1,3-di(3-piperidine-2-hydroxypropyl)-6-methyluracil for increase of capacity for survival and yeild of poultry

FIELD: chemistry.

SUBSTANCE: invention refers to veterinary science, in particular to products intended to increase capacity for survival and yield of poultry. For this purpose common composition 1,3-di(3-piperidine-2-hydroxypropyl)-6-methyluracil of formula: is used. Composition is characterised by natural resistance, antioxidant activity, activates nonspecific factors of immune system, as well as possesses medicinal properties to provide detoxification of nitrates and nitrites. Composition has the appearance of white powder, is highly soluble in water and can be added in specified doses to chickenfeed.

EFFECT: production of composition providing increase of capacity for survival and yield of poultry.

6 tbl, 5 ex

 

The invention relates to a tool representing DPOA that increase the safety and productivity of birds, to enhance natural resistance and antioxidant protection of the body, for the prevention and treatment of nitrate intoxication.

The prototype of the invention is to oximetery (WMD) [1]. Chemical name auximetilurazil-oxy-6-methyluracil

The structural formula. Empirical formula C5H6N2About3.

The disadvantage of the prototype is a weak antioxidant protection.

DPOA-1,3-Bis(2'-hydroxy-3'-piperidinoethyl)-6-methyluracil corresponds to structural formula

. Empirical formula - C21H36N4O6. The connection is well known and has a biologic response modifier, antioxidant, and anti-inflammatory action. The authors of the present invention was found a new effect : therapeutic properties of the compounds in the administration of nitrites and nitrates.

The invention allows to obtain a new technical effect of improving the safety and productivity of birds, for the treatment and prevention of diseases of birds, including nitrate of intoxification.

The scheme of synthesis DPOA. 1,3-Bis(2'-hydroxy-3'-piperidinoethyl)-6-methyluracil get method [2]. To 33,9 g (0,109 mol) 1,-bis(2'-hydroxy-3'-chloropropyl)-6-methyluracil in 250 ml of methanol are added 82.8 g (0.6 mol) 2CO3and then added dropwise to 25.5 g (0.3 mol) of piperidine for 30 minutes the Reaction mixture was stirred 1 h at room temperature, then at 60-65°C for 3 h and left overnight. The next day precipitated salt is filtered off, the mother liquor is distilled off the solvent under reduced pressure and obtain 41.8 g (94%) of 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-6-methyluracil in the form of a yellow semi-crystalline mass. The substance contains 4 molecules of water. C21H36N4O6·4H2O. Rf=0,65. The product is soluble in water (6%); benzene, alcohol, acetone, chloroform, and insoluble in pentane, hexane. IR spectrum (v, cm-1): 1050-1250 (VN=c); 1670-1715 (Vc=o =N-C=o); 3400. (H2O). NMR1H (CDCl3), δ, ppm: 1.4 to about 1.75 (m, N, 4BCH2, 2CCH2); 2,266 (m, 3H, CH3-With6); and 2.3 to 2.6 (m, 8H, 4CaH2); 3,29 (t, 4H, J 5.6 Hz, With9,12H2); of 3.48 (t, 2H, J 5.6 Hz, With8,11N); 3,7-3,95 (m, 4H,9,12H2); 3.95 to to 4.15 (m, 2H, WITH8,11-HE); 8,00 (s, 1H, WITH5H). NMR13With (CDCl3), δ, ppm: 162,44. (With4=O); 153,25 (2=O); 144,66 (6); 100,00 (5); 14,62 (CH3-Withb); 66,39 (8); 65,79 (11); 57,78 (9,12); 54,49 (4a); 51,48 (7); 47,42 (10); 26,13 (46); 24,64 (2c).

The product has the appearance of white powder, soluble in water, introduced in the definition is the R doses in food animals and birds. Has a faint smell of sour milk.

Comes in a 3% and 5% powder.

Sredneseriynoe dose for white mice is for white mice 4450,0±49,1; for white rats 4200,0±51,2.

Sredneseriynoe dose auximetilurazil for white mice 2720,0±37,8; for white rats 3000,0 42,6.

The preparation should be stored in containers in a dry, dark place at temperatures from minus 20°C to 40°C.

The shelf life is 3 years from date of manufacture.

The essence of the technical solution is illustrated by the following examples.

Example 1. Influence DPOA on the immune system of chickens.

The study of the effects DPOA on non-specific parts of the immune system of chickens it is shown that all the original factors of nonspecific immune protective factors did not differ significantly from the values of the control group and the immune system of subjects of birds prior experience corresponded to its normal values.

From table 1 it is evident that the preparation of comparison oximetery dose of 50 mg/kg sharply reduced phagocytic activity of chickens (phagocytic number on br15.15% and phagocytic index 8.3%). Significantly decreased and absorption activity pseudosinella. So when spontaneous NBT-test the activity index of pseudosinella decreased by 25%, and with the induction of pseudosinella latex in the "induced" nst-Neste - 15.6%. Similarly, the decrease in p is creased activity faguoqitirute cells with the introduction of oxymethyluracili in chickens was a decrease and the level of activity of complement by 26%.

Application DPOA showed that in contrast to the comparison drug (oxymethylphenyl) connection has an activating effect on the nonspecific immune system factors (on the phagocytic immune system and the level of serum complement activity).

Indicators of absorptive activity of phagocytes in the application DPOA dose of 50 mg/kg significantly increased when compared to the control group, and their level in the group treated with oximetery (phagocytic number of 18.2% and 39.3%, as well as phagocytic index by 21.4% and 32.3%, respectively). The indicators of the functional activity of neutrophils in the test recovery narasinga of tetrazole when applying the study of the complex showed that significantly increased the ability of pseudosinella to intracellular digestion.

Table 1
Influence DPOA on the indices of non-specific immune system in peripheral blood of chickens (n=20)
GroupDose, mg/kgPhagocytosisNst-testLevel complem. (CH50)
FC, %PHI, % neutrophilsSpent.In-Doc lat CEN
Baseline before applying medication-3,50±0,330,40±0,040,19±0,010,49±0,0434,0±0,35
DPOA504,00±0,15*#0,45±0,03*#0,24±0,01*#0,48±0,03*#37,9±0,42*#
DPOA753,69±0,09*#S0,40±0,02*#0,20±0,01*#S0,48±0,02*#36,9±0,50*#$
WMD (prototype)502,80±0,20*0,33±1,20*0,15±0,02*0,40±0,01*24,9±1,40*
Control-3,2±0,140,36±0,500,17±0,020,46±0,0531,1±0,8
Note:* - differences with the control group statistically significant, (p<0,05);
# - differences with group oximetery statistically significant (p<0,05).
$ - differences with the group treated DPOA dose of 50 mg/kg, statistically significant (p<0,05).

Thus, the activity index of psev is eosinophiles in "spontaneous" test increased as compared with intact animals by 50% and with the group treated with oximetery 2 times. When the induction of immune responses latex particles this increase was less pronounced (by 6.7% and 26.3%, respectively). Figure humoral non-specific immune activity of complement in serum (CH50) significantly exceeded the comparison values of the control groups in chickens, significantly exceeded the comparison values of the control groups in chickens treated with oximetery (26% and 70.2 per cent respectively).

When applying DPOA dose of 50 mg/kg in chickens, it was found that a further increase in the dose used, the connection is impractical. So if you increase the dose to 50 mg/kg to 75 mg/kg decrease in the stimulatory effect on the nonspecific immune system factors. Significantly decreased the number faguoqitirute cells (6.1%), also decreased the spontaneous activity index of neutrophils (18.7%), and the level of activity of complement decreased by 4.2%. However it is noted that these values remained significantly higher than control values.

Example 2. Influence DPOA on quality parameters of eggs of chickens.

Proper organization of housing, feeding and mandatory sanitary control ensures the production of ecologically pure products of high sanitary quality, and guarantees the protection of the public about the diseases common to animals and humans.

At the age of 120 days 2 groups of young chickens were transferred to the Department of industrial herds. In the research and production experience to 6000 hens-layers found that the incorporation in the diet connection DPOA dose of 50 mg/kg for 5 days has a positive impact on the safety and productivity of birds.. it is Established that during the period of the experiments in the control group departure was 50 goals (1,73%), while in the experimental group only 8 goals (0,26%).

Table 2
Influence DPOA on quality parameters of eggs
IndicatorsControlDPOAWMD (prototype)
The mass of eggs,49,0±0,8556,6±0,9050,0±1,1
The shell thickness, mm0,350±0,010,370±0,010,351±0,01
The relative mass of the shell, g5,91±0,130,32±0,15of 5.92±0,15
The index of the protein, %6,80±0,207,22±0,226,89±0,19
The yolk index, %47,2±0,5150,9±1,447,8±0,72
The mass of yolk, g12,0±0,41 14,9±0,3012,1±0,45
Protein mass, g27,7±0,5233,9±1,5227,9±0,68
The density of eggs, g/cm31,0791,0871,080
Vitamin a, g/g5,22±0,296,22±0,295,51±0,32
Vitamin B2g/g1,61±0,051,92±0,221,70±0,04

At the end of the experience egg production in the control group increased in comparison with the beginning of the experience of 1.81%, in the experimental group increased egg production totaled 11,84%, which allowed to obtain 30 days additionally 132 eggs per 100 hens. In addition, we found a higher content of vitamin a - 19,23% and vitamin b2on 17,28% (tables 2, 3).

Waste for the period of experience in the control group was 16.6%, and experienced 0,13%. Egg production in the beginning of the experiment, 100 hens 71.7 units in the control group, the experimental group 71,8 pieces, and the end of the experiment in the control group 73,9 pieces, experienced 82,3 pieces. Additionally obtained for the whole period of experiment 100 hens 147 eggs. Thus, the use of DPMU dose of 50 mg/kg in diet composition of laying hens reduces mortality, culling birds and increase its productivity.

Application DPOA chickens-ness what am contributes to the conservation Fund biooxidation as in the body of the bird, and the egg, which improves its quality indicators and increases the nutritional value. WMD reduces the mortality of birds in 31 times, however, the egg production compared with the control group were not significantly changed.

Table 3
Influence DPOA on the safety and productivity of chickens
IndicatorsControlDPOAWMD (prototype)
The number of chickens, a goal.300030003000
Waste for the period of experience:
Goals50416
in %16,6%0,13%0,53%
Including case, a goal.27312
in %0,9%0,1%0,4%
Has killed, a goal.2314
in %15,70,30,13
Egg production in the beginning of the experiment, PCs per 100 hens71,771,872,1
Egg production at the end of the experiment, PCs per 100 hens73,9 82,374,6
Received additional eggs for the whole period of experiment 100 hens, PC30,814735

Example 3. Influence DPOA on indicators of egg incubation.

The experiments were conducted using eggs obtained from hens of parent flock experimental and control groups. For incubation were selected eggs from each group of 100 pieces. Incubation of eggs was carried out in incubation cabinets type CSI-f-45 with adherence and conditions of incubation under constant control of the operator for incubation and electrician specialist in the incubation cabinets.

Indicators of incubation, we determined: egg weight (g), the height of the air chamber (mm), oplodotvorennogo eggs, hatchability, livability. The picture of the anatomic changes the character of the anomalies.

The impact of the new derivative of pyrimidine DPOA in different doses on indicators of egg incubation are shown in table 4.

From the table it is seen that the eggs obtained from all groups of laying hens, suitable for incubation. Significant changes in data - height air chamber, we have not installed. Data of fertilisation of the eggs showed that a high percentage (95%) was noted in the 2nd group, lower in the 1st and the control group (90,3% and 90.0%, respectively). Hatchability of eggs in the first group amounted to 90.3%, in the second group - 95,0%control to 90%. The safety of the Chicks during the first 3 days of life, in all experimental groups was high and ranged from 87,0% to 88.0%, while in control group it was 75.0%. In eggs of hens in the control group awesomechickin method were found frozen embryos and shadowlike". The study of patterns of pathological changes "sadahiko" showed characteristic phenomena, as stunting, distortion of limbs, swelling of the skin, underdevelopment, curly tail and other signs of metabolic disturbances that were observed in eggs obtained from experimental birds.

Analyzing the impact of the new derivative of pyrimidine DPOA on indicators of egg incubation, it should be noted improving the quality of hatching eggs, getting healthy Chicks and high safety during the use of these drugs.

Table 4
Influence DPOA on indicators of egg incubation
the number of drug doseQty laid down for hatching eggs, piecesThe mass of eggs,The height of the air chamber, mmFrozen embryos, %Sacklike, all %Anomalies in the development, %Hatchability, %Save the oneness of chickens within 3 days %
1. DPPEA at a dose of 75 mg/kg10054,0±2,202,48±0,194,04,025,092,3of 87.0
2. DPOA dose of 50 mg/kg10058,0±1,862,46±0,163,04,025,0for 95.288,0
3. WMD (prototype)10051,2±1,22,49±0,176,06,028,091,086,0
4. The control group10050,0±1,32,50±0,117,08,050,090,075,0

Example 4. Influence DPOA on the processes of lipid peroxidation and antioxidant defense system of chickens

Currently, it is proved that the processes of free radical oxidation of lipids are one of the most important aspects of metabolism and play an important role in maintaining life processes. The stationary level of intensity of lipid peroxidation (LPO) is characteristic for all normal cells and tissues and is one of the main biological tools modify the properties of biomembranes and membranostabilizing processes. The intensity of Yunosti this class of biochemical reactions in the body, on the one hand, is determined by the activity systems that generate free radicals and, above all, active forms of oxygen, on the other hand, multi-level system of antioxidant protection. Adequacy of protection against excessive formation of reactive oxygen species is provided by the consistency of the actions of all parts of the antioxidant system, and each component operates in a well-defined borders at various stages of free radical oxidation of lipids. Failure in compliance of these systems leads to uncontrolled activation and accumulation in the body of toxic products in the FLOOR, which inhibit cellular mechanisms of energoobespechenija, inhibits a large number membranes.obesity enzymes, biosynthesis of proteins and nucleic acids, disrupt the processes of cell division, differentiation, permeability, transport of substances across membranes. Therefore, the intensity of the flow of peroxidation processes and the functional state of different parts of the antioxidant system is of paramount importance in implementing the body's protective and adaptive reactions, maintaining homeostasis, and in the course and outcome of various pathological processes.

In biochemical studies have widespread method for the determination of carbonyl products of lipid peroxidation, in cast the STI formation by the reaction of 2-thiobarbituric acid.

In chickens treated with DPOA for 5 days at a dose of 50 mg/kg body weight of the birds, in comparison with females of the control group showed a lower concentration of primary and intermediate products of lipid peroxidation.

Table 5
Influence DPOA on the processes of lipid peroxidation and antioxidant protection of birds (n=30)
IndicatorsThe source dataAt the end of the experiment
controlexperience
Conjugated diene unit opt. PL/mg lipids0,25±0,0590,259±0,0220,152±0,02
Malonic dialdehyde, m/l1,58±0,0621,50±0,021,20±0,06
The glutathione peroxidase G-SH/l.min9,70±0,629,43±0,79up 11,86±0,60
The glutathion reductase G-SS-G/l.min149,2±5,32137,2±9,8162,2±9,8
Catalase, TNM2About2/l.min44,6±3,638,8±1,1633,0±2,2
Note: P<0,05

Thus, the level couger is of dienes in the blood of experimental birds was lower than the control on 42,09%, and malondialdehyde in 20,19%. Experienced hens installed a tendency to increase the level of glutathione peroxidase in 20,14%, glutathione reductase on 25,79% and catalase 13,13% (P<0.05 with respect to control group) (table 5).

Table 6
Influence DPOA on the level of vitamins a and E in the body of chickens (n=30)
IndicatorsGroups of animals
The source dataControlExperience
Blood
Vitamin E, m/l23,3±1,224,0±0,3029,2±1,85
Vitamin a, m/l2,30±0,222,41±0,203,29±0,29
Liver
Vitamin E, m/l41,8±2,442,9±2,660,3±2,92
Vitamin a, m/l27,8±0,9229,0±0,8245,7±2,22
Note: P<0,05

Regulation of lipid peroxidation is carried out by enzymes: catalase, oxidase and glutathione peroxidase. The Central place in nonenzymatic link antioxidan the Noah protection is such a fat-soluble vitamin, as tocopherol (Vitamin E), to a much lesser extent carotene and retinol (vitamin a).

Increasing the level of vitamin E on 21,757% in the blood and 40,42% in the liver, vitamin And 36.6% in the blood and 56,01% in the liver, carotene, glutathione peroxidase, glutathione reductase and decreased malondialdehyde and catalase activity after application DPOA in the studied dose of 50 mg/kg indicates the beneficial effect of study drug on metabolic processes in the body (table 6).

In our opinion, DPOA inhibits the processes of destruction of the biological and functional activity of glutathione reductase and glutathione peroxidase, and functioning in animals mechanisms of antioxidant protection play a vital role in maintaining homeostasis.

Thus, the use of complex compounds DPOA dose of 50 mg/kg reduces in the body products of lipid peroxidation, a trend toward increasing the level of glutathione peroxidase, vitamin a and E.

Example 5. Antitoxic properties DPOA.

The experiments were conducted at 60 geese Hungarian breed, divided into 6 groups (1 control and 5 experimental). Acute toxicity reproduced by introducing the probe into the stomach of an aqueous solution of sodium nitrate at the rate of 500 mg/kg. Animal 4 groups every day additionally gave DPOA in doses with the responsibly of 50 and 100 mg/kg once daily for 7 and 14 days, geese one experimental group after priming was obtained only isotonic sodium chloride solution. The control were intact animals.

The liver of animals killed 24 hours after injection of sodium nitrate at a dose of 500 mg/kg was slightly increased in volume, the edges rounded, the shape is not changed, motley painting dominated plots cherry red color, the cut surface was bathed in blood, lobed structure is weak. Individual slices were stained in dark red color, giving these areas a marble appearance.

At low magnification microscope drew attention to the fact that the Central vein and draining into them sinusoids were dilated and filled with blood. On the periphery of the lobules hyperemia expressed weaker. Hepatic plates slightly thinned and separated from each other or even observed their discomplete.

At high magnification it was clear that the boundaries of hepatocytes blindly, their nuclei in the bulk is reduced, dark colored. In some hepatic cells could be detected yellow-brown or brown grains of pigment lipofuscin. On the periphery of the lobules, swollen hepatocytes, their cytoplasm muddy, rich granules or droplets of protein nature. Some hepatocytes were increased, with large nuclei, or even contained two nuclei.

In a separate slices centre who have been severely damaged. Around the Central vein hepatocytes contained small drops of fat, resulting boundaries of the cells were viewed poorly or were not visible. The nucleus in some cells were enlarged, poorly painted, others were noticeable only by their outlines, and in some they were absent (karyolysis). In the zone of necrosis was observed cellular detritus, among which was the red and white, brown glybki pigment macrophages. Cells von Kupffer were able resorptive obesity.

Through 7 days after the administration of sodium nitrate, the liver was enlarged. The consistency of it was loose, the surface of the body was unevenly colored, with patches of yellowish color, delicately expressed. Histological examination on the first plan were degenerative changes in the hepatocytes. The structure of the hepatic cords are broken. Hepatocytes are enlarged, irregular polygonal or rounded shape, with mesh or reticulated cytoplasm, especially on the periphery of the lobules. Jumper between cells represented the remnants of the cytoplasm. The nucleus of hepatocytes was in the center, reduced in volume, wrinkled, irregular angular shape. In some areas, was diagnosed with micronecrosis parenchyma of the organ.

Central vein and sinusoids were dilated and filled with blood, but the phenomenon of venous hyperemia expressed not as bright as h is rez 24 hours after poisoning. Midorikawa connective tissue, portal areas, areas of micronecrosis infiltrated lymphoid, plasma cells, histiocytes and fibroblasts.

In areas of the liver with relatively well-preserved parenchyma was observed an increase in the number of hepatocytes with signs of hyperplasia. This was evidenced by the increase in the number of nucleoli, the number of dual-core and dividing liver cells. Apparently, undamaged hepatocytes were significantly activated to compensate for the failure associated with reduced function of cells in lipogenesis. Thus, by 7 days after poisoning in the liver developed parenchymatous hepatitis, characterized by prominent alterative changes in the parenchyma of the organ, the infiltration of the stroma of the organ cells, blood-borne and tissue of origin, stagnation.

After 14 days the liver characterized by the following morphological changes. The periphery of the liver lobules were stained lighter due to the predominance of cells, containing small and medium-sized lipid droplets. The heart slices were characterized by a predominance of closely located to each other hepatocytes with grains protein nature in the cytoplasm and pinnatifida cores. Central vein and sinusoidal capillaries in the heart slices were expanded and crownpointe. This svidetel the part about that fatty degeneration at this stage toxicity developed as a secondary phenomenon and has been associated with congestive hyperemia.

In total the slices of the body was clearly seen that the degree of development of alternative changes and venous hyperemia depended on the depth location of the slices. Characteristically, in the lobules, which are located closer to the capsule body, the degree of degenerative changes and circulatory disorders were more pronounced, which may be attributed to different levels of blood flow.

Lots of micronecrosis along with cellular debris were filled with connective tissue cells. Midorikawa connective tissue and portal areas were infiltrated cells, mostly fibroblasts and collagen fibers, and the number of lymphoid and plasma cells was significantly decreased.

In the group of animals that, along with sodium nitrate was received DPOA dose of 50 and 100 mg/kg and killed after 7 days after poisoning, liver was characterized by moderate venous hyperemia and mild protein-fatty degeneration of hepatocytes Central parts of the lobules. To the 14th day after poisoning the infusion of drug the liver was characterized by signs of mild venous hyperemia and granular dystrophy of hepatocytes Central regions of lobules. This indicates snizeni the negative effects of lack of oxygen in the tissue of the liver.

Thus, on the basis of clinical and morphological studies photomorphogenic liver of geese in acute poisoning can be characterized by the following scheme. The toxin is rapidly absorbed into the blood in the stomach and intestines without causing there expressed alterative changes. The formation of methemoglobin leads to hypoxia and heart failure, which is manifested by congestive phenomena in the liver and the development of protein-fatty degeneration of hepatocytes, especially in the third zone of acinus. The direct effect of the toxin on the liver cells leads to the development of some segments of toxic dystrophy with Central necrosis areas and filling them with debris, erythrocytes and cellular infiltration.

Further, to the 7th day after poisoning dystrophic phenomena are increasing, despite a reduction in congestive hyperemia, there are signs of fatty degeneration, developing type lipogenesis. Micronecrosis of the liver parenchyma are formed not only in the Central parts of the lobules, but on the periphery. On the background of alterative and vascular changes observed infiltration of the connective tissue stroma of the organ that allows us to classify these changes as alterative hepatitis.

To the 14th day after the poisoning symptoms of hepatitis are saved and proliferative component becomes more pronounced the output. Changes the nature of the fatty dystrophy, which is exacerbated by the conservation of circulation.

Along with destructive changes stated the development of compensatory-adaptive processes in the body, which are characterized by hypertrophy of hepatocytes, activation of protein synthesis, regeneration of parenchyma and stroma.

The use of the drug reduces the negative effect of the toxin primarily due mitigate developed hypoxia, which is expressed weakly expressed protein and fatty degeneration of hepatocytes and no necrotic changes within 7 days after poisoning. To 14 days is almost complete normalization of the structure of the digestive system, despite preserved signs of venous hyperemia and granular dystrophy of hepatocytes Central zones of the lobules.

The order of application

Derived pyrimidine - dipeptidylpeptidase (DPOA) affects the safety and productivity of birds.

Derived pyrimidine - dipeptidylpeptidase (DPOA) increases the natural resistance of birds.

Derived pyrimidine - dipeptidylpeptidase (DPOA) helps restore liver intoxicated with nitrates.

Derived pyrimidine - dipeptidylpeptidase (DPOM is) ask thoroughly mixed with the feed, individually or in batch process daily at the rate of 50 mg/kg for 7 days.

Products of slaughter animals used for food purposes without restriction.

When using the drug in the recommended quantities of side effects and complications are not installed. There are no contraindications.

Precautions

When working with the product should comply with the normal rules of personal hygiene and safety.

Empty containers of the drug he is neutralized boiling in a 5%solution of soda.

The source of information

1. Krivonogov VP and other Synthesis and immunotropic activity of pyrimidine derivatives. Message 4. Synthesis, immunotropic and anti-inflammatory activity of pyrimidine acyclonucleosides. Chemical and pharmaceutical journal, Moscow, Folium, 1997, No. 6, p.23-27.

The tool, which represents a 1,3-di(2'-hydroxy-3 '-piperidinoethyl)-6-methyluracil formula

to improve the safety and productivity of birds.



 

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12 cl, 1 tbl, 171 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to 2-thio substituted derivatives of imidazole with formula I , where R1 represents aryl, which can be substituted by a halogen atom or halogen-C1-C6-alkyl; R2 is chosen from a group, containing a) aryl-C1-C4-alkyl, and b) C1-C6-alkyl; R3 is chosen from a group, containing (a) NR4R10, (b) NR7COR10, (c) OR10, (d) NH2; R4 represents H; R3 and R6, which can be the same or different, represent H, halogen, OH, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl; R7 represents R4; R10 has one of the following values: (a) A-B, (b)-(e), (f) C1-C6-alkyl, which is substituted with 2 phenyl groups; A represents linear or branched C1-C6-alkylene; B is chosen from a group, containing (a) H, (b)-(e), (f) OC1-C6-alkyl, (g) OH; Hy represents 3-10-member non-aromatic, mono-, bi- or tricyclic carbocycle, which can be or not be condensed with a benzene ring; Ar represents 5- or 6- member aromatic heterocycle, which has 1 heteroatom, chosen from a group, consisting of O, S, and N, and which may not be condensed with a benzene ring, Het represents 5- or 6-member non-aromatic heterocycle, which has 1 heteroatom, which represents O, which may not be condensed with a benzene ring; m is 0,1 or 2; or its optical isomers or physiologically used salts. Compounds with formula I are used when making pharmaceutical compositions with inhibiting effect on release of cytokines.

EFFECT: obtaining of derivatives, which have inhibiting action to release of cytokine action.

13 cl, 4 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and deals with acizol application as preventive and therapeutic means in neurotoxin poisoning cases. The present invention showed high efficacy of acizol in complex treatment for toxico-hypoxic encephalopathy and pneumonia (normalisation of homeostasis indices, lowering of mortality and disabling complications).

EFFECT: lowering of the risk of complications in neurotoxin poisoning cases.

15 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: wood of Siberian or Daurian larch is debarked, cleaved and dried at 40-50°C to residual moisture 23-27%. Dried wood is chopped, and soluble substances are extracted with 75-85% ethyl alcohol aqueous solution at temperature 45-50°C in ratio raw material:extracting agent 1:(7-10). Further extracting agent is distilled off, and sawdust is supplied to press for additional alcohol return. Then extract aqueous part is cooled to 20-25°C within 20-30 minutes for isolation of resinous impurity accompanying dihydroquercetin (DHQ). Deresined extract aqueous part is added with methyltertbutyl ether (MTBE) in ratio 1: (0.3-0.45), and DHQ is reextracted within 2-3 hours. Extract ether part is isolated separate from aqueous part through sedimentation within 2-2.5 hours and supplied to MTBE evaporation, while target product is crystallised of hot water. Invention enables to produce DHQ with yield 2.2-2.5% of bone-dry wood mass with grade 90-96%.

EFFECT: simplification of process and production of high-quality product.

4 cl, 2 ex

FIELD: medicine; veterinary.

SUBSTANCE: method describes the use of 2,4-diphenyl-7,8-benzo-5,6-dihydroselenochromen as a means of treatment and prevention of poisoning with heavy metal compounds.

EFFECT: higher resistance in animals and humans to poisoning with heavy-metal compounds.

8 tbl, 1 ex

FIELD: organic chemistry, toxicology.

SUBSTANCE: invention describes a method for using 2,4,6-triphenyl-4H-selenopyrane as an agent for treatment and prophylaxis of poisoning with arsenic compounds. Sodium arsenite was used as a toxicant. Using the claimed preparation reduces lethality of animals up to 40-60% (100% in control group). Also, significant improving blood indices and visceral organs of animals occurred, i. e. the severity degree of poisoning was decreased.

EFFECT: enhanced effectiveness of agent.

2 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to biologically active substances displaying perspective using medicine, veterinary science, cosmetics and dairy industry. Agent comprises polyoxyarylene ester and hydroquinone in their ratio from 83:17 to 5:95, respectively. Agent comprises 2-(1-oxy-4-hydroxyphenylene)benzoquinone or 4-hydroxyphenylene-2,4-dioxybenzene as a polyoxyarylene ester. Method for preparing agent involves mixing polyoxyarylene ester with hydroquinone and wearing the prepared mixture up to formation of the uniform mass. Invention provides creature of a novel agent of the broad spectrum of effect, namely: antioxidant, antihypoxic, antitumor, radioprotective, immunostimulating and biocide effects.

EFFECT: valuable properties of agent.

7 cl, 20 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: claimed adsorbent contains spherical activated carbon having size diameter of 0.01-1 mm, specific surface determined in accordance to Langmuir equation of 1000 m2/g or more, ratio of diffraction intensities R of 1.4 or more (R is determined as R = (I15-I35)/(I24-I35) (1), wherein I15 is diffraction intensity at diffraction angle (2θ) of X-ray diffraction is 15°C; I35 is diffraction intensity at diffraction angle (2θ) of X-ray diffraction is 35°C; I24 is diffraction intensity at diffraction angle (2θ) of X-ray diffraction is 24°C), and pore volume having diameter of 7.5-15000 nm is less than 0.25 mg/ml. In another embodiment claimed adsorbent contains abovementioned spherical activated carbon with modified surface. Also disclosed are pharmaceutical composition and method for prevention or treatment of kidney or liver diseases containing said adsorbent.

EFFECT: new adsorbent for peroral administration.

20 cl, 5 ex, 2 tbl, 12 dwg

FIELD: organic chemistry, medicine, hepatology.

SUBSTANCE: invention relates to using 2-methylthiopyrimido[4,5-b]indole of the formula (1): showing melting point at 243°C (with decomposition) and value LD50 > 1000 mg/kg used in liver protection from poisoning with carbon tetrachloride. Proposed compound exceeds activity of the "Essentiale" as a comparison preparation.

EFFECT: valuable medicinal property of compound, enhanced effectiveness.

1 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: claimed adsorbent contains spherical active carbon, obtained from thermosetting resin as carbon source, having particle size of 0.001-1 mm, specific surface determined by Langmuir adsorption equation of 1000 m2/g or more and pore volume of 7.5-15000 nm in diameter less than 0.25 ml/g. Also disclosed is adsorbent being similar to abovementioned one, wherein total content of acidic groups is 0.40-1.00 meq/g; total content of basic groups is 0.4-1.1 meq/g. Pharmaceutical compositions contain said adsorbents and pharmaceutically acceptable carriers and recipients. Agents of present invention are useful in treatment of kidney or liver diseases or disorders associated with uremic substance by administration of said adsorbents.

EFFECT: products of increased selectivity.

21 cl, 5 ex, 2 tbl, 11 dwg

FIELD: chemical and pharmacological industry.

SUBSTANCE: invention relates to encapsulated form of Acyzol containing Acyzol and pharmaceutically acceptable fillers in specific component ratio.

EFFECT: encapsulated mass with high technological characteristics, high biological availability and effectiveness of Acyzol component.

5 tbl, 3 dwg

FIELD: veterinary science.

SUBSTANCE: in case of dioxine intoxication animals should be prescribed with dimephosphon at the dosage of about 50-150 mg/kg body weight daily for 10-30 d. The innovation provides decreased embryonic lethality in animals.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: (I) , in which R1 and R2 independently represent C1-6alkyl, C3-5cycloalkyl C1-3alkyl or C3-6dikloalkyl; Q represents CR4R5, where R4 represents hydrogen; or C1-6alkyl, and R5 represents carbon; Ar represents 5-6-membered aromatic ring system, where heteroatoms can represent up to 2 ring atoms, independently selected from nitrogen and sulphur, notably that this ring system can be substituted by one or more then one substitute, independently selected from C1-4alkyl; Ar2 represents 5-6-membered aromatic ring system containing up to 2 ring atoms, independently selected from nitrogen and sulphur, notably the ring contains at least one heteroatom and can be substituted by one or more then one group, independently selected from C1-4alkyl. The compositions can be used in autoimmune disease modulation. The methods of compounds production, pharmaceutical composition and use of the compounds in the treatment of respiratory disease are described.

EFFECT: production of thienopyrimidindion compounds for autoimmune disease modulation and respiratory disease treatment.

14 cl, 3 ex

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