Mixed cobalt (ii) salts of ketocarboxylic and mercaptocarboxylic acids and hydrates thereof, or solvates thereof, methods for production and use thereof as cyanide antidotes

FIELD: chemistry.

SUBSTANCE: invention relates to mixed cobalt (II) salts of ketocarboxylic and mercaptocarboxylic acids of general formula (I):

where R=Alk, R'=H, Alk, NH2, NHCOCH3, m=0-3, R"=H, Alk, COOH, n=0-3, where Alk=alkyl C1-C3, or to such compounds as a cobalt (II) salt of mercaptoacetic acid and pyruvic acid, a cobalt (II) salt of mercaptoacetic acid and α-ketoglutaric acid, a cobalt (II) salt of N-acetyl-L-cysteine and pyruvic acid, a cobalt (II) salt of α-ketoglutaric acid and L-cysteine, a cobalt (II) salt of pyruvic acid and 2-mercaptopropionic acid or hydrates or solvates thereof. A method of producing salts of general formula (I) is also disclosed.

EFFECT: invention enables to obtain mixed cobalt (II) salts of ketocarboxylic and mercaptocarboxylic acids, having cyanide antidote activity.

7 cl, 7 ex

 

The invention relates to the field of organic chemistry, specifically to new chemical compounds, specifically to the undocumented in the literature of mixed cobalt(N)EW salts and ketocarboxylic mercaptocarboxylic acids of the General formula (I):

where R=H, Alk, R'=H, Alk, NH2, NHCOCH3, m=0-3, R"=H, Alk, COOH, n=0-3, where Alk=alkyl (C1-C3or their hydrates or their solvates.

The LEVEL of TECHNOLOGY

The main representative group of toxic substances common toxic action is hydrocyanic acid (HCN, hydrocyanic acid). Let's consider it in more detail.

Hydrogen cyanide was first synthesized by the Swedish scientist Carl Scheele in 1782 (it is believed that after 4 years Scheele was the victim of his discovery, as he died suddenly in his lab while working). At the same time discovered its poisonous properties. In the period of the Napoleonic wars hydrocyanic acid was proposed to fill artillery shells. Hydrocyanic acid and its salts were first widely used in agriculture as a means of combating pests of fruit trees (1886) and in industry to extract gold and silver from ores (from the end of the nineteenth century-present).

As poisonous substances hydrocyanic acid was first applied on 1 July 1916 on the Somme, the French army against the German. Vyra�military combat effect could not be obtained, since the relative density of HCN vapor in the air less than 1. Attempts to weight pair of hydrocyanic acid by the addition of arsenic trichloride, tin chloride and chloroform also led to the establishment of martial concentrations of these vapors in the atmosphere.

During the second world war the Nazis had used hydrocyanic acid for the mass extermination of people in gas chambers, which used the so-called cyclones (methyl cyclone and ethyl Zyklon B), which represent the esters zanarini acid).

According to who, hydrocyanic acid is a substance lethal action, and the main condition of hydrocyanic acid vapour.

Hydrocyanic acid is a colorless transparent liquid with a smell of bitter almonds (at low concentrations). The characteristic smell is felt when air concentrations of 0.009 mg/l Hydrocyanic acid boils at +25,7°C, freezes at -13,4°C. the relative density of vapor in the air is equal to 0,93. Pair of hydrocyanic acid is poorly absorbed by activated charcoal, but well are sorbed other porous materials.

Hydrocyanic acid can be considered as the nitrile of formic acid, which exists in two structural forms in equilibrium:

Hydrocyanic acid is a very weak acid, so it can�t to be displaced from its salts of the weak acids (e.g., coal):

Therefore the salts of hydrocyanic acid store in a airtight container.

When interacting with alkalis hydrocyanic acid forms salts, which are toxic little inferior to the hydrocyanic acid, however, another route of administration.

Below are some chemical properties of hydrocyanic acid, which we will need when considering its antidotes.

Hydrocyanic acid and its salts interact with colloidal sulfur or substances, its produce, forming Rodney - non-toxic products:

And with organic sulfur compounds thiocyanates, which are much less toxic:

Interacting with aldehydes and ketones, hydrogen cyanide and its salts form a low-toxic tangerine:

Examples of such a reaction is the detoxification of cyanide with glucose.

Cyanides easily enter into the complexation with heavy metal salts, such as sulphates of iron and copper that is used in the manufacture of a chemical absorbent in the filter masks. The complexation is used for indication purposes hydrocyanic acid and its salts, and cobalt salt of EDTA is used as an antidote.

Osnovnymne penetration of vapors of hydrocyanic acid in the organism is inhaled. Not exclude the possibility of penetration of the poison through the skin at high concentrations of HCN vapor in the atmosphere. Fatal poisoning by the salts of hydrocyanic acid may at penetration into the body with contaminated water or food at a dose of 70 mg. According to the who LD50hydrocyanic acid - 2 g min/m3.

Under the action of cyanide at high concentrations or large doses develops fulminant form of poisoning. The victim loses consciousness. Develop seizures. Blood pressure after short-term growth is falling. After a few minutes stops breathing, followed by a cardiac arrest.

At relatively low concentrations of HCN leads to the intoxication of the slow-flow patterns. Latent period of virtually no.

Pair of hydrocyanic acid enters the body with inhaled air, overcome lung membranes into the blood and the blood travels to the organs and tissues. Thus there is a partial detoxification, mainly, by the formation of toxic compounds (thiocyanate), which are excreted mainly in the urine and partly with saliva. Enzyme rhodanase involved in this reaction, is located in mitochondria, mainly in the liver and kidneys:

In the body of hydrocyanic acid enter�t in the interaction cystine, cysteine, glutathione, with the formation of derivatives of 2-aminothiazoline acid.

In the process of neutralization of cyanide in the body participate carbohydrates, with the result of low cyanhydrin. Possible and oxidation of part of the hydrogen cyanide in cyanide, which is then hydrolyzed to form ammonia and carbon dioxide.

Mechanisms of toxic action of cyanides

It is established that the cyanide due to the special chemical affinity for ferric iron selectively, albeit reversibly interact with zitohromoksidasy, disrupting the activation of oxygen, interfere in the redox processes in the tissues. Thus, blocking one of the iron-containing respiratory enzymes, cyanides cause a pathological condition known as tissue or gistologicheskoe hypoxia, which is manifested by dyspnea, severe heart damage, convulsions, paralysis.

Acute injury hydrocyanic acid can occur in two forms: slow and fast. On the severity of the slow form of the lesion is divided into light, medium and heavy.

A light degree of damage. Inhalation defeat there is a characteristic smell of bitter almonds, there are unpleasant pungent metallic taste in mouth, weakness, dizziness, Golovnya, then there is nausea, vomiting, salivation, numbness of the tip of the tongue and difficulty speaking. Marked shortness of breath from the beginning of intoxication.

The average degree of damage is characterized by the fact that the signs that occur when mild, joined by a feeling of fear, a state of excitement. Breathing becomes shallow, visible mucous membranes and the skin of the face become scarlet color, pulse rare, stressful, blood pressure increased. On this background, there may be clonic convulsions and transient loss of consciousness.

Severe lesions occurs after a short latent period (minutes) and has four stages. The initial stage is characterized by subjective sensations (unpleasant pungent bitter taste and a characteristic odor of bitter almonds, etc.), difficult speech. Occurs dyspnea. Observed hypertension and tachycardia. You can observe the redness of the conjunctiva.

Diplomaticheskaja stage is characterized znachitelnim impaired respiratory activity: dyspnea, painful gasp, then replaced bradypnea with rhythm and depth of breathing. Increasing weakness, generalized anxiety, there is fear of death. Is broken, and then lost consciousness. Marked mydriasis, exophthalmos appears. Frequency CoE�heart contractions slowed down, the pulse is tense. Visible mucous membranes and skin scarlet sclera injected.

Convulsive stage runs in the background of tonic convulsions. Consciousness is lost, the irregular breathing, rare. The pulse is even more rare. Blood pressure increased. Distinct mydriasis and exophthalmos. The convulsions alternating with short periods of remission.

Paralytic stage is characterized by the cramps weaken, muscle tone decreases and induces a state of deep coma. Breathing rare, superficial, irregular, intermittent, occasional type of Cheyne-Stokes. The pulse quickens, arrhythmic, blood pressure drops sharply. The deaths from cardio-pulmonary failure.

After suffering severe poisoning often have expressed deep functional and structural abnormalities in the nervous system underlying an intoxication syndrome toxic encephalopathy. Severe lesions are often complicated by pneumonia and disorders of the cardiovascular system.

Lightning (apoplectic) form develops very quickly, within seconds. Manifested by loss of consciousness, tachypnea, tachycardia, arrhythmia, and seizures. The poisoned death occurs within a few minutes from respiratory arrest.

Mechanisms of action of antide�s

Methemoglobinaemia.

The main cyanide antidotes are metgemoglobinoobrazovatelami - nitrite reagents sodium, amyl nitrite, 4-dimethylaminophenol (antican), etc. as well As other methemoglobinaemia, these substances oxidize ferrous iron of hemoglobin to ferric state.

The main mechanism of toxic action of cyanide trapped in the blood is a tissue penetration and interaction with ferric iron the cytochromoxidase, which thus loses its physiological activity. The iron is in the divalent state (hemoglobin), these toxins do not react. If poisoned quickly type in the required number of methemoglobinaemia, the resulting methemoglobin (trivalent iron) will enter into chemical interaction with poisons, binding them and preventing the flow in the tissue. Moreover, the concentration of free toxins in the blood plasma decreases and there are conditions for the destruction of the reversible connection CYANOGEN-ion battery with zitohromoksidasy.

Practically, this competition may be important in the formation of a sufficient amount of methemoglobin in the blood:

It should be borne in mind that the methemoglobin is not capable of contact with oxygen, it is therefore necessary to apply strictly defined �Uzzah metgemoglobinoobrazovateley, since inactivation of hemoglobin by more than 25-30% develop gemicheskaja hypoxia.

Methemoglobin binds primarily cyanide, dissolved in the blood. By reducing the concentration of cyanide in the blood, the conditions for recovery of cytochromoxidase activity and normalization of tissue respiration. This is due to reverse current of cyanide from the tissues into the blood in the side of lower concentration. Formed by the complex of the cyan-methaemoglobin connection is fragile. Through 1-1,5 h this complex begins to decompose with the formation of hemoglobin and hydrogen cyanide. Therefore, the possible recurrence of toxicity. However, the process of dissociati CNMtHb extended in time, which is conducive to partial neutralization of the poison through the formation of toxic compounds. This process is accelerated if the body to enter a medication containing sulphur.

Antidote effect of dimethylaminophenol fast and stable due to the formation of MtHb, stimulation of the oppressed cyanide tissue respiration. Sodium thiosulfate potentiates its antidotal action.

Amyl nitrite is designed for first aid.

Powerful metgemoglobinoobrazovatelami is sodium nitrite (NaNO2). When assisting poisoned sodium nitrite is administered intravenously (slowly) in the form of a 1-2% solution in a volume of 10-20 ml.

Partial Mathem�globinopathiae action has methylene blue. The main action of this drug is to acceptee of hydrogen and activation of tissue respiration. In this case the recovered methylene blue can oxidize oxygen delivered by the blood, with formation of the final product of oxidation is water. The drug is administered intravenously in a 1% solution in 25% glucose solution 50 ml.

Cobalt salts

It is known that cobalt forms a strong bond with the cyanide ion. This gave the basis to test a metal salt (including cobalt chloride) as an antidote for poisoning by cyanide. The result was the positive effect. However, inorganic cobalt compounds are highly toxic, therefore of minor therapeutic breadth, which makes questionable the feasibility of their use in clinical practice. Been tested and other cobalt compounds, among the tested substances were: acetate, gluconate, glutamate, histidine cobalt and disabilitata EDTA salt. The least toxic and most effective was disabilitata EDTA salt, which comes in the form of a 15% solution in 20% glucose solution called kaloleni.

The efficiency of hydroxycobalamin for the treatment of cyanide poisoning, therapeutic effect of the drug is the result of the formation of cyanocobalamin (vitamin b12), The drug is very effective, �of Ecotoxical, but very expensive. In France, the USA and Japan it is available as a cyanide antidote (one dose of this drug costs more than 2000 $).

Carbohydrates.

Marked antitoxic action has glucose, which with hydrocyanic acid forms toxic tsiangidrin. In addition, glucose has a beneficial effect on respiration, heart function and increases diuresis. Such methemoglobinaemia as methylene blue and cobalt EDTA salt, are introduced into the glucose solutions. Other carbohydrates that contain ketogroup, for example fructose, less reactive.

Recently as cyanide antidotes were offered other activated ketones that explore mainly the oral route of administration. More detail will be discussed below.

Substances containing sulphur.

It is established that one of the ways of transformation of cyanide in the body is the interaction with organic compounds of sulphur with the formation of toxic compounds. The resulting Rodney significantly less toxic than cyanide, and excreted in the urine. The true mechanism is not fully installed, but it is shown that the introduction of sodium thiosulphate, the rate of elimination of cyanide increases by 15-30 times. This was the basis for the proposal as an antidote sodium thiosulfate.

It is possible that the process goes through the cleavage of sulfur from the hyposulphite, which the body is relatively slow. Usepurchase sulfur reacts with cyanide, forming thiocyanate.

The drug is administered intravenously in the form of a 30% solution of 50 ml.

As donor of sulfur in the body can be compounds such as cysteine, cystine, glutathione, etc.

There is evidence of a favorable therapeutic effect of unithiol, who, not being the donor of sulfur, activates the enzyme Radonezh, and, thus, accelerates the process of detoxification of HCN.

The effect of antidotes is enhanced by their use as the background of oxygenerator. In the experiment it is shown that oxygen under pressure promotes faster recovery of cytochromoxidase activity.

Thus, by the time of this study only activated derivatives of alpha-keto acids have been described as oral prophylaxis and treatment of mild and moderate lesions cyanide. Alpha-keto-acids are intermediate products of amino acid metabolism:

Alpha Ketoglutarate acid (SCC) is an important intermediate product in the processes of respiration and metabolism of proteins, fats and carbohydrates in animals, including humans. SCC is not toxic and can be applied to�sufficiently large doses. In the first reported study of the SCC, it was found that SCC and/or its combination with sodium thiosulfate has a weak, but statistically significant effect of the cyanide poisoning [1]. At the end of the last century - the beginning of this century was investigated in detail antidotal activity of both the SCC and its combinations with other antidotes, mostly with thiosulfate and sodium nitrite at various ways of introducing [2-19].

Among the 13 studied carbonyl compounds the most effective was the SCC [16]. In 1997 received a patent on a method for the treatment of cyanide poisoning with 2-propandiol (mesoxalic) acid [20]. In the text of the patent States, metaxalona acid is active at low doses (dose 0.2 g/kg by intraperitoneal route of administration) proactively protects against diabetes50cyanide. Continuation of works on mesoxalic acid was not followed, which is probably due to insufficient stability of this acid.

It was shown that the tread SCC index equal to 5 and in conjunction with intravenous sodium thiosulfate he reaches 100[2]. High antidotal effectiveness of the SCC confirmed not only in rodents but also in dogs [5]. Shows dose and time dependence of the efficiency of the SCC, the optimal time oral administration of the SCC is the time for 60 minutes prior to the introduction of cyanide [12].

P�and combined with the application of SCC with N-acetylcysteine is possible to avoid cytotoxicity and oxidative stress caused by cyanide [17,18].

It is established that the SCC when orally administered to rats prior to the introduction of CYANOGEN in doses of DM50successfully protects from poisoning acetonitrile, Acrylonitrile, malononitrile, propionitrile and sodium nitroprusside [19].

It is shown that SCC efficiency exceeds such antidotes as aminopropiophenone, cobalt edetate and sodium thiosulfate and equal in activity to the oksikobalamin; and in combination with sodium thiosulfate, their efficiency is still increasing [10].

Thus, it is clear that the SCC has an extremely high antidotal activity against cyanide and research in this direction appear relevant.

Described the synthesis of derivatives of 3-mercaptopropionate acid [21] the interaction of pyruvic acid with sulphur and sodium. The new compounds when administered 30 min. Before the action of cyanide have tread the index of 3,8-4,3. Intraperitoneal administered 5 minutes after the introduction of the cyanide zinc-index is about 4. In this work was the first to combine in a single connection 2 mechanism of action: "hidden" keto acids and sulfur-containing compound, however, the proposed compounds are unstable in air.

In the present work, the proposed compounds in the molecule which contains the elements independently �Ruga has the ability to convert the cyanide into less toxic derivatives (thiol ketocarboxylic acid and cobalt salts). The undoubted advantage of the proposed new compounds is extremely low toxicity, with an oral method of administration that allows you to quickly inactivate significant amounts of cyanide. A special advantage of these substances is their compatibility with known metgemoglobinoobrazovatelami.

Synthesized new chemical compounds mixed cobalt(II)inhibiting salt and ketocarboxylic mercaptocarboxylic acids of the General formula (I):

where R=H, Alk, R'=H, Alk, NH2, NHCOCH3, m=0-3, R"=H, Alk, COOH, n=0-3, where Alk=alkyl (C1-C3or their hydrates or their solvates.

The proposed compounds of the General formula (I) can be obtained by reacting a mixture of equinoctal aqueous solutions ketocarboxylic acids of the formula(II):

and mercaptocarboxylic acid of formula (III):

with the salt of divalent cobalt with easily detachable acidic residue, for example a basic carbonate cobalt (II) or cobalt acetate (II), and the target product is isolated in the form of a mixed salt or its hydrate or its solvate.

As the salt of divalent cobalt is convenient to use the basic carbonate cobalt (II), taken in excessive quantities. Thus unreacted primary carbonate to�of cobalt (II) was filtered off, and the target product is isolated from the aqueous solution by conventional methods.

As ketocarboxylic acids are preferably used thioglycolic (mercaptoacetate) or mercaptopropionic acid and cysteine or N-acetylcysteine.

As ketocarboxylic acids it is advisable to use existing acids in the body, for example mitxelena, pyruvic, Ketoglutarate acid.

The proposed connection can find the most diverse applications, in particular they are the antidotes cyanide.

The proposed compounds have low toxicity. Their advantage is the possibility of combining with metgemoglobinoobrazovatelami, which allows to increase the effective time of exposure to cyanide.

It gives significant benefits during oral application of the proposed compounds, therefore, priority is to be tableted dosage form.

The following examples illustrate but do not limit the claims of the applicant.

EXPERIMENTAL EXAMPLES

Despite the fact that the oxidation of divalent cobalt salts in trivalent when operating under normal conditions is unlikely, all the processes were carried out in a current of inert gas (argon) and used the prepared water is deionized water, obezvojennaya by boiling in a stream of argon and cooled in flowing argon.

Example 1.

Cobalt(2+) salt of mercaptoacetic and pyruvic acids

In odnogolosy round-bottom flask with a capacity of 0.25 l mixed 4,60 g (0,05 mole) of thioglycolic acid, 4,41 g (0,05 mole) of pyruvic acid and 100 ml of water. To this solution is added with stirring in a stream of argon 6,35 g (~0.051 mole) of the basic carbonate of cobalt (2+) [Soso3·Co(OH)2·n H2About] and the resulting brown suspension was heated on a water bath with a temperature of 40-45°C to form a dark brown solution (about 15-20 minutes), accompanied by the release of carbon dioxide. Cooled in flowing argon, the reaction mixture was filtered through a membrane filter from a small number of non-dissolved residue in odnogolosy round bottom flask with a capacity of 0.5 l. the Filtrate is dark brown evaporated to dryness on a rotary evaporator in a water jet vacuum pump and the temperature of the bath ~45°C. the Solid residue after evaporation was dried to constant weight in a vacuum desiccator over fresh portions phosphoric anhydride at a residual pressure of ~0.5 mm Hg. Get 11.9 g of dry solid dark brown color, which corresponds to a quantitative yield of the desired mixed cobalt(2+) salts of pyruvic acid and thioglycolic acid in the calculation of the monohydrate.

Found, %: 23,4; 23,2; 3,1; 3,2; S 12,9; 12,7. C5 6O5SCo·H2O. Calculated, %: C Of 23.54; N 3,16; S 13,03.

IR spectrum (tablet with KBr): 3415, and 3274 sh. cm (stretching vibrations of HE water of hydration), arr. 2919 cm (stretching vibrations of C-H), 1704. cm (characteristic oscillation frequency ketonic carbonyl group), 1601 sh. cm (stretching vibrations of C-O carboxylate groups), 1394, 1372 and 1342 sh. cm (deformation vibrations of C-H), and 1117 1224 sh. cm (deformation vibrations of HE water of hydration), 795 sh. cm (stretching vibrations of C-S).

These data confirm the structure of cobalt(2+) salt of mercaptoacetic and pyruvic acids

Example 2.

Cobalt(2+) salt of mercaptoacetic and α-Ketoglutarate acids

In a flask with a capacity of 0.25 l of dissolved 7,31 g (0,05 mole) of α-Ketoglutarate acid in 100 ml of water and to the resulting clear colorless solution was added with stirring a solution 4,61 g (0,05 mole) of thioglycolic acid in 50 ml of water. In the obtained homogeneous colorless solution pour when mixing is 8.84 g (~0,075 mol) of the basic carbonate cobalt(II). While there was a foaming reaction mixture (due to the release of carbon dioxide) with staining it a dark brown color. The reaction mixture was heated on a water bath with a temperature of ~50°C for half an hour with periodic stirring, and then, without cooling, it was filtered through a porous glass filter� No. 4 in ovoid flask 0.25 l Small residue of dark brown color on the filter was washed three times with small portions (3×30 ml) water. The combined filtrate is evaporated to dryness on a rotary evaporator in a water jet vacuum pump (temperature of the bath ~45-50°C). The solid residue after evaporation was dried to constant weight in a vacuum oil pump. Get 17,94 g of solid crystalline product is dark brown (almost black) color

Found, %: 23,4; N 3.2. C14H14O14S2Co·4H2O. Calculated, %: 23,38; N Is 3.08.

These data confirm the structure of cobalt(2+) salt of mercaptoacetic and α-Ketoglutarate acids:

The IR spectrum of the product does not contradict the proposed structure

Example 3

Cobalt(II) salt of N-acetyl-L-cysteine and pyruvic acid,

In Erlenmeyer flask with a capacity of 0.25 l load 8.16 g (0,050 mole) of N-acetyl-L-cysteine and ~50 ml of water. With about half taken N-acetyl-L-cysteine goes into solution. To the resulting suspension is added to 4.40 g (0,050 mole) of pyruvic acid, and adding portions of water to dissolve the remaining crystals of N-acetyl-L-cysteine. To the resulting colorless solution was added with stirring 5,90 g (~0,05 mole) of the basic carbonate cobalt(II). Almost immediately thereafter, the reaction mixture began to bubble up due to the intense selection carbonic�about gas and stained a dark brown color. To complete the salt formation reaction, the reaction mixture is heated with stirring to ~50°C, after which, without cooling, was filtered through a porous glass filter No. 4. Brown-violet precipitate on the filter is washed three times with water(3×20 ml). The combined filtrate is evaporated to dryness on a rotary evaporator in a water jet vacuum pump the temperature of the bath was 40°C. the Residue after evaporation was dried to constant weight in a vacuum desiccator (at a residual pressure of ~1 mm Hg. tbsp.) over phosphorus pentoxide. Got 16,30 g of solid powdered dark brown product, which according to the results of elemental analysis and IR spectroscopy was identified as the monohydrate mixed cobalt(II) salt of N-acetyl-L-cysteine and pyruvic acid,

Found, %: 29,3; 29,5; 4,0; 4,2; N 4,0; 4,0; S 9.7; 9,6. C8H11NO6SCo·H2O. Calculated, %: 29,46; N 4,02; 4,29 N; S Case 9.83.

IR spectrum (Tablet with KBr): 3385 sh. cm (NH stretching vibrations of amide groups of N-acetylcysteine), 3274 sh. cm (stretching vibrations of HE water of hydration), ~2920 sh. cm (stretching vibrations of C-H), ~2650 sh. cm (SH stretching vibrations), 1764. cm (stretching vibrations of C=O), 1701 sh. cm (characteristic oscillation frequency ketonic carbonyl), 1608 arr. see (applying the stretching vibrations of C=O carboxylate group and the Amide I band 1540 arr. cm (Amide II band - deformation vibrations of the NH amide group N-ACO�intestinalnogo residue), 1401, 1372 and 1342 sh. cm (deformation vibrations of C-H), 1224,1200 and 1109 sh. cm (stretching vibrations of C-O and deformation vibrations of O-H water of hydration), ~795 sh. cm (stretching vibrations of C-S).

Example 4

Cobalt(2+) salt of α-Ketoglutarate acid and L-cysteine

In odnogolosy round-bottom flask with a capacity of 0.5 liters mixed in the dry state 6,00 g (0,0495 mole) of L-cysteine and of 7.24 g (0,0495 mole) of α-Ketoglutarate acid and to this mixture are added with stirring 150 ml of prepared water. The resulting suspension pretty quickly dissolved to form a clear, slightly yellowish solution. In pour this solution with stirring in a stream of argon 6,35 g (~0,051 mol) of the basic carbonate of cobalt(2+) [Soso3·Co(OH)2·n H2O] and the resulting brown suspension was heated on a water bath with a temperature of ~50°C for 20-30 minutes until formation of a brown solution with a small amount of not dissolved into a brown residue. The solution was cooled in flowing argon to room temperature and filtered through a membrane filter into a round bottom flask with a capacity of 0.5 l. the Residue on the filter was washed three times prepared with water (3×50 ml) and the combined filtrate evaporated to dryness on a rotary evaporator in a water jet pump vacuum at a residual pressure of 10 mm Hg. column and the temperature of the bath ~40�C. The residue obtained solid brown color with a slight purple hue, which is finally dried to constant weight in a vacuum desiccator at a residual pressure of ~0.5 mm Hg over phosphorus pentoxide. Get 16,49 g of solid powdered product brown color, which corresponds to a quantitative yield of cobalt(2+) salt of α-Ketoglutarate acid and L-cysteine in terms of semihydrate.

Found, %: 28,3; 28,4; N 3,6; 3,6; 4,0 N; 4,1. C8H11NO7SCo·0,5 H2O. Calculated, %: 28,84; 3,63 N; N 4,20.

The IR spectrum of the product (Tablet with KBr): 3442 and 3335 sh. cm (stretching vibrations of Oh groups of water of hydration), 3162 sh. cm (stretching vibrations of NH3), 2963 sh. cm (stretching vibrations of C-H linkages), 2563 sh. cm (SH stretching vibrations), 1704. cm (characteristic oscillation frequency ketonic carbonyl group C=O), 1603 and 1635 arr. cm (absorption bands of ionized carboxyl groups), 1588 sh. cm (deformation vibrations of NH3- band 1 amino acid), 1431, 1406 1366 and arr. cm (deformation vibrations of CH2group), 1272, and 1194 1237 sh. cm (stretching vibrations of C-O in carboxylate group and the stretching vibration of C-N), and 829 877 arr. cm (deformation vibrations of hydrated O-H group), 633 sh. cm (stretching vibrations of C-S).

These data confirm the structure of semihydrate cobalt(2+) salt of α-Ketoglutarate acid And L-cysteine of the formula/p>

Example 5.

Cobalt(2+) salt of pyruvic acid and 2-mercaptopropionic acid

In odnogolosy round-bottom flask with a capacity of 0.25 l of dissolved 5,57 g gram (0,050 mole) of 2-mercaptopropionic acid in 50 ml of treated water, To the resulting clear solution is added to 4.40 g (0,050 mole) of pyruvic acid and to this mixture was added at turns 75 ml of prepared water. In pour this solution with stirring in a stream of argon 6,50 g (~0,052 mol) of the basic carbonate of cobalt(2+) [Soso3·Co(OH)2·n H2About]. In this case the reaction mixture immediately turned brown with simultaneous foaming due to the release of carbon dioxide, which lasted about 10 minutes. After stirring the reaction mixture at room temperature in a stream of argon for 30 min it was filtered through a porous glass filter No. 3. Gray-brown with a violet tint the precipitate on the filter represents the excess of the basic cobalt carbonate, unreacted. The filtrate obtained is dark brown (almost black) color was evaporated to dryness on a rotary evaporator in a water jet pump vacuum (at a residual pressure of 10 mm Hg. column and the temperature of the bath at 40-50°C). The residue after evaporation was dried to constant weight � a vacuum desiccator (at a residual pressure of 1 mm Hg. column) over phosphorus pentoxide. Got 14.2 g of product, which output, to the data of elemental analysis and IR spectroscopy was identified as the target dehydrate mixed complex of cobalt(II) salt of 2-mercaptopropionic and pyruvic acids.

Found, %: 25.3; 25.4 Mm; N 3,8; 3,9; S 11,3; 11,1; 20,5; 20,2. C6H8O5SCo·2H2O. Calculated, %: 25,10; N 4,21; S 11,17; With Of 20.52.

The IR spectrum of the product (tablet with KBr): 3393 sh. cm (stretching vibrations of O-H water of hydration), 2987 and 2933 sh. cm (stretching vibrations of C-H), 1760 sh. cm (stretching vibrations of C=O ketogroup), 1590 sh. cm (asymmetric and symmetric stretching vibrations of C-O carboxylate group); 1453,1401 and 1374 sh. cm (deformation vibrations of C-H); 1280,1224,1158 and 1076 sh. cm (deformation vibrations of IT and stretching vibrations of C-O); 729,660 and 585 sh. cm (stretching vibrations of C-S). As can be seen from the spectrum, the absence of pronounced absorption band in the region 2550-2600 arr. cm most likely indicates that the formation of mixed cobalt(II) complex is actively involved mercaptopropyl the thioglycolic acid.

Example 6.

Cobalt(II) salt of pyruvic acid and 3-mercaptopropionic acid (1E).

Prepared analogously to example 1 from 12,67 g (~0,1 mole) of cobalt carbonate basic aqueous 9,00 g (0,10 mol) of pyruvic acid and 10,72 g of 3-mercaptopropionic acid (0,10 mol). Got 24,98 � solid powder (after grinding the pieces in a porcelain mortar) product which output, the results of elemental analysis and IR spectroscopy corresponds to the formula:

Found (%): 28,96; 29,02; 3,34 N; 3,33; S 12,97; 13,23. C6H8O5SCo. Calculated (%): 28,70; N 3,21; S 12,77.

The IR spectrum of the product (tablet with KBr): 3429 sh. cm (stretching vibrations of O-H water of hydration), 2937 sh. cm (stretching vibrations of C-H), 1702. cm (stretching vibrations of C=O ketogroup), 1599 sh. cm (asymmetric and symmetric stretching vibrations of C-O carboxylate group); 1402 and 1360 sh. cm (deformation vibrations of C-H);,1141 sh. cm (deformation vibrations of IT and stretching vibrations of C-O); 660 sh. cm (stretching vibrations of C-S), 2554 sh. cm (SH stretching vibrations).

Example 7.

As an example, described experiments with cobalt(2+) salt of mercaptoacetic and pyruvic acid (Example No. 1).

All of the proposed compounds have low toxicity.

The indicators of the acute toxicity of cobalt(2+) salt of mercaptoacetic and pyruvic acids (I) include experiments on rats and rabbits of both sexes.

Experimental studies showed that the antidote I with acute administration of experimental animals has a toxic effect at doses of 2000-5000 mg/kg in rats and 1000-3000 mg/kg in rabbits.

The magnitude of LD50after intragastric administration range from 300±460 mg/kg (rats males) up to 3100±350 mg/kg (female rats) and from 1500±120 mg/kg (rabbits males) to 1800±220 mg/kg (female rabbits).

The death of animals after intragastric administration was observed within a day from the time of introduction at the phenomena of physical inactivity, lethargy, shortness of breath, lethargy, ataxia, transient seizures in atonal stage and paralysis.

Most survived the intoxication of the animals on the first day was marked lethargy, lethargy, reduced feed and water consumption, diarrhea. Further, no noticeable violations of state or behavior of animals in the experimental groups compared to control were observed throughout the observation period. The clinical picture of intoxication in all experimental groups was the same. Sex differences in the course of intoxication were observed.

According to the autopsy and macroscopic studies of acute intragastric administration of dosage forms of cyanide antidote in non-lethal doses does not cause macroscopic changes in the internal, endocrine organs and brain of experimental white rats and rabbits, and is not accompanied by changes in the mucous membrane of the stomach and intestines.

The autopsy of the dead rats and rabbits revealed a venous plethora of internal organs, subpleural and subdural hemorrhages, and small hemorrhages in the medulla oblongata and the cerebral hemispheres of the cortex.

Thus, the results of toxicometric, with observations in the experimental�the remaining animals for 14 days in an intoxication the acute toxicity, and these necropsia allows us to include the investigational antidote (I) class IV, low-toxic drugs [22], since the LD50after intragastric administration of antidote rats is in the range 500 - 5000 mg/kg.

Found that while the introduction of poison (sodium cyanide) in doses of LD50and LD99the antidote shot leading symptoms of intoxication by 75-100% and prevented the death of animals. Index of protection (FROM) and antidotal power (AM) after intragastric administration of antidote at a dose of 300 mg/kg immediately after poisoning with sodium cyanide amounted to 1.40 and 1.08, respectively.

Prophylactic administration of antidote for 30 minutes before the poison in a 1.8 times increased these indicators, in line with I3 - 2.5, PM - 1.9.

It is shown that the duration of preventive therapeutic action of the antidote is in the range of 30-60 min, during which was attenuated symptoms of poisoning, and survived most of the affected animals with severe toxicity at a dose of LD99. When studying the effect of the antidote on the oxygen consumption of the body and the external respiration for poisoning rats by sodium cyanide showed that administration to rats of antidote in the tested doses weakened the characteristic toxic effect of cyanides effect, consisting in the violation of the body's ability to utilize oxygen.

In experiments on gry�the University (rats of both sexes) the antidote (I) cyanide was administered intragastrically atraumatic iron probe in aqueous solution daily for 5 days in 3 doses: effective for rodents 300 mg/kg; maximum, not causing death after a single use, and 1000 mg/kg), intermediate (500 mg/kg.

During the experiment observed the death of experimental animals, indicating the Presence of possible cumulative properties. In the experiment, the rats of the third experimental group received a total of 5000 mg/kg of the drug. The proposed LD50repeated dose (3000 mg/kg) to the LD50after a single dose (2500 mg/kg) is more than 1.2, indicating a weak accumulation [23].

At the maximum dose of 1000 mg/kg, most rabbits were observed lethargy, lethargy, decreased feed intake, water and diarrhea. The introduction of the antidote in the doses of 300 and 500 mg/kg did not affect the appearance, General condition and behavior of animals. In some animals to the sixth day of the study indicated liquid stools. In the recovery period negative effects in the gastrointestinal tract were observed, the General condition or behaviour of the animals compared to the control were observed. Animals slightly lagged in weight on day 6 of the study, but at the end of the recovery period on the 28 day weight experimental groups did not differ from the weight of the control animals. Sex differences also were observed.

Animals of the experimental group during the introduction of drug consumption�Yali food in smaller, and the water in greater numbers than in the control groups. During the recovery period forage and water consumption among all experimental groups was the same. Sex differences or differences related to the level of dosing, were observed.

Significant changes of renal function when administered antidote to white rats was observed.

These measurements of rectal temperature may indicate differences in animals from the experimental and control groups.

In the study of the patterns of behavior of rats in "open field" At a dose of 300 mg/kg is noted statistically significant increase of the latent period, while all other parameters remain unchanged. At doses of 500 and 1000 mg/kg there has been a General decrease in the activity of the animals, as measured by the duration of the latent period, the number of vertical pillars of crossings and zaglyadyvanie compared to background data and control while on maximum dose of these changes was significantly significant. At the end of the recovery period in the structure of behavior authentically significant changes in the experimental groups were not observed.

In experimental animals when administered antidote dose of 300 mg/kg 6 days after the start of administration, a slight decrease in spontaneous locomotor activity (SDA) compared with LM�now one control group. At doses of 500 and 1000 mg/kg reduced SDA was statistically significant. The observed effect of the antidote on SDA wore dogowosajy character. At the end of the recovery period SDA in the experimental groups did not differ from baseline values.

The investigational antidote did not cause changes in heart rate, as well as the ECG.

On day 6 studies in experimental animals, the use of the antidote did not cause significantly significant pathological haematological changes, except a slight increase in the hematocrit and coagulation time of the blood of animals Received a dose of 1000 mg/kg. Sex differences have not been identified. On day 28 of the study, significant differences between the performance of control and experimental groups is not fixed.

As can be seen from the data presented above, both the males and females of the experimental groups at doses of 300, 500 and 1000 mg/kg after 5 days of continuous use of the drug biochemical parameters were within the physiological norm compared to the background and control. The only exception was the rate of prothrombin time, which was significantly increased on day 6 when administered 1000 mg/kg as rats males and females. 28 day observation of significant differences between the study groups for all indicators were absent.

Thus, at the end of the observation period peripheral blood of rats of all ek�experimental groups according to their quantitative and qualitative composition corresponded to species physiological norm.

The details of the dissection and macroscopic examination showed that significant differences in mass ratios of organs of rats of all experimental groups are absent for 6 days, and at 28 day recovery period.

The dead rats that received a dose of 1000 mg/kg, the brain was edematous, smart smoothed, flattened furrow. Throughout the distribution of gray and white matter of the brain was right with preservation of topographic-anatomical relationships. Noted marked hyperemia of the vascular bed. The rest of necropsy rats in this group did not differ from necropsy animal carcasses,

At the end of the recovery period (28 days) these necropsy rats receiving doses of 300, 500 and 1000 mg/kg, did not differ from the control animals.

According to the results of necropsy and histological study of daily oral administration of the dosage form of cyanide antidote in the doses of 300, 500 and 1000 mg/kg for 5 days to rats of both sexes does not cause irritation, inflammation or destruction of tissue in the gastrointestinal tract and is not accompanied by the development of dystrophic and destructive, focal sclerotic changes in the parenchymal cells and the stroma of internal organs.

Thus, the use of oral dosage forms of the antidote cyanide� in rats of both sexes intragastrically once a day for 5 days at doses of 300 and 500 mg/kg did not significantly affect the appearance, the General condition and behavior of animals, not have a negative impact on biochemical parameters of blood and basic physiological functions of the body, does not cause pathological changes, indicating a good tolerability and low toxicity of the drug.

Changes in the maximum dose of antidote - 1000 mg/kg, short-term and are not recorded after the recovery period.

In experiments on rabbits it was shown that sub-acute intragastric administration of a dosage form of antidote to the rabbits of both sexes once a day for 5 days at doses of 40 and 200 mg/kg did not affect the appearance, General condition and behavior of animals. However, in some animals to the sixth day of the study indicated liquid stools. In the recovery period negative effects in the gastrointestinal tract was observed. At maximum dose, 500 mg/kg, most rabbits were observed lethargy, lethargy, decreased feed intake, water and diarrhea. In the recovery period, no noticeable violations of state or behavior compared to the control were observed.

It should be noted that during the experiment the 5-day administration of the drug was observed the death of the test animals at the highest dose, indicating the presence of possible cumulative properties � antidote. In the experiment, the rabbits of the third experimental group received a total of 2500 mg/kg of the drug. The proposed LD50repeated dose (2000 mg/kg) to the LD50after a single dose (1650 mg/kg is the average between the LD50rabbits males and LD50rabbits females) is more than 1.2, indicating a weak accumulation [23].

Animals treated with the antidote, slightly lagged in weight on day 6 of the study, but at the end of the recovery period on the 28 day weight of rabbits in experimental groups did not differ from the weight of the control animals. Sex differences also were observed.

Animals of the experimental group during the introduction of the drug consumed food in smaller, and the water in greater numbers than in the control groups. During the recovery period forage and water consumption among all experimental groups was the same. Hearth differences or differences related to the level of dosing, were observed.

These measurements rectal temperature indicative of the absence of differences the registered rate in animals of the experimental and control groups.

Significant changes in renal excretory function with the introduction of the sample antidote rabbits were observed.

At a dose of 500 mg/kg antidote evoked in rabbits statistically significant increase in h�in frequency of heart-throbs, the decrease in the voltage of teeth R and R, as well as reduction of intervals PQ and QT. The maximum change was observed after 30-120 minutes after administration of the antidote. On the sixth day and at the end of the recovery period, significant differences between control and experimental groups as well as sex differences have not been recorded. Doses of 40 and 200 mg/kg had no effect on heart rate and nature of the electrocardiogram of rabbits.

It should be noted that experimental animals on day 6 of the study were observed authentically significant pathological haematological changes, except a slight increase in the hematocrit and the erythrocyte sedimentation rate in animals that received a dose of 500 mg/kg. Sex differences have not been identified.

On day 28 of the study, significant differences between the performance of control and experimental groups is not fixed. Thus, at the end of the observation period peripheral blood of rabbits in all experimental groups according to their quantitative and qualitative composition corresponded to species physiological norm.

In rabbits of experimental groups at doses of 40, 200 and 500 mg/kg after 5 days of continuous use of the drug, biochemical indices of peripheral blood were within the physiological norm compared to the background and control. The only exception was the rate of prothrombin time, which �octobern increased on day 6 when administered 500 mg/kg as rabbits males, and females. On the 28th day of the study significant differences between the study groups for all indicators were absent.

The details of the dissection and macroscopic examination showed that significant differences in mass ratios of the organs of rabbits in all experimental groups are absent for 6 days, and at 28 day recovery period.

The dead rabbits that received a dose of 500 mg/kg, with the view of histological preparations of the brain was observed uneven dystrophic changes of neurons in combination with irregular perivascular and pericellular edema. Noted marked hyperemia of the vascular bed, in combination with multicentric circulation disorders - microchromosomes in various stages of progression. The rest of the data necropsied rabbits of this group did not differ from data obtained in the study of bodies of dead animals.

When viewing of histological preparations of organs of control animals and organs of animals treated with the drug at doses of 40, 200 and 500 mg/kg, after the recovery period, on day 28 of the study, differences between groups were not found.

Changes in the maximum dose of antidote - 500 mg/kg, short-term and are not recorded after the recovery period.

In the results of�there necropsy and histological study of daily oral administration of the dosage form of cyanide antidote in doses of 40, 200 and 500 mg/kg for 5 days in rabbits of both sexes does not cause irritation, inflammation or destruction of tissue in the gastrointestinal tract and is not accompanied by the development of dystrophic and destructive, focal sclerotic changes in the parenchymal cells and the stroma of internal organs.

Thus, the introduction of the cyanide antidote cobalt(2+) salt of mercaptoacetic and pyruvic acids (I) rabbits of both sexes intragastrically once a day for 5 days, at doses of 40 and 200 mg/kg does not affect the appearance, General condition and behavior of animals, not have a negative impact on biochemical parameters of blood and basic physiological functions of the body, does not cause pathological changes, indicating a good tolerability and low toxicity of the drug.

Further proof of the extremely low toxicity of the proposed compounds is to compare the relative toxicity per cobalt ion With++. In inorganic compounds of cobalt(2+) in experiments on mice and rats by oral method of administration toxicity in the calculation of the cobalt ion is 30÷80 mg/kg, salts of amino acids up to 150 mg/kg. Given that the proposed toxicity of compounds in experiments on rats is 3000 mg/kg, molecular weight of safener(I), 255, cobalt ion ha�are consistent with approximately 700 mg/kg, what toxicity is significantly below all described in the literature of cobalt.

LITERATURE

1. C. Schwartz, R. L. Morgan, L. M. Way et al., Toxicol. Appl. Pharmacol., v. 50, p. 437-441, 1979.

2. S. J. Moore, J. C. Norris, K. H. Ing et al., Toxicol. Appl. Pharmacol., v. 82, p. 40-44, 1986.

3. R. Bhattacharya, R. Vijayaraghavan, Biomed. Environ. Sci., v. 4, p. 452-460, 1991.

4. H. A. Yamamoto, Toxicol., v. 61, p. 221-228,1990.

5. J. C. Norris, W. A. Utley, A. S. Hume, Toxicol., v. 62, p. 275-283, 1990.

6. R. R. Dalvi, S. G. Sawant, P. S. Terse, Vet. Res. Comm., v. 14, p. 411-414, 1990.

7. G. Delhumeau, A. M. Cruz-Mendoza, Lojero C. G., Toxicol. Appl. Pharmacol., v. 126 p. 345-351, 1994.

8. A. S. Hume, J. R. Mozino, V. L. Bryon et al., Clinical Toxicol., v. 33, p. 721-724, 1995.

9. A. S. Hume, J. S. Moore, A. T. Hume, Toxicologist, v. 3, p. 98, 1996.

10. A. S. Hume, J. R. Mozino, L. A. Chaney, Toxicol. Lett., v. 95 (Suppl. 1), p. 84, 1998.

11. R. Bhattacharya, Indian J Pharm., v. 32, p. 94-101, 2000.

12. R. Bhattacharya, R. Vijayaraghavan, Hum. Exp. Toxicol, V. 21, p. 297-303, 2002.

13. R. K. Tulsawani, M. Debnath, S. C. Pant et al., Chem. Biol. Interact., v. 156, p. 1-12, 2005.

14. R. K. Tulsawani, R. Bhattachafya, Biomed. Environ. Sci, v. 19, p. 61-66, 2006.

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16. R. Bhattaeharya, R. K. Tulsawani, Drug Chem. Toxicol., v. 31, p. 149-161, 2008.

17. R. M. Satpute, J. Hariharakrishnan, R. Bhattacharya, Neurotoxicol., v. 29, p. 170-178, 2008.

18. J. Hariharakrishnan, R. M. Satpute, G. B. K. S. Prasad et al., Toxicol. Lett., v. 185, p. 132-141, 2009.

19. R. Bhattacharya, R. M. Satpute, J. Hariharakrishnan, Food Chem. Toxicol., v. 47, p. 2314-2320, 2009.

20. U.S. patent No. 5674904, CL. 514/574, published. 07.10.1997.

21. H. T. Hagasawa, D. J. W. Goon, D. L. Crankshaw et al., J Med. Chem., v. 50, p. 6462-6464, 2007.

22. H. Hodge et al., Clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV, Baltimore, 1975, 427 R.

23. Methodological guidelines for the study obstacleavoidance pharmacological substances, quoted in kN. "Manual on experimental (preclinical) study of new pharmacological substances". M.: Medicine, 2005, pp. 41-53.

1. Mixed cobalt(II)inhibiting salt and ketocarboxylic mercaptocarboxylic acids of the General formula (I):

where R=Alk, R'=H, Alk, NH2, NHCOCH3, m=0-3, R"=H, Alk, COOH, n=0-3, where Alk=alkyl (C1-C3
or compounds such as cobalt(II)inhibiting salt of mercaptoacetic and pyruvic acid, cobalt(II)inhibiting salt of mercaptoacetic and α-Ketoglutarate acid, cobalt(II)inhibiting salt of N-acetyl-L-cysteine and pyruvic acid, cobalt(II)inhibiting salt of α-Ketoglutarate acid and L-cysteine, cobalt(II)inhibiting salt of pyruvic acid and 2-mercaptopropionic acid or their hydrates or their solvates.

2. Mixed salt according to claim 1, characterized in that as mercaptocarboxylic acids are thioglycolic or mercaptopropionic acid, or cysteine or N-acetylcysteine.

3. Mixed salt according to claim 1, characterized in that as ketocarboxylic acids are mitxelena, or pyruvic acid, or Ketoglutarate acid.

4. A method of obtaining a mixed cobalt(II)inhibiting salts and ketocarboxylic mercaptocarboxylic acids of the General formula (I):

where R=Alk, R'=H, Alk, NH2, NHCOCH3, m=0-3, R"=H, Alk, COOH, n=0-3, where Alk=alkyl (C1-C
namely that of an equimolar mixture of ketocarboxylic acids of the formula (II):

and mercaptocarboxylic acid of formula (III):

in the aqueous solution is subjected to the interaction with the salt of divalent cobalt with easily detachable acid residue, and the target product is isolated in the form of a mixed salt or its hydrate.

5. A method according to claim 4, characterized in that as the salt of divalent cobalt with easily detachable acid residue use basic carbonate cobalt (II) or cobalt acetate (II).

6. Mixed cobalt(II)inhibiting salt and ketocarboxylic mercaptocarboxylic acids according to claim 1, having antidote activity against cyanide.

7. Mixed salts of the General formula (I) according to claim 1 which has preventive and therapeutic anthocyanines activity by oral route of administration.



 

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3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to zinc-containing antidote of lethal and severe poisonings with ethanol. Claimed antidote represents intramolecular tricyclic complex of triethanolamine with zinc salts of inorganic or organic acids (2, 8, 9-trihydrozincatran), the ratio of triethanolamine to zinc salts being 1:1. Invention also relates to method of treating ethanol poisoning by introduction into organism of zinc-containing antidote in 5 vol.% ethanol in dose range 30-60 mg/kg of body weight.

EFFECT: prevention of lethal outcome in case of ethanol poisoning and reduction of acute toxicity of zinc-containing antidote.

9 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: Chinese magnolia is extracted with liquefied carbon dioxide. The obtained CO2 extract undergoes chromatographic separation on aluminium oxide and eluated with hexane. After eluation the obtained hexane fractions are frozen and recrystallised from the chloroform-hexane mixture in ratio of 1:10-3:10.

EFFECT: high output of product.

1 ex

FIELD: medicine; veterinary science.

SUBSTANCE: method consists in introduction to an experimental animal of Acyzol 30 mg/kg once a day combined with daily subcutaneous introduction of cadmium sulphate solution in a dose 0.1 mg/kg.

EFFECT: prevention of cadmium toxic effect in chronic poisoning in experimental animals.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antifungal preparation, containing effective quantity of methyl ether of 2-benzimidazolylcarbamic acid, or its salts with inorganic and organic acids, or their hydrates, or its complex compounds with organometallic and inorganic salts, containing transition metal. Claimed invention demonstrates antifungal activity with respect to causative agents of mycoses from the group, including Trichophyton mentagrophytes var. Interdigitale, Trichophyton rubrum, Microsporum canis, Trichophyton mentagrophytes var. granulosum, Candida albicans. Antifungal activity has been detected with respect to pathogenic and opportunistic fungi, causing mycoses of mucosa and skin in humans and animals.

EFFECT: increased activity of preparation.

9 cl, 4 tbl, 28 ex

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