RU2281007C2 - Method for production of bioactive substance selenopyran, selenopyran and products containing the same - Google Patents

Abstract

FIELD: production of biologically active compounds useful in producing of biologically active food supplements, functional foodstuffs, feed additives for prophylaxis of selenium failure in human and animals.

SUBSTANCE: bioactive substance selenopyran has antioxidant, antiatherogenic, detoxifying, hypolipidemic, immunomodulating and other properties, as well as anabolic effect. Method for production thereof includes providing of 9-phenyl-symmetric octahydroxanthene slurry in ice acetic acid. Then slurry is saturated in inert atmosphere with hydrogen chloride for 15 min and further with mixture of hydrogen selenide and hydrogen chloride for 15 min. Then hydrogen selenide is passed for 2 hours. Preferable temperature of aqueous solution is 20-50°C, and total hydrogen selenide consumption is 2.3-2.3 l. After dissolving of 9-phenyl-symmetric octahydroxanthene acetic anhydride is introduced into reaction mixture and saturation with hydrogen selenide is carried out. Precipitated crystal deposit is filtered and recrystallized from acetone with filtration of hot solution through filter to produce selenopyran with yield up to 92-96 %; purity of at least 92.2 % and selenium content in target product of 23.2-24.0 %.

EFFECT: effective and accelerated method for bioactive selenopyran production with increased yield.

13 cl, 5 tbl, 11 ex

Description

The invention relates to the field of technology for the production of biologically active compounds used in the production of biologically active food additives (BAA), functional foods, feed additives in order to prevent selenium deficiency in humans and animals.

Currently, the attention of researchers and clinicians is attracted by the trace element selenium, which is an essential element for the implementation of immunological processes, for the normal functioning of the antioxidant system, the monooxygenase system of the liver.

In this regard, selenium-containing drugs are becoming more common. So, as a trace element, selenium is introduced into various vitamin and mineral complexes, for example, Centrum (Vidal Handbook. Medicinal Products in Russia. M: Astrafarmservis, 1997, p.654 - the closest analogue for the vitamin and mineral complex).

Various functional foods with selenium are known, for example selenium-containing algae (RF patent No. 2096037), bread (RF patent No. 2103874), confectionery (RF application No. 2003102630), beer (RF patent No. 2209237) and yeast (RF patent No. 2194523, RF patent No. 2146874), as well as selenium-containing L-amino acids - selenomethionine or selenocysteine. The closest analogue to the claimed functional food product is the RF patent No. 2103874. The closest analogue to the claimed dietary supplement for food is the RF patent No. 2146874.

However, these products have several disadvantages. Inorganic compounds of selenium, for example sodium selenite, have high toxicity and the associated risk of toxic overdoses, and the lack of selenium-containing algae and yeast is the wide variability of the amount of selenium absorbed. Hence, difficulties arise with accurate dosing of the drug and monitoring the effectiveness of prevention and treatment. In addition, selenium-containing amino acids are difficult to obtain and therefore expensive.

The prior art there are many methods for producing various compounds of selenium (USSR copyright certificates: No. 325843, 963988, 1167184, 1246566, 1816762, RF patents: No. 2221793 and 2226192).

For example, from the USSR author's certificate No. 929642, a method is known for producing α, α'-disubstituted derivatives of selenophene, including the interaction of a furan compound with hydrogen selenide at a temperature of 0-50 ° C in the presence of an acid and an organic solvent. Perchloric acid or hydrochloric acid or gaseous hydrogen chloride are used as the acid, and methyl or ethyl alcohol is used as the organic solvent. The corresponding furan compound in an organic solvent is placed in a reaction flask equipped with a stirrer, a dropping funnel and a gas supply tube, the reaction flask is purged with argon for one hour, the reaction mixture is saturated with hydrogen selenide for 45 minutes, then the acid solution is slowly added dropwise, the reaction mixture is stirred in a stream of hydrogen selenide at 20 ° C for 1 h, then neutralized with sodium bicarbonate solution until neutral, the product is extracted with ether, dried, the ether is distilled off, and the residue is distilled in vacuo. In the case of using gaseous hydrogen chloride, it is passed simultaneously with hydrogen selenide for 1.5 hours. The target product thus obtained can be used as a biologically active compound.

The USSR author's certificate No. 1051089 describes a method for the synthesis of selenopyrilium salts obtained by treating 1,5-diketones with hydrogen selenide and hydrogen chloride in an acetic acid medium in the absence of hydrogen. It is indicated that the target products may be of interest as biologically active substances or intermediates in the synthesis of drugs.

However, in practice, there is an advantage of selenopyran over the salts of selenopyrilium and selenophen, since it was found that these compounds have neither antioxidant, nor immunomodulating, nor detoxifying properties characteristic of selenopyran. In this regard, these compounds have not found adequate use either in medicine, or in veterinary medicine, or in the food industry.

Closest to the proposed method is a method for producing 9-phenyl-symmetric octahydroselenoxanthene by reacting 9-phenyl-symmetric octahydroxanthene with hydrogen selenide and hydrochloric acid in a mixture of glacial acetic acid and acetic anhydride in the ratio 4: 1 (RF patent No. 2213092).

The disadvantage of this method is the length of the process, the significant consumption of expensive acetic anhydride and the low conversion of hydrogen selenide due to its decomposition in the presence of water, which is contained in hydrochloric acid, with insufficient acidity of the reaction mixture at the stage of gas saturation.

In addition, the known methods for producing selenopyran cannot ensure the production of compounds with a wide range of biologically active properties and obtain the target product with a purity of at least 99.2%, and also cannot provide large-tonnage industrial production of the final product without reducing its quality and yield, significant time and material costs.

Known anti-tumor pharmaceutical preparation containing selenium in the form of a compound of selenophen (application WO 97/46225). The patent RU No. 2213092 mentions the possibility of obtaining a pharmaceutical product intended for the regulation of metabolism, and which can be used to eliminate selenium deficiency. This pharmaceutical product is the closest analogue for the claimed drug, however, it is ineffective and has poor quality.

From the USSR author's certificate No. 1526626, a feed additive for cows is known containing vitamins A, D, E, sulfates of copper, zinc, cobalt, potassium iodide and sodium selenite. However, its disadvantage is the lack of a stable content of selenium in the additive due to its free state, as well as limited species use.

The closest analogue to the inventive feed additive is a feed additive containing sodium selenite (patent RU No. 2164758). This powdery composition is used to prevent selenium deficiency in farm animals and birds, however, it has a number of disadvantages, namely low quality, insufficient selenium content and the presence of side effects.

In addition, not one of the above sources of information does not solve the problem posed in the claimed invention.

The objective of the proposed group of inventions is the creation of a biologically active substance (BAS) - selenopyran, which has a set of qualitatively new biologically active properties, as a result of the development of a more advanced and effective method for its industrial production. Another objective is the introduction of the obtained selenopyran into a number of products of functional food, feed and medical purposes, which would not be accompanied by side effects, but would cause a systemic preventive as well as therapeutic effect.

Given the disadvantages of the methods for producing selenium compounds from the prior art, the inventors of the present invention have developed a new inexpensive and effective method. According to this method, a biologically active substance is obtained, which is also the subject of the claimed invention. The biologically active substance includes a low molecular weight organic heterocyclic selenium-containing compound obtained by chemical synthesis. Full name 9-phenyl-symmetric octahydroselenoxanthene or selenopyran with the formula

The object of the present invention is solved in that the biologically active substance selenopyran has antioxidant, detoxifying, lipid-lowering, anti-atherosclerotic, anti-atherogenic, immunomodulating, immunocorrecting properties and anabolic effect, and it is obtained in accordance with the following method. The method involves preparing a suspension of 9-phenyl-symmetric octahydroxanthene in glacial acetic acid, which is then saturated in an inert atmosphere for 15 minutes, first with hydrogen chloride and then for 15 minutes with a mixture of hydrogen selenide and hydrogen chloride gases, then hydrogen selenide is passed for 2 hours , the optimal temperature of the reaction mixture is 20-50 ° C, and the total consumption of hydrogen selenide is 2.3-2.6 L, after dissolving 9-phenyl-symmetric octahydroxanthene, vinegar is introduced into the reaction mixture th anhydride and saturated with selenium hydrogen over 30 minutes, the precipitated crystalline precipitate is filtered off and recrystallized from acetone by filtering the hot solution through a filter and obtaining selenopyran with a yield of up to 92-96%, purity of at least 99.2% and the content of selenium in the target product 23, 2-24.0%.

Additionally, after filtration, the mother liquor is diluted with water, and the precipitate formed is extracted with ether, then the ether extract is dried and the solvent is distilled off, after which the residue is recrystallized from acetone and combined with the previously obtained target product.

A biologically active food supplement (dietary supplement) contains a biologically active substance - selenopyran obtained by the claimed method, is another object of the present invention. Supplements for food can be made in the form of tablets, powders, capsules, lozenges, microcapsules, pills, chewing gum, dragees, aqueous and oily solutions.

A functional food product, for example vegetable oil, contains a biologically active substance - selenopyran, obtained precisely by the claimed method, which is also the subject of the present invention. At the same time, it should be clear to a specialist in the food industry that selenopyran can be added prophylactically to any food product.

In addition, the feed additive contains a biologically active substance - selenopyran, obtained precisely by the claimed method. The feed additive can be made in the form of granules, powders, aqueous and oil solutions.

Also, the vitamin-mineral complex contains a biologically active substance - selenopyran, obtained precisely by the claimed method. The complex can be made in the form of tablets, powders, capsules, microcapsules, dragees, lozenges, pills, chewing gum, water and oil solutions.

Another object of the invention is a pharmaceutical preparation for eliminating selenium deficiency, which contains a biologically active substance - selenopyran obtained by the claimed method. The drug can be made in the form of tablets, powders, capsules, microcapsules, dragees, lozenges, pills, chewing gum, water and oil solutions, solutions for intramuscular injection and enteral nutrition.

In comparison with the closest analogue, an improvement of the method consists in the fact that there is a synergistic effect, which is that the conversion of selenium hydrogen increases due to the replacement of concentrated hydrochloric acid with gaseous hydrogen chloride, which, in turn, allows to reduce the amount of acetic anhydride introduced into 2 times. In addition, the task is achieved by treating 9-phenyl-symmetric octahydroxantene with a mixture of hydrogen selenide and hydrogen chloride gases and introducing acetic anhydride at the final stage of synthesis. With this method of synthesis, the consumption of selenium hydrogen is reduced by 20-25% and the duration of the synthesis process is reduced by 1-1.5 hours and the corresponding material costs for it. However, unexpectedly increases the yield of the target product and its quality (purity), and the selenium content in selenopyran is 23.2-24.0%.

Obtained according to the claimed method, the biologically active substance exhibits antioxidant properties in vivo, stimulating the enzymatic and non-enzymatic systems of the human and animal body.

The biologically active substance obtained according to the claimed method also exhibits immunomodulating properties, since it was found that under conditions of oxidative stress, selenopyran prevents the decrease in the number of T-lymphocytes and C-, M- and A-class immunoglobulins in animals and humans.

The biologically active substance obtained according to the claimed method also exhibits immunocorrective properties, since it has been established that after chemotherapy and radiation therapy it restores the number of T-helpers and normalizes the ratio of T-helpers and T-suppressors, the functioning of phagocytic cells and the number of blood leukocytes. Moreover, anti-apoptotic effect on thymus cells is manifested in age animals, prolonging the life of T cells.

Obtained according to the claimed method, the biologically active substance selenopyran also has a lipid-lowering effect, reducing the amount of atherogenic type cholesterol and triglycerides in the blood serum.

Obtained according to the claimed method, the biologically active substance selenopyran also has an anti-atherosclerotic effect, reducing focal thickening of the aortic wall and branches of the abdominal aorta with the development of atherosclerosis.

Obtained according to the claimed method, the biologically active substance selenopyran also has a detoxifying effect in relation to compounds of heavy metals.

In addition, the biologically active substance obtained according to the claimed method also has an anabolic effect, since it provides a smooth muscle growth and muscle tone.

Thus, the basis of the present invention is the creation of a substance - selenopyran with unique properties - antioxidant, detoxifying, lipid-lowering, anti-atherosclerotic, anti-atherogenic, immunocorrecting, immunomodulating and anabolic, which can be used as a biologically active principle in various end products to eliminate signs of selenium deficiency human and animal. Such a biologically active substance that simultaneously possesses all of the above properties can be obtained only in accordance with the claimed method with a specially developed method for conducting the synthesis process and selected modes. Only the application in the method of the claimed techniques with the indicated modes allows to obtain selenopyran with a high degree of purity on an industrial scale with the improvement and expansion of its original biological properties.

Thus, all of the above is the technical result of the claimed group of inventions, since it provides a solution to the problem, including the creation of a highly efficient method for the industrial production of selenopyran with a number of biologically active properties, high yield of the target product and shortening the duration of its production process. Along with this, the introduction of the obtained selenopyran into a number of products of functional food, feed and medical purposes provides them with a systemic preventive and therapeutic effect without side effects, which is proved by the following examples.

Example 1. A method of producing selenopyran.

A suspension of 15.9 g of 9-phenyl-symmetric-octahydroxantene in 93.5 ml of glacial acetic acid in an inert atmosphere is saturated for 15 minutes with hydrogen chloride at a flow rate of 1.5 liters per hour, and then 15 minutes with a mixture of hydrogen selenide gas and hydrogen chloride with same speed. After that 2 hours selenium hydrogen is passed. The optimum temperature of the reaction mixture is 40 ° C. After dissolving 9-phenyl-symmetric-octahydroxanthene, 6.5 ml of acetic anhydride are added to the reaction mixture and saturated with hydrogen selenide for 30 minutes. The precipitated copious crystalline precipitate is filtered off and recrystallized from acetone with filtration of a hot solution through a No. 4 Schott filter. Recrystallization from acetone requires the initial product to be dissolved in acetone when it is boiled, then a hot acetone solution is immediately filtered to ensure that the dissolved starting product passes through the filter and the insoluble impurities remain on the filter.

Get 16.7 g of the target product (85.0%), melting point 95-96 ° C (from acetone). The selenium content in the preparation is 23.2%. Hydrogen selenide consumption is 2.3 liters. The NQ spectrum contains absorption bands of 1660 and 1675 cm ^-1 characteristic of the vibration of the γ-selenopyranium cycle.

Example 2. A method of producing selenopyran.

A suspension of 15.9 g of 9-phenyl-symmetric-octahydroxantene in 93.5 ml of glacial acetic acid in an inert atmosphere is saturated for 15 minutes with hydrogen chloride at a flow rate of 2 liters per hour, and then 15 minutes with a mixture of hydrogen selenide and hydrogen chloride gases with the same speed. After that 2 hours selenium hydrogen is passed. The optimum temperature of the reaction mixture is 30 ° C. After dissolving 9-phenyl-symmetric-octahydroxanthene, 6.5 ml of acetic anhydride are added to the reaction mixture and saturated with hydrogen selenide for 30 minutes. The precipitated copious crystalline precipitate is filtered off and recrystallized from acetone with filtration of a hot solution through a No. 4 Schott filter. The mother liquor is diluted with 50 ml of water. The precipitate was extracted with diethyl ether. The ether extract is dried and the solvent is distilled off. The residue was recrystallized from acetone and combined with the obtained target product. Receive a 96.0% yield. The selenium content in the preparation is 24.0%. Hydrogen selenide consumption is 2.6 liters. The IR spectrum contains absorption bands of 1660 and 1675 cm ⁻¹ , characteristic of the vibration of the γ-selenopyranium cycle.

Example 3. Antioxidant properties of selenopyran.

To obtain data on the antioxidant properties of selenopyran in vivo, the authors conducted a special study in which the feed stress was simulated in broiler chickens (table 1).

The research results showed that with the introduction of oxidized fat in the diet (1 experimental group), a sharp decrease in the activity of enzymes of the antiradical protection system (superoxide dismutase (SOD) and glutathione peroxidase (GPO)) was observed, which indicated a high intensity of free radical processes, a high concentration of peroxides and depletion the enzymatic system of the body of chickens.

The antioxidant properties of selenopyran (the second experimental group) contributed to a decrease in the number of free radicals and the concentration of peroxide products.

Table 1
The activity of enzymes of the antiradical system of body protection Age, Enzyme activity (E / g protein) day SOD GPO the control 1 experienced 2 experienced the control 1 experienced 2 experienced one 11.3 11.0 11.7 260 263 258 fourteen 18.3 7.0 17.6 359 226 444 28 9.0 6.1 8.3 345 283 655

Thus, the antioxidant nature of selenopyran was proved, due to the electrodonor properties of its molecules, which manifests itself indirectly through stimulation of selenium-containing GPO.

Example 4. A functional food product with selenopyran.

Additional antioxidant properties of selenopyran have also been investigated in vitro. Obtained by the claimed method, selenopyran in vitro, for example, as part of a functional food product - vegetable (sunflower) oil inhibits the accumulation of organic acid hydroperoxides. It was additionally established that selenopyran has an effect on the food product itself and prevents the development of processes of autooxidation of fatty acids, and, therefore, allows to extend the shelf life of oils.

Selenopyran is dissolved in vegetable oil at a concentration of from 0.0005 to 0.001% by weight. Autooxidation was carried out under mild conditions - at room temperature without forced air passage. The control was vegetable oil, for example, sunflower oil without selenopyran. In the first experimental group, selenopyran was added to the composition, and in the second group, vitamin E was used as an antioxidant. Research results showed that even at such low concentrations (0.0005%), the organo-selenium compound significantly slows down the oxidation of fatty acids. After 6.5 months in the control group, the peroxide value reached 14 mmol of active oxygen per 1 kg of product, while in the first experimental group, only after 8 months of storage. Vitamin E did not give a similar effect.

Example 5. Immunomodulating and immunocorrecting properties of selenopyran.

Immunological studies on young animals showed that during stress there is a decrease in the immune status of the body, characterized by a decrease in the absolute number of T-lymphocytes in the blood, a decrease in the level of immunoglobulins of M- and A-classes, as well as bactericidal activity of blood serum and the functional activity of neutrophils. The research results indicate that the chemical composition of the introduced selenium compound affects the T-cell population of lymphocytes. The inorganic form, sodium selenite, did not significantly affect the quantitative characteristics of T cells, while selenopyran in a stressful situation prevented a decrease in the concentration of T lymphocytes in the peripheral blood of young cattle (table 2). A similar situation was observed with experimentally induced stress in piglets and lambs, regardless of the nature of the stress — feed or early weaning of the young from their mothers.

table 2
The content of T-lymphocytes in the blood of young cattle (thousand / μl of blood) Day experiment the control Experienced groups First (selenopyran) The second (sodium selenite) one 2.53 ± 0.08 2.40 ± 0.11 2.46 ± 0.10 7 2.00 ± 0.12 2.29 ± 0.09 2.15 ± 0.09 eighteen 1.91 ± 0.11 2.42 ± 0.12 2.00 ± 0.15 46 1.95 ± 0.11 2.20 ± 0.13 1.90 ± 0.10

Under stress, selenium compounds stimulated the synthesis of M-class immunoglobulins in piglets, lambs, and gobies, and selenopyran (unlike sodium selenite) also increased the concentration of A-class immunoglobulins.

The immunomodulatory properties of selenopyran have been demonstrated in experiments on laboratory animals. So feeding mice for 21 days with selenopyran significantly and dose-dependently increased the number of antibody-forming spleen cells in response to ram erythrocyte immunization. At a dose of 200 ng of selenopyran per day per head, this indicator was 120 cells per 10 million spleen cells compared to thirty in the control. A significant increase in antibody-forming cells was noted in the lymph nodes.

In the secondary immune response to the T-dependent antigen, both drugs also had a stimulating effect. The number of antibody-forming cells both in the spleen and in the lymph nodes increased dose-dependently.

Immunocorrective properties were most pronounced in old mice (males 18 months old). The number of antibody-forming cells in the spleen with the introduction of selenopyran at a dose of 200 ng / mouse increased 10 times. In the lymph nodes, the effect was less pronounced than in the spleen.

However, it was found that with the introduction of selenopyran, an increase in the expression of the tumor necrosis factor receptor on the cells of the lymph nodes and spleen was observed. With this in mind, additional studies were conducted to identify the relationship between the expression of receptors for tumor necrosis factor receptors, selenopyran and apoptosis signaling pathways (programmed cell death).

It is known that this receptor initiates four signaling pathways, two of which are coupled to apoptosis signals, while the others carry out activation stimuli. Apoptosis was induced by the introduction of recombinant tumor necrosis factor alpha. The results of the studies showed that the selenium preparation reduces the negative effect of tumor necrosis factor on the number of thymic apoptotic cells. Selenopyran reduces the number of cells that have gone into apoptosis from 14 to 8% at a dose of 10 mmol of recombinant tumor necrosis factor and from 21 to 11% at a dose of 20 mmol.

Thus, it was concluded that the increase in the expression of the tumor necrosis factor receptor is associated with activation processes and does not increase the percentage of cells entering apoptosis. On the contrary, the anti-apoptotic effect of selenopyran on thymus cells was demonstrated.

For example, a dietary supplement - an immunomodulator is an oily solution of selenopyran in a concentration of 0.1-10 mg of selenopyran in one milliliter. As a solvent, you can use olive oil.

Example 6. Hypolipodemic effect of selenopyran.

The hypolipodemic effect of selenopyran is proven by clinical trials of a biologically active substance.

Studies were performed on the following groups of patients:

- control group - 15 people, men who suffered myocardial infarction, aged 48 to 70 years, overweight in 75% of patients,

- an experimental group of patients - 25 people, was similar to the control in terms of age and sex composition and clinical symptoms.

Patients of the experimental group received anti-atherosclerotic diet and additionally selenopyran in a dose of 420 mcg per day. Patients in the control group received a similar diet and placebo.

During the period of clinical trials (30 days), not a single case of drug intolerance, allergic reactions, or other side effects was noted.

Analysis of the dynamics of lipid metabolism indicates a pronounced lipid-lowering effect. So, the serum cholesterol content was significantly reduced by 14% compared with the control. There was also a marked decrease in the level of VLDL cholesterol of atherogenic type and triglycerides in patients of the experimental group by 38 and 37%, respectively. The noted changes led to a decrease in the atherogenic coefficient by 17% (table 3).

Table 3
Lipid spectrum of blood serum under the influence of a diet with the inclusion of selenopyran Indicators Control group Experienced group Before After Before After Cholesterol, mol / L 6.44 ± 0.32 6.60 ± 0.22 7.01 ± 0.30 6.10 ± 0.29 HDL cholesterol, mmol / l 0.96 ± 0.15 1.00 ± 0.06 1.30 ± 0.06 1.25 ± 0.05 HS VLDL, mol / l 0.99 ± 0.30 1.07 ± 0.16 1.40 ± 0.20 0.88 ± 0.10 LDL cholesterol, mmol / l 4.53 ± 0.33 4.30 ± 0.23 4.26 ± 0.27 3.96 ± 0.23 Triglycerides 2.16 ± 0.49 2.35 ± 0.36 3.11 ± 0.43 1.94 ± 0.23 Atherogenic coefficient 6.94 4.25 4,57 4.12

Supplements to food can be used as a means of having a lipid-lowering effect. For example, dietary supplement contains selenopyran in an amount of 0.01-0.1 wt.%, Vitamin C 10-20 wt.% And vitamin E 1-5 wt.%. Additional components may enhance the hypolipodemic properties of selenopyran.

When vitamins and a set of macro- and microelements are added to selenopyran in amounts of daily requirement in 1 tablet, a vitamin-mineral complex is prepared,

for example, such as Centrum.

Example 7. Antiatherosclerotic effect of selenopyran.

The antiatherosclerotic effect of selenopyran has been experimentally proven in laboratory rats of the Wistar breed. The first group served as a control and received a semi-synthetic diet. In the second group, an atherosclerosis development model was used. The process was initiated with a high-fat, oxidized diet by introducing cholesterol (1% by weight of feed) and pre-oxidized sunflower oil. The diet of the third group was similar to the second, however, selenopyran was introduced into the fat component.

The results of macro- and microscopic studies of the aorta showed that visual examination of the aorta in the group where atherosclerosis without selenopyran was simulated showed aortic wall compaction in both the abdominal and thoracic regions, as well as a decrease in the elasticity of the vessel walls. In this group, under microscopic examination, focal thickenings of the aortic wall in the abdominal region and to a lesser extent in the thoracic region were noted in all samples due to the proliferation of connective tissue. In some places, intimacy of fibrin is noted. In all samples, signs of sclerosis of the branches of the abdominal aorta were found. In general, in this group there were all signs of atherosclerosis in the stage of formation of fibrous plaque.

The inclusion of selenopyran in the diet significantly inhibited the development of atherosclerosis. Visual examination of 70% of the aortic samples revealed changes similar to the first experimental group, but they were less pronounced. In 30%, no visible changes were noted. Microscopic examination only in the abdominal region showed mild focal thickening of the wall and moderately pronounced signs of sclerosis of the branches of the abdominal aorta in 70% of the samples. In this case, in no sample was obliteration of their lumen (table 4).

Supplements to food can be used as a means for the prevention of atherosclerosis. In addition to selenopyran, a biologically active food supplement may additionally contain polyunsaturated fatty acids, such as linoleic and linolenic, in an amount of 45-58 wt.%. As a source of polyunsaturated fatty acids, oils of flax, milk thistle, sea buckthorn, camelina, and sunflower are used. The concentration of selenopyran is in the range from 0.01 to 10 mg per milliliter.

Example 8. Biologically active food supplement with selenopyran.

Biologically active food supplement contains 0.01-0.1 wt.% Selenopyran, adaptogens of plant origin, in particular licorice roots in an amount of 10-15 wt.%, Powder of milk thistle cake 15-20 wt.%, Powder of black currant fruit 10-15 wt.%, Carrot powder 20-25 wt%, nettle and strawberry leaves in an amount that provides the daily need for the human body in vitamins C, E and carotene. Technological components for tabletting are used. The resulting mixture is tabletted in the form of tablets or capsules and packaged in airtight packaging. Supplements for food (0.15 g per tablet) are prescribed 2-3 tablets twice a day.

Analysis of preclinical studies in laboratory rats showed that the claimed composition and its amount is sufficient for the manifestation of immunomodulating, adaptogenic and detoxifying properties.

Example 9. The anabolic effect of selenopyran.

The use of selenopyran in feeding sex and age gobies confirmed the anabolic effect of the drug. Selenopyran was included in the diet of animals at a dose of 0.4-1.2 mg / kg of dry food. After 6 months of the experiment, the live weight of the experimental bulls exceeded the control by 6.6% (table 5). It was found that the mass of the meat part of the carcass of the experimental animals exceeded the control by 4.0%, and the area of the muscular ocellus by 12.7%. Anabolic effect is confirmed by chemical analysis of muscle tissue. In the longest muscle of the back, the content of total protein is higher in the experimental group compared to the control group by 8.0%.

Thus, the use of selenopyran in feeding animals increases their live weight by increasing muscle tissue.

Additionally, clinical trials suggest that selenopyran can be recommended as a dietary supplement in food for patients in the postoperative period and athletes after surgery and injuries to restore muscle tone.

Table 5
The results of the control slaughter and deboning of the carcass of sex and age gobies treated with selenopyran (M ± m) Indicators Groups Percentage of Control The control Experienced Live weight kg 345 ± 2.8 368 ± 5.0 106.6 The mass of carcass meat, kg 125 ± 4.3 130 ± 3.3 104.0 Muscle eye area 67.9 ± 3.3 76.5 ± 3.9 112.7 The protein content in muscle tissue, g% 19.8 ± 0.33 21.4 ± 0.08 108,0

Example 10. A pharmaceutical preparation for eliminating selenium deficiency.

Selenopyran oil solution is an effective drug for the correction of immune system disorders in various pathological processes. The method of stimulation and correction of the immune system is as follows: the resulting preparation in the form of an oil solution (use a mixture of flaxseed oils and milk thistle in equal amounts) is administered orally. The dose depends on the clinical condition of the patient, his age and weight. The daily dose of selenopyran is 1-120 μg per 1 kg of live weight. An effective therapeutic daily dose for a patient is from 0.05 to 5 mg of active substance in 10 g of a mixture of oils. The drug is administered simultaneously or fractionally. The duration of treatment can vary from 1 to 3 months. During the period of treatment, the immunological status of the patient is monitored by the expanded clinical blood formula and immunogram.

For example, in a patient V.V.A. 56 years was immunological deficiency due to tumor pathology, after standard therapy. In this case, the immunogram showed before treatment: lymphocytes - 1.4 × 10 ⁹ per liter, T-helpers of diabetes 4-40% (0.56 × 10 ⁹ per liter), diabetes 8-31% (0.43 × 10 ⁹ per l), SD4 / SD8 = 1.3.

Blood test: white blood cells - 3.0 × 10 ⁹ per liter, basophils - 1%, eosinophils - 2%, stab neutrophils - 6%, segmented neutrophils - 33%, lymphocytes - 46%, monocytes - 12%.

After treatment for one month, the immunogram was as follows: T-helper cells, CD4 - 42%, type 8 diabetes - 27%, type 4 / type 8 = 1.5.

Blood test: white blood cells - 5.1 × 10 ⁹ per liter, eosinophils - 3%, stab neutrophils - 5%, segmented neutrophils - 72%, lymphocytes - 16%, monocytes - 4%.

Thus, it has been clearly established that during treatment, the number of T-helpers and T-killers increases and the number of suppressors decreases, as well as the number of leukocytes increases and the leukogram normalizes.

Using the proposed tool, 16 patients were treated in whom immunological selenium deficiency was mainly due to infectious and tumor pathology.

Example 11. Feed additive with selenopyran.

Usually in feed additives - premixes for animals and birds, an inorganic compound of selenium is used - sodium selenite. A distinctive feature of the proposed premix is that sodium selenite is replaced by selenopyran in the same doses per selenium. Selenopyran can be introduced into premixes for birds P1-1 - for laying hens, P1-2 - for laying hens of an industrial herd, P5-1 - for broilers of the first age, P6-1 - for broilers of the second age, KS-1 - for pigs, P51-1 - for piglets up to 4 months of age.

For example, the experiment was conducted on broilers of the cross "Isa" from daily to 36 days of age. In the control, standard premix P5-1 for the first age and P6-1 for the second age were added to the feed on a corn and wheat basis in the experimental group, premixes were used where sodium selenite was replaced by selenopyran. The research results showed that the broilers of the experimental group by the end of the cultivation exceeded the control by 5% in live weight and 2.5% in safety. The yield of gutted meat in the experimental group increased by 1.5% and carcasses of the first category by 2.8%.

Table 4
Antiatherosclerotic effect of selenopyran SIGNS Atherosclerosis Atherosclerosis + Selenopyran % power % power Macroscopic studies Seal of the aortic wall in the abdominal region one hundred ++ 70 + Thoracic aortic wall one hundred ++ - - Decreased wall elasticity one hundred ++ 70 + Microscopic examination Focal thickening of the aortic wall in the abdominal region one hundred ++ 70 + Focal thickening of the aortic wall in the thoracic region fifty + - - Fibrin overlay one hundred ++ - - Sclerosis of the branches of the abdominal aorta one hundred +++ 70 ++ Obliteration of the lumen of the branches of the abdominal aorta 40 + - -

Claims (13)

1. The biologically active substance is selenopyran, which has antioxidant, detoxifying, lipid-lowering, anti-atherosclerotic, anti-atherogenic, immunomodulating, immunocorrecting properties and anabolic effect, which is obtained by the method of claim 10 or 11. 2. A biologically active food supplement, characterized in that it contains a biologically active substance - selenopyran according to claim 1. 3. Dietary supplement for food according to claim 2, characterized in that it is made in the form of tablets, powders, capsules, lozenges, microcapsules, pills, chewing gum, dragees, aqueous and oil solutions. 4. A functional food product, characterized in that it contains a biologically active substance - selenopyran according to claim 1. 5. The functional food product according to claim 4, characterized in that it is a vegetable oil. 6. A feed additive, characterized in that it contains a biologically active substance - selenopyran according to claim 1. 7. The feed additive according to claim 6, characterized in that it is made in the form of granules, powders, aqueous and oil solutions. 8. Vitamin-mineral complex, characterized in that it contains a biologically active substance - selenopyran according to claim 1. 9. The complex of claim 8, characterized in that it is made in the form of tablets, powders, capsules, microcapsules, dragees, lozenges, pills, chewing gum, water and oil solutions. 10. A method of obtaining a biologically active substance - selenopyran of the formula 9-phenyl - symmetric octahydroselenoxanthene

involving the preparation of a suspension of 9-phenyl symmetric octahydroxanthene in glacial acetic acid, which is then saturated in an inert atmosphere for 15 minutes, first with hydrogen chloride and then for 15 minutes with a mixture of hydrogen selenide and hydrogen chloride, then selenium hydrogen is passed for 2 hours, the optimum the temperature of the reaction mixture is 20-50 ° C, and the total consumption of hydrogen selenide is 2.3-2.6 L, after dissolving 9-phenyl symmetric octahydroxanthene, acetic anhydride is introduced into the reaction mixture and saturate with hydrogen selenide for 30 min, the precipitated crystalline precipitate is filtered off and recrystallized from acetone by filtering a hot solution through a filter to obtain selenopyran with a yield of up to 92-96%, purity of at least 99.2% and selenium content in the target product 23.2-24, 0% 11. The method according to claim 10, characterized in that in addition, after filtration, the mother liquor is diluted with water, and the precipitate formed is extracted with ether, then the ether extract is dried and the solvent is distilled off, after which the residue is recrystallized from acetone and combined with that obtained in claim 10 target product. 12. A pharmaceutical preparation for eliminating selenium deficiency, characterized in that it contains a biologically active substance - selenopyran according to claim 1. 13. The drug according to item 12, characterized in that it is made in the form of tablets, powders, capsules, microcapsules, dragees, lozenges, pills, chewing gum, water and oil solutions, solutions for intramuscular injection and enteral nutrition.