administration of a single dose of 45 mg/kg streptozotocin (STZ, Sigma, St. Louis, MO)dissolved in physiological saline. Development of diabetes was monitored after 1 day using test glucose in the blood, considering a value greater than 15 mmol/L.

The analyzed and reference compounds were administered to the animals orally once daily.

After anesthesia (kalipsovet, 125 mg/kg, intraperitoneally, Richter Rt., Hungary eyes willusually and were fixed in 4% formaldehyde dissolved in phosphate buffer (pH 7.4).

Then they were inserted into the wax (Medim DDM P800, a machine for impregnation: Lignifer L-120-92-014, pigment paste for tinting: Shandon Elioti, Microtome: Leica SM 2000R, Microscope: Jenaval Karl Zeiss Jena). Prepared several 6-micron sections of the eye and used hematoxylin/eosin (Fluka) and TIME (period acid-Schiff, Fluka) is Androsterone. Assessed using a light microscope at a magnification increases 40× and 100×. Got pictures and slide positives representative samples.

Conducted histological assessment of encoded samples, the separation of the groups was not known to the researcher. Pathological abnormalities of the retina was graduated on a scale from 0 to 20, whereas deviations for lens - on a scale of 0-3.

Statistical calculations were performed using Statistica 4,5 (SatSoft, USA). Set value for negative cases was 0.1. Also built block and filiform graphic image.

For each group in the experiment was calculated the average value of the ± WITH (standard error) and were compared using the nonparametric U-test Mann-Whitney (Graphpad Instat, San Diego, CA).

The results:

Daily single dose of 5 mg/kg compound a and daily single dose of 20 mg/kg of bioclave significantly improved diabetic retinopathy, caused by pathological histological changes after treatment for 1 month. Of these two compounds, the compound a was statistically more effective when compared with diabetic animals not exposed to processing. The results are shown in table 6.

Table 6

The treatment effect of the compound a and bipolaron on pathological histological changes caused by early STZ-diabetic retinopathy.
The value in points
The average value of the ±Improvement %
Group
Control1,785±0,342100
STZ-diabetes10,571±1,962
SZ-diabetes+20 mg/kg bioklima5,185±1,019*61,3
SZ-diabetes+ 5 mg/kg compound a4,028±0,961**74,5

*p<0,05

**p<0,01 compared to diabetic animals not exposed to processing.

Experiment 5

The treatment effect of the compound a and bipolaron the pathological loss of protein in the urine caused by diabetic nephropathy, in STZ-diabetic Wistar rats after treatment for 1 month

Materials and methods:

In our experiments we used male Wistar rats (Charles River Laboratories Inc.), in the beginning of the experiment they weighed 340-370, Diabetes was induced by intravenous administration of a single dose of 45 mg/kg streptozotocin (STZ, Sigma, St.Louis, MO), dissolved in physiological saline dissolve the E. Development of diabetes was monitored after 1 day using test glucose in the blood, considering a value greater than 15 mmol/L.

The analyzed and reference compounds were administered to the animals orally once daily.

For a 24-hour period of urine collection, animals were placed in individual metabolic cages. During this period, the animals received water as required, but did not receive food. The last measure was necessary to prevent possible contamination of the protein content of the food. Urine was collected in a calibrated glass containers, which placed the crystal of thymol (Reanal 3135-1-08-38) to prevent bacterial contamination.

Before measuring the urine samples were centrifuged (2500 rpm) and filtered through a filter paper (Whatmann 1). If necessary, they kept up measurement at -20°C.

The total protein content in the urine was determined using the method of colouring according to Bradford (Bradford) (Sigma-6916, St. Louis, MO) and the colour intensity was determined spectrophotometrically (Hitachi U-3200).

The results:

Vimolmal, administered in single daily dose of 20 mg/kg, significantly reduced STZ-induced diabetic increased loss of protein in the urine. Connection And entered in a daily single dose of 10 mg/kg, slightly reduced the loss of protein. However, the (+) enantiomer of compound A, is led in a single daily dose of 5 mg/kg, significantly reduced diabetic protein loss. The results are presented in table 7.

Table 7

The treatment effect (+) enantiomer of compound a and bipolaron on the loss of protein in urine, caused by diabetic nephropathy, in STZ-diabetic Wistar rats
24-hour protein loss in the urine (mg/24 h)

The average value of the ±
Group
1. STZ-diabetes8,302±2,40
SZ-diabetes+vimolmal, 20 mg/kg3,66±1,39*

*p<0,05
2.STZ-diabetes13,03±2,63

SZ-diabetes+ compound a, 10 mg/kg12,06±1,70
STZ-diabetes + (+) enantiomer of compound A, 5 mg/kg5,61±1,08*
*p<0,02

Experiment 6

The effect of compounds a and its (+) and (-) enantiomers on pathological changes of peripheral neuropathy in STZ-diabetic Wistar rats after treatment for 1 month

Materials and methods: experimental animals and the methods applied were the same as described in experiment 2.

The results:

Connection And in a single daily dose of 10 mg/kg) and compound a(+) in a single daily dose of 5 mgkg were equally active, and has greatly improved insufficient physical (SNP) and sensory (/MOP) the speed of nerve conduction in diabetic animals. The compound a(-) was not significantly improve actions on each of the parameters. The results are presented in table 8.

Table 8

The effect of compounds a and its(+) and(-) enantiomers at the lack of speed of nerve conduction (SNP) in STZ-diabetic Wistar rats
GroupThe speed of nerve conduction (DPR)
MSNP m/sImprovement %/ MOP m/sImprovement %
Control62,7±0,464,09±0,7
STZ-DB control46,9±0,948,4±1,0
STZ-DB+soeda 10 mg/kg59,3±0,3***78,961,4±0,7***79,2
STZ-DB+A(+) 5 mg/kg58,1±0,5***71,359,7±0,5***68,5
STZ-DB+ A(-) 5 mg/kg53,1±0,7***39,454,1±0,9***34,9
***p<0,001 compared to STZ-diabetic, not exposed to processing

Experiment 7

The effect of compounds a and its(+) and the(-) enantiomers on pathological histological changes in early diabetic retinopathy in STZ-diabetic rats after 2-month treatment

Materials and methods: experimental animals and the methods applied were the same as described in experiment 2.

The results:

A(+) enantiomer in a single daily dose of 5 mg/kg significantly improved the pathological histological changes of the crystalline lens and the retina, caused by diabetic retinopathy after 2 months of treatment, whereas the effect of compounds in a single daily dose of 10 mg/kg was not significant, and A(-) enantiomer in a single daily dose of 5 mg/kg was ineffective. With regard to histological changes of the retina, were effective as compound a and its(+) enantiomer, whereas the action And the(-) enantiomer was not significant. The results are presented in table 9.

Table 9

The effect of compounds a and its(+) and(-) enantiomers on histological changes in early diabetic retinopathy in STZ-diabetic rats
GroupPoints
lens+retin-aRetin-a
The average value of the ±Improvement %The average value of the ±Improvement %
Control0,56 0,361000,46±0,36100
STZ-diabetes6,69±0,76of 4.38±0,68
STZ-DB+soeda 10 mg/kg4,55±0,6934,71,80±0,75*65,8
STZ-DB+A(+) 5 mg/kg4,05±0,80*42,91,68±0,63**68,9
STZ-DB+A(-) 5 mg/kg6,02±1,0910,33,53±1,0721,7
*p<0/05 compared to diabetic, not exposed to processing

**p<0,01 compared to diabetic, not exposed to processing

Experiment 8

Action A(+) and(-) enantiomers on in vivo insulin-dependent glucose uptake using induced food insulin-resistant animal model

Materials and methods:

In the experiment used male Wistar rats (Charles River Laboratories Inc.) with an initial body weight of 300-350 g

Insulin resistance induced by manipulation of food: animals were given within 3 weeks of food with high fat content (residence permit). In the residence permit diet the proportion of saturated fat was the main and gave 70% of the total daily calorie intake. A(+) and(-) enantiomers were given once daily prevention is the label dose of 20 mg/kg/day.

At the end of 3 weeks explored the processing of the following options: 1. carbohydrate and lipid parameters for serum and 2. in vivo insulin-mediated glucose uptake using applicationscope method of fixing the glucose, which is currently the most accurate way to quantify the absorption of glucose (DeFronzo et al., American Journal of discrimination, 1979/237/E214-223 pages). Summary: stable glucose concentration in different groups of animals must be identical. The experiments were performed in conscious, freely moving, constantly kanalirovannykh rats: originally began the introduction of insulin to 6.4 IU/kg/min, and then parallel continuous glucose to maintain the concentration of glucose in the blood in applications.com range. After the stabilization of the number entered glucose was measured for a period of 90 minutes (the rate of infusion of glucose=GVS, mg/kg/min), which is a quantitative parameter of sensitivity to insulin.

The results:

A(+) and(-) enantiomers at a daily dose of 20 mg/kg/min did not affect body weight, food consumption, and sustainable levels of blood glucose in rats.

In contrast, both compounds induced normalize residence permit diet high sustained concentrations of insulin and triglycerides, and significantly reduce the high content of isicelo triglycerides. Test applicationscope fixation glucose showed that the residence permit diet significantly inhibited in vivo insulin-mediated glucose uptake: control: 26,7±0,68 mg/kg/min, residence permit diet: 15,0±0,39 mg/kg/min

This reduced insulin-mediated glucose uptake is increased when using both enantiomers: residence permit+A(+): 20,5±0,89 mg/kg/min/ residence permit+A(-): 19,7±to 1.38 mg/kg/min (significant increase in both cases at the level of p<0,01).

In accordance with these results, both enantiomers increase insulin-mediated glucose uptake, which confirms the new perspectives of the compounds according to the invention, reducing insulin resistance.

Experiment 9

Antidiabetic activity And(+) enantiomers in rats with constant introduction

Materials and methods:

Chose genetically diabetic animal model and were used in the experiments Zucker Diabetic Fatty rats (ZDF). This model represents the diabetes with the option of immunity to insulin, suffering with obesity, but medicationsbuy animal model Zucker fa/fa (see experiment 1). In ZDF rats diabetes develops at the age of 6-8 weeks preceding phase of immunity to insulin.

Action (+) enantiomer was investigated during processing using a dose of 2×20 mg/kg/day, starting in nediabeticescoy phase at the age of 7 weeks and continuing education the processing within 6 weeks.

Clinical chemical parameters were measured by standard methods.

The concentration of insulin in serum was measured using a recently developed method (ELISA method (enzyme-linked immunosorbent assay), DRG International, Inc. USA.

The results:

In this experiment, it was discovered as a new result that A(+) enantiomer has a strong anti-diabetic activity in diabetic animals.

The results obtained after 3 and 5 weeks of treatment are presented in table 10.

Table 10

Fueled by glucose concentration in serum (mmol/l)
Group3 weeks5 weeks
Control6,23±0,08by 5.87±0,08
ZDF18,56±1,9421,28±1,65
ZDF+A(+) 2×20 mg/kg10,82±1,36*13,25±0,76**
*p<0.02 and **p<0.005 in comparison with ZDF, not exposed to processing.

Although treatment And (+) - enantiomer does not normalize the concentration of glucose in the blood, a strong anti-diabetic activity and the previously identified significant therapeutic efficacy, combined together, make the connection at ically character in chronic diabetic complications.

Therapeutic specified region And the(+) enantiomer can be greatly expanded on the basis of this new combination of efficiency.

Subsequent experiments lead to the conclusion that in addition to their effect on the pathological complications of diabetes compounds according to the invention can be used in the treatment of other injuries of the peripheral nerves caused by diabetes. This conclusion is supported by the results of the following experiment neuroregenerative.

Experiment 10

therapeutic effect of compound a and a(+) enantiomer to neuroregeneration in STZ-diabetic Wistar rats

Materials and methods:

The experiments were conducted on Wistar rats with body weight 320-350, Diabetes was induced and controlled as described in experiment 2. When this test in animals suffering from diabetes for 3 weeks, was damaged by freezing the left sciatic nerve, and the nerve on the right side was used as intact controls. Regeneration was observed by monitoring the signals flexor reflex caused by stimulation of the sole, i.e. the area under the curve (AOC) electromyograms transmitted from the anterior tibial muscle. For stimulation and detection used the system described in experiment 2.

A single dose, comprising 10 mg/kg for the compounds a and 5 mg/kg DL is A(+) enantiomer, was administered for 5 weeks after injury by freezing.

The results:

At the end of 3-week period of diabetes before damage through freezing developed sensory neuropathy and caused 23-25% decrease in AUC on both legs. Within 2 weeks after damage by freezing response was not observed. After 5 weeks, the degree of neuroregenerative was 63%. Regeneration was increased to 73% of compound a, And the degree of effectiveness And the(+) enantiomer was 93%. Neuroregenerative in 83% and only 44% was observed for the nerves, not subjected to freezing, as a result of processing And (+) - enantiomer and the connection accordingly. Therefore, A(+) enantiomer has a strong neuroregeneration action.

N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated can be obtained in the following way, which is not known from the prior art.

According to the oxidation method described in WO 97/16349, from the acid chloride O-(3-piperidino-2-hydroxy-1-propyl)-3-pyridin-hydroximino acid can be derived oxidized to nitrogen atoms in both rings, or use a smaller amount of reagent can be derived, oxidized in acyclic ring, as the alicyclic nitrogen atom is preferred for the reaction of okelani is. To obtain compounds according to the invention regioselectivity of oxidation should be directed to the pyridine ring, and thus the method was modified. The main point of the modification is that to facilitate selective oxidation of the pyridine ring percolate oxidation is carried out in the presence of a strong acid, preferably methanesulfonic acid, which protonium alicyclic nitrogen atom and thus prevents its oxidation; therefore, the oxidation of pyridine becomes the primary, as the oxidizing agent can be used any percolate, preferably peracetic acid.

Optically active enantiomers of the compounds according to the invention is obtained using a suitable optically active enantiomer of the acid chloride O-(3-piperidino-2-hydroxy-1-propyl)-3-pyridin-hydroximino acid as the starting material, which can be obtained, for example, according to EP 0417210 B1, by separation of the enantiomers of racemic compounds. During the reaction the chirality of the molecules is not disturbed and the resulting product has the same optical purity as the original substance.

If desired, the obtained N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or one of its optically active enantiomers can be turned from outside time ways in an acid additive salt with a mineral or organic acid.

N-[2-Hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated, its optically active (+) or (-) enantiomer, mixture of enantiomers with any ratio, and a racemic compound, and furthermore, the acid additive salts formed from any of the above compounds with mineral or organic acids, are objectives of the present invention. All possible geometric isomeric forms of N-[2-hydroxy-3-(1-piperidinyl) propoxy] pyridine-1-oxide-3-carboxymethylamino included in the scope of the invention. The term “stereoisomers of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxymethylamino” shall include all possible geometrical and optical isomers of the compounds.

According to the invention these compounds are used to treat abnormal resistance to insulin for the treatment and prevention of related illnesses.

A particular variant embodiment of the invention is one in which data connections are used for simultaneous treatment or prevention of chronic induced diabetes complications, especially retinopathy, neuropathy and nephropathy, and pathological immunity to insulin and related pathological disease conditions.

According to another particular variant embodiment invented the I N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or its stereoisomers or their acid additive salt is used to treat abnormal resistance to insulin and related pathological disease conditions and simultaneous increase induced diabetes pathologically reduced peripheral neuroregenerative.

Compounds of the present invention can be used for the treatment of human and veterinary medicine.

Therefore, an object of the present invention is also a method of treating a pathological resistance to insulin and the treatment and prevention of associated pathological disease conditions, with patients given N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or one of its stereoisomers, in the form of a base or an acid additive salt. The preferred embodiment of the method according to this invention is one in which the patient suffering from diabetic retinopathy, neuropathy or nephropathy, enter N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or one of its stereoisomers, or an acid additive salt.

According to another particular variant embodiment of the invention N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or one of its stereoisomers, or its acid additive salt is administered to the patient in the case of pathological reduction neuroregenerative caused by diabetes.

The dose of a compound depends on the t condition and disease of the patient, and the daily dose is 0.1-400 mg/kg, preferably 0.1 to 100 mg/kg In the treatment of human oral dose is preferably 10-300 mg, in the case of rectal introduction 1-15 mg, whereas parenteral she is 1-15 mg for an adult patient. These doses are preferably administered in the form of preparative dosage forms, which in some cases can be divided into 2-3 smaller doses a day, especially in oral treatment.

Preferably use a stereoisomer of racemic compounds, most preferably the (+) enantiomer. In this case, to ensure sufficient is a smaller amount of active ingredient in the above ranges.

Pharmaceutical preparations suitable for treatment, are also an object of the present invention. Data pharmaceutical compositions contain, in addition to the usual auxiliary substances and carriers, as an active ingredient N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated or one of its stereoisomers, or an acid additive salt of one of them.

The pharmaceutical compositions according to this invention can be obtained in the form of a solid or liquid formulation commonly used in the treatment of human or veterinary medicine. Can be obtained through simple Liparite shell tablet, pills, granules, capsules, solutions or syrups for oral administration, suppositories for rectal administration and liofilizovannye or heliopolitanus injection or infusion solutions for parenteral administration. They can be obtained in the usual way. Products for oral use contain fillers, such as microcrystalline cellulose, starch or lactose, lubricants, such as stearic acid or magnesium stearate, coating materials, such as sugar, film-forming materials such as hydroxymethylcellulose, flavorings or sweeteners such as methylparaben or saccharin or dyes. Suppositories can contain cocoa butter or polyethylene glycol as auxiliary substances. Parenteral products may contain, in addition to effective substance, saline solution, or in some cases, dispersing and wetting agents such as propylene glycol.

The invention is additionally illustrated by the following examples:

Example 1

Obtain (Z)-2-butenedioate N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated (1:1)

of 40.4 g (0,136 mol) of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridine-carboxymethylated dissolved in a mixture of 238 ml of glacial acetic acid and 13.0 g (0,136 mol) is ethanesulfonic acid. At 60°add to 61.5 ml (0,591 mol) of 30% hydrogen peroxide solution. The reaction mixture was stirred at 60°With over 3.5-4 hours. The solution is cooled to 10°and then add to it the 91 ml of 0.5 M solution of Na2S2O5. From the solution is distilled 315 ml of a mixture of water-acetic acid to the residue add 250 ml of 4n. NaOH solution (pH 10,55) and shaken with chloroform. Phase containing chloroform, washed with water, dried, treated with activated charcoal and then evaporated. To the residue water is added and extracted with isopropyl ether and then with chloroform. Phase containing chloroform, dried, treated with activated charcoal, filtered and evaporated. The residue is dissolved in acetone and converted into the salt with maleic acid. The precipitate is filtered off, washed with acetone and dried. The product is crystallized from boiling ethanol.

Yield: 20 g (35%)

TPL 150,5-154,5°

1H-NMR (solvent DMSO; relative to DMSO; ν=300 MHz) [ppm]: 8,55 (s, 1H, 2-pyridine); 8,35 (d, 1H, 6-pyridine); to 7.68 (d, 1H, 4-pyridine); at 7.55 (m, 1H, 5-pyridine); 6,00 (s, 2H, CH=CH); 4,23-4,48 (m, 3H),HE NOCH2); 2,95-3,50 (m, 6N, 3 × NCH2); 1,20-1,90 (m, 6N, piperidine; 3 × CH2).

13C-NMR (solvent DMSO; relative to DMSO; ν=300 MHz) [ppm]: 167,6 (2C, 2 COOH); 141,0 (2-pyridine); 136,8 (6-pyridine); to 136.4 (2C, CH=CH); 33,4 (CCL); 131,9 (3-pyridine); 127,2 (4-pyridi is); 123,6 (5-pyridine); 77,9 (DOWN2); 63,6 (CH2N); 58,3 (SNON); 52,0-55,0 (2C, piperidine; 2 × NCH2); and 22,6 21,7 (3S, piperidine; 3 × CH2).

Example 2

Obtain (Z)-2-butenedioate (+)-/R/-N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated (1:1)

Repeat the procedure of example 1 with the difference that instead of the racemic N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridine-carboxymethylated use its R enantiomer. Pure form compounds isolated from the crude base by crystallization from hexane.

Yield: 31%

TPL: 91-93°

IR spectrum (KBR, cm-1): 3167 (Shir.); 2840; 2710; 1575; 1560; 1480; 1443 (W); 1293 (C); 1279 (); 1093; 1053; 1043; 1023 (C); 834 (); 810; 688

If desired, from the crude base in acetone solution can also be obtained malata salt as described in example 1.

Output: 33%

TPL: 132,0-133,0°

The ratio of enantiomers: 98/2 (HPLC measurements on chiral AGP column 100×4 mm)

1H-NMR and13C-NMR are the same as the spectra of racemic compounds.

Example 3

Obtain (Z)-2-butenedioate (-)-/S/-N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated (1:1)

Follow the procedure of example 1 with the difference that instead of the racemic N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboxymethylated use its S-enantiomer.

Yield: 34%

So what.: 132,0-133,0° With

The ratio of enantiomers: 98/2 (HPLC measurements on chiral AGP column 100×4 mm)

1H-NMR and13C-NMR are the same as the spectra of racemic compounds.

Example 4

Tablet

(+)-N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-

oxide-3-carboxymethylated 20.0 mg

Corn starch 100.0 mg

Lactose 95,0 mg

Talc 4.5 mg

Magnesium stearate 0.5 mg

The finely ground active ingredient is mixed with the auxiliary materials, the mixture homogenized and granularit. Then the granulate is pressed into tablets.

Example 5

Capsule

Maleate (+)-N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-

oxide-3-carboxymethylamino 20.0 mg

Microcrystalline cellulose 99,0 mg

Amorphous silicon dioxide 1.0 mg

The finely ground active ingredient is mixed with the auxiliary materials, the mixture homogenized and fill it gelatin capsules.

Example 6

Pills

N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-

oxide-3-carboxyethylgermanium 25.0 mg

Lactose 82,5 mg

Potato starch of 33.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 0.5 mg

The active ingredient and the polyvinylpyrrolidone is dissolved in ethanol. A mixture of lactose and potato starch evenly moistened granulating solution of the active ingredient.

After filtration of the granulate is dried at 50°and sieved. Add the magnesium stearate and pressed into tablets, which are then covered by the sugar-coated and polished with beeswax.

Example 7

Suppository

(+)-N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-

oxide-3-carboxymethylated 4.0 mg

Cocoa butter 3.5 g

Solid fat mass to 50

suppositories 15.0 g

Cocoa butter and weight for suppositories heated to 40°and the active ingredient is dispersed in the molten mixture, then the mass fill the form of suppositories.

Example 8

Solution

(+)-N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-oxide-

3-carboxymethylated 500 mg

Sorbitol 10 g

Saccharin sodium 0.05 g

Bidistilled water as you need to

100 ml

Example 9

Injection

(+)-N-[2-hydroxy-3-(1-piperidinyl)-

propoxy]pyridine-1-oxide-3-

carboxyethylgermanium 2 mg

Physiological saline, and pyrogen-free, as required sterile solution to 2.0 ml

The solution is poured into 2 ml ampoules and sealed.

Example 10

Infusion solution

Received 500 ml of infusion solution of the following composition:

N-[2-hydroxy-3-(1-

piperidinyl)propoxy]pyridine-1-oxide-

3-carboxyethylgermanium 20.0 mg

Physiological saline, and pyrogen-free, skolik will need to

sterile solution to 500 ml

1. N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated, its stereoisomers and acid additive salt.

2. A method of treating a pathological resistance to insulin and related pathological conditions, which includes the introduction of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxymethylamino or one of its stereoisomers patient in the form of a base or an acid additive salt.

3. The method according to claim 2, which includes the introduction of N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino or one of its stereoisomers, in the form of a base or an acid additive salt to a patient suffering from diabetic retinopathy, neuropathy and/or nephropathy.

4. The method according to claim 2, which includes the introduction of N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylamino or one of its stereoisomers, in the form of a base or an acid additive salt to a patient in the case of pathological reduction neuroregenerative caused by diabetes.

5. Pharmaceutical composition for treating abnormal resistance to insulin and related pathological States containing N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboxymethylated, or one of its stereoisomers, or its keys, the ratio of the additive salt as an active ingredient in a mixture with, at least one commonly used pharmaceutically acceptable auxiliary substance or medium.



 

Same patents:

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention proposes two variants of the improved method for preparing anti-ulcerous therapeutic agents of the formula (I): wherein radicals R1-R6 have values given in cl. 1 and cl. 2 of the invention claim. Method involves interaction of corresponding sulfides with m-chloroperoxybenzoic acid in acetone or a mixture acetone/water as a solvent. According to the first variant pH value of the reaction mixture is increased to the value above 7 after the reaction interaction and solvent is removed and crystals of compound of the formula (I) are separated. According to the second variant the interaction is carried out at pH ≥ 7.0 followed by addition of water if necessary and compound of the formula (I) crystals are separated. Invention is directed for preparing omeprazole or pantoprazole preferably. Invention provides preparing the end products of high purity and with high yield.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

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EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a form with reduced size of particles of the compound (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid described by the formula (I)

or its pharmaceutically acceptable salt or any solvate. Above said compound is useful in treatment of metabolic disorders, such as insulin resistance syndrome determined as reduced sensitivity to insulin effect. Also, invention relates to pharmaceutical compositions containing form with reduced size of particles of this compound or its pharmaceutically acceptable salt or their solvate as an active component, and to methods for preparing form with reduced size of particles of this compound or its pharmaceutically acceptable salt.

EFFECT: improved preparing methods, valuable medicinal properties of compound.

12 cl, 5 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

FIELD: pharmaceutical agents, in particular glyburide containing composition.

SUBSTANCE: claimed composition contains 5-chloro-N-[2-[4-[[(cyclohexylamino) carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide, known under generic name as glyburide, and has the next grain-size classification (%): undersize of 3-11 mum - 25; undersize of 6-23 mum - 50 %, and undersize of 15-46 mum - 75 %. Such grain-size classification affords the ability to increase glyburide dissolution rate and provide reproducible biological availability of glyburide.

EFFECT: pharmaceutical composition useful for treatment of II- type diabetes.

11 cl, 2 tbl, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

The invention relates to new derivatives and analogs 3-arylpropionic acid having the General formula (I), and their stereo and optical isomers and racemates, as well as their pharmaceutically acceptable salts, wherein in the formula And is located in the meta - or para-position and represents a

where: R represents hydrogen;

-ORawhere Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRaRbwhere Raand Rbare the same or different and represent hydrogen, alkyl, phenyl, alkylphenyl, cyano;

R1represents alkyl, cyano;

-ORewhere Rerepresents alkyl, phenyl or alkylphenyl;

-O-(CH2]m-ORfwhere Rfrepresents alkyl, and m is an integer of 1-2;

-SRdwhere Rdrepresents an alkyl or phenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-COORdwhere Rdrepresents alkyl;

R2represents hydrogen or alkyl;

R3and R4

D is situated in the ortho-, meta - or para-position and represents a

-OSO2Rdwhere Rdrepresents alkyl, phenyl or alkylphenyl;

-OCONRfRawhere Rfand Rarepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCOORdwhere Rcrepresents hydrogen or alkyl and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCORawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcRdwhere Rcand Rdrepresent hydrogen, alkyl, phenyl or alkylphenyl;

-NRcSO2Rdwhere Rcrepresents hydrogen or alkyl, and Rdrepresents alkyl, phenyl or alkylphenyl;

-NRcCONRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, alkyl, phenyl or alkylphenyl;

-NRcCSNRaRkwhere Rcrepresents hydrogen, Raand Rkare the same or different and each represents hydrogen, phenyl иLASS="ptx">-SRcwhere Rcrepresents alkyl, phenyl or alkylphenyl;

-SO2ORawhere Rarepresents alkyl, phenyl or alkylphenyl;

-CN;

-CONRcRawhere Rcrepresents hydrogen or alkyl, and Rarepresents hydrogen or alkyl;

D’ is located in the meta-position and represents-ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

D’ is located in the ortho - or para-position and represents-NO2, -ORfwhere Rfrepresents alkyl; or is located in the ortho-, meta - or para-position and represents hydrogen;

where specified, the alkyl means a straight or branched alkyl group having from 1 to 6 carbon atoms, or cyclic alkyl having from 3 to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one group of alkyl, alkoxy, halogen or phenyl; where the specified phenyl may be substituted by one or more than one group of alkyl, alkoxy, nitro, thiol, or halogen; the invention also relates to a method of their production, pharmaceutical preparations containing them, the Sabbath.

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction

The invention relates to medicine and can be used as a means of regulating the level of glucose for the prevention and treatment of diabetes

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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