Drug (versions) and the method of its production

 

The invention relates to medicine, namely to drugs with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect. Drug (7 options) contains a mixture of two or three alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. The method of manufacture of a medicinal product is to obtain these salts and their mixtures by conducting cycle of the source compounds and intermediate compounds to obtain the target product with reuse mother solutions in the specified process after the selection of these solutions intermediate composition and the target product. Developed variants of the drug differ in duration and spectrum of activity, and pharmacokinetic parameters and depending on the execution of alkaline salts can be used in oral and intramuscular injecting and other medical procedures. The proposed method of production of drugs is a high-tech low-waste process of pharmaceutical production. 8 C. and 34 C.p. f-crystals, 3 tab., 4 Il.

The invention of pharmaceutical production of of these medicines.

Known drug "sodium nucleate" sodium salt of nucleic acid representing the preparation of immunomodulating actions in the form of a white or slightly yellow powder, easily soluble in water with formation opalestsiruyuschih solutions, with the ability to stimulate migration and cooperative T and b-lymphocytes, increase the phagocytic activity of macrophages and the activity factors of nonspecific resistance (see, for example, M. D. Mashkovsky. Drugs.-M.: Medicine, 1985, so 2, S. 172).

However, injecting this drug painful, and this necessitates the introduction of additional patients painkillers that are not always shown.

The closest pharmacological analog prototype is used as immunomodulator and has anti-inflammatory and antioxidant properties of the drug, sodium salt of 5-amino-2,3-dihydrophenazine-1,4-dione, representing salt lyuminola in the form of a white or light yellow easily water-soluble crystalline powder (see , for example, the patent of the Russian Federation 2163122 priority from 01.08.2000, IPC And 61 To 31/502, And 61 R 37/02, 29/00).

The above drug-in-1,4-dione with a weak reaction of cellular immunity, for example, in the presence of malignant tumors, causes activation of macrophages, which is manifested by the release of their TNF (tumor necrosis factor, interleukins and other ostrofsky proteins. In inflammatory processes this immunomodulator for a few hours inhibits the activity of macrophages, but also reinforces the microbicide system cells.

This medicine does not cause allergic reactions and other side effects, but it has a limited range (a range) of validity limited to the duration of the activity (renewal) in biological systems, and, in addition, because of the impurities which it contains, it does not provide long term storage it in aqueous solutions, prepared, for example, injection, irrigation, or inhalation.

A method of obtaining 5-amino-2,3-dihydropteridine-1,4 (lyuminola), including the recovery of 3-nitrophthalic acid in aqueous medium by hydrazinehydrate in the presence of skeletal Nickel catalyst followed by evaporation of the solution and it is heated at a temperature of 120oIn the presence of hydrazine hydrate is added and acetic acid, which is used as chemiluminescence (see, naati target product in powder form, having good luminescence properties. However, the application of lyuminola as drug ineffective, since it is practically not soluble in water or in saline and isotonic solutions of different types, or in the usual organic solvents. Therefore, when applying lyuminola, for example, as phosphor its not clear after synthesis, and use in technical form.

The closest in terms of the synthesis of pharmaceuticals the analog prototype is a way to obtain the sodium salt of 5-amino-2,3-dihydrophenazine-1,4-dione (see, for example, the patent of the Russian Federation 2155043 with priority dated 28.03.2000), including the interaction of 3-nitrophthalic anhydride with hydrazinehydrate in acetic acid at temperatures (90-120)oWith receipt of 5-nitro-2,3-dihydrophenazine-1,4-dione, by restoring whose hydrazinehydrate in aqueous-alkaline medium in the presence of skeletal Nickel catalyst to produce 5-amino-2,3-dihydrophenazine-1,4-dione, after processing, of which sodium hydroxide with the addition of a lower alcohol or ketone obtain the target product.

However, the chemical structure and the individuality of this product and its purity in the above method of synthesis actually technical capabilities does not give a convincing answer to these questions. At the same time, technical sodium salt lyuminola, and the technical luminal, which, after their synthesis does not purged, in addition to the main substances that contain impurity chlorides, sulphates, heavy metals (trace Ni-catalyst), nitro and amino compounds, aromatic acids, activated carbon and other Technical sodium salt lyuminola additionally contaminated with sodium hydroxide, which was used in the process.

Studies have shown that, although this method provides a synthesis of the product with medicinal properties, the resulting preparation is contaminated with numerous impurities, which does not allow its storage in aqueous solutions, prepared, for example, injection, irrigation, or inhalation. In addition, this method is imperfect technologically, as used in its implementation of the components after separation of the target product are no longer used, and they go to waste, and this waste falls and uncovered from the reaction mixture the residue of the target product after separation of the mass from the reaction environment.

The essence of the invention lies in the fact that the drug, obrazuetsa fact, it contains a mixture of lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. %: sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 1,0-98,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, antitumor, anti-inflammatory and antioxidant effect, characterized by the fact that it contains a mixture of lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. % of: potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - 1,0-98,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione-rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, antitumor, anti-inflammatory and antioxidant effect, characterized by the fact that it contains a mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. %: sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 1,0-98,0; potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, about the camping lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt.%: sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 1,0-85,5; potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 1,0-55,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized by the fact that it contains a mixture or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and drinking water or water for injection in the following ratio of components, wt. %: the mixture of these alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 0,5-25,0; water - the rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized by the fact that it contains a mixture or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and a filler pane With, when the following ratio of components, wt.%: the mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 5,0-50,0; filler - rest.

The essence of the invention lies in the fact that the drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized by the fact that it is made in the form of a solution mixture or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and filler in the form of five - or setiathome alcohol, such as xylitol, or carbohydrate, such as glucose, and/or vitamin, such as vitamin C, or in drinking water, or in water for injection in the following ratio of components, wt.%: the mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 0,25-25,0; filler 0,25-25,0; water - the rest.

While this mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione made in the form of salts or technical, or chemically pure salts, or salts of high purity, or drug chemically pure salts, or pharmaceutical salts of high purity.

The invention consists in that in the method of production lekarstvi action including the impact of an aqueous solution of alkali metal hydroxide to the original composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione, followed by precipitation using an organic solvent the resulting impact of intermediate composition in the form of alkali metal salts of 5-amino-2,3-dihydro-3-dihydro-1,4-phthalazinedione, and obtaining the target product, the production of medicines are repetitive cycles, each of which on the source composition containing commercial or technical, or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione, or mixtures thereof, affect aqueous solution of alkali metal hydroxide or mixture of hydroxides of alkali metals, and the intermediate composition correspondingly in the form of technical or chemically clean the corresponding salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixture of such salts, and then this intermediate composition is dissolved in water or in a suitable bicarbonate buffer solution and treated to obtain the target product, respectively, in the form of chemically pure or drug chemically pure or purity, or medical high purity salt of 5-amino-2,3-dihydro-1,4-phthalazinedione after isolation of the intermediate part or the target product uterine solutions processed, and received after this processing residue and remainder of uterine fluids or removed from the loop, or a mix or original composition, or the reaction mixture obtained in the subsequent production cycle.

For interaction with 5-amino-2,3-dihydro-1,4-phthalazinedione choose aqueous solutions of hydroxides or lithium, or sodium, or potassium, or an aqueous solution of a mixture of hydroxide or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium, and the target product is obtained in the form of, respectively, or in the form of a mixture of lithium and sodium, or a mixture of lithium and potassium, or a mixture of sodium and potassium, or a mixture of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

For the interaction of 5-amino-2,3-dihydro-1,4-phthalazinedione individual hydroxides of alkali metals or mixtures of these hydroxides their number is chosen in the ratio of their moles, equal to 1:(0,85-3,0), and upon receipt of mixtures of lithium and sodium, lithium and potassium, potassium, sodium and lithium, potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione the amount of the hydroxide or lithium and sodium, or lithium, and potassium, or potassium and sodium, the acting

While cleaning alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione of impurities is carried out using adsorption chromatography was carried out by passing in the appropriate chromatographic column of aqueous solutions of these salts through the layer of sorbent, such as a layer or aluminium oxide, or cellulose for chromatography, or bentonite clay, and the mass of the alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and sorbent is chosen in the ratio of 1: (0.1 to 15).

In addition, the allocation of intermediate composition - technical or chemically pure alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures of these salts are produced by introducing into the reaction mixture obtained after the interaction, respectively, commercial, technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione with an aqueous solution of alkali metal hydroxide or mixture of hydroxides, acetone or isopropyl alcohol, cooling this reaction mixture to a temperature of-1-+15oWith and keeping at this temperature for 0.25 to 24 hours.

In addition, when processing intermediate composition - technical or chemically pure alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as mixtures according to the alkaline salts and receive, respectively, chemically pure or high purity product.

When processing the first intermediate composition using ion-exchange chromatography conduct a full or partial ion exchange, and then spend the adsorption chromatography was carried out or crystallization obtained after carrying out this procedure, the alkaline salt or a mixture of alkaline salts.

Technical or chemically pure alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione crystallized or in the air, after which receive, respectively, chemically pure or high purity alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or, for example, in Boxing under conditions of high sterility, for example in an atmosphere of purified air or inert gas and then receive respectively medication chemically pure or medical high purity alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

In addition, the crystallization of intermediate composition (alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures thereof) is conducted by dissolving in water or in aqueous solutions of the corresponding hydrocarbons at a temperature of 45-80oC, cooling the aqueous solution to a temperature of-1-+15oC and keeping it at this temperature is of Indiana) during crystallization from water or bicarbonate buffer solutions chosen in the ratio of their masses, equal to 1:(2,0-12).

In addition, the crystallization of intermediate composition in the form of potassium or sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione carried out from aqueous buffer solutions, respectively, of potassium bicarbonate or sodium bicarbonate, and crystallization from water or bicarbonate buffered aqueous solutions used or deionized (demineralized, or distilled water and water previously subjected to boiling for 0.1 to 2 hours.

In addition, when processing intermediate composition or the target product after their allocation in the form of alkaline salts, or a mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione produce their drying, and the drying of the intermediate part or the target product in the form of alkaline salts, respectively, or a mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione after their separation to produce a dry powder or in a drying Cabinet at a temperature of 60-70oC for 2-5 hours, or beginning on air, for example, at room temperature or in the stream is cooled to a temperature of 4-15oWith inert gas, for example argon or nitrogen, and then, for example, in a drying Cabinet at a temperature of 60-70oC for 2-5 h is of anhydrous powder, but as lithium or sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione to crystalline with two moles of water of crystallization was performed at room temperature for 10-14 hours.

In addition, remaining after the allocation of intermediate composition or the target product uterine solutions processed by exposure to an aqueous solution of acid or mixture of acids to obtain a precipitate in the form of 5-amino-2,3-dihydro-1,4-phthalazinedione, and as an aqueous solution of acid or mixture of acids, respectively, using an aqueous solution or organic, e.g. acetic or propionic, or inorganic, such as sulfuric or hydrochloric, or phosphoric acid, or an aqueous solution of a mixture of these organic and inorganic acids.

Thus in the form of the precipitate from the mother liquor technical alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures of these salts produce technical 5-amino-2,3-dihydro-1,4-phthalazinedione, and from the mother liquor chemically pure alkali metal salts or from the mother liquor drug chemically pure alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or mixtures of these salts, or high purity alkali metal salts, or medical high purity alkaline southindian.

In addition, remaining after the allocation of intermediate composition or the target product mother liquor recycle by distillation or evaporation, and the processing by distillation or evaporation of the remaining after isolation of the intermediate composition of the mother liquor removed previously introduced organic precipitator and 30-70% of water, and if the processing of the remaining after separation of the desired product, the mother liquor is removed 30-70% of water.

In addition, the lithium salt or a mixture of lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), for example through the ion exchange column filled with resin KU-2-cs in Li+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

In addition, the lithium salt or a mixture of lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), water with simultaneous control of acidity (pH) of the obtained solution.

In addition, the sodium salt or the mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), for example through the ion exchange column filled with resin KU-2-cs in Na+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

In addition, the potassium salt or a mixture of potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), for example through the ion exchange column filled with resin KU-2-cs in+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

This lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through a column of ionoobmennoi resin in Li+-the form of an aqueous solution of sodium or potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione a speed of 0.1-1.0 ml/min, the sodium salt of 5-amino-2,3-dihydro-1,4 who and the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione a speed of 0.1-1.0 ml/min, and the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through a column of ionoobmennoi resin in To the+-the form of an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione a speed of 0.1-1.0 ml/min.

In addition, a mixture of lithium and sodium, lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion exchange column in Li+-the form of aqueous solution, respectively, sodium or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione with a speed of more than 1.0 ml/min, and the mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion exchange column in PA+-the form of an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or by passing through an ion exchange column To+-the form of an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione at speeds of more than 1.0 ml/min.

When conducting ion-exchange chromatography using 0.5 to 2.0 molar solutions of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in the water, and the working volume of the column for chromatography choose based 300-2000 cm31 mol passed through this column alkali metal salts of 5-amino-2,3-dihydro-1,4-faluting the sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione is produced by mixing the components in the specified proportions.

Studies have shown that the introduction of the patient as a drug or a mixture of lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a mixture of lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or a mixture of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione affects the patient, similar to the above effect of sodium salt lyuminola (see, for example, the patent of the Russian Federation 2163122).

So, when the weak response of cellular immunity, for example in the presence of malignant neoplasms, with the introduction of the above drugs is observed release of TNF (tumor necrosis factor, interleukins and other ostrofsky proteins, indicating that the activation of macrophages. At the same time also specifically react to the introduction of a drug T-lymphocytes.

Inflammatory processes in the medicines all considered variants selectively inhibit the activity of macrophages, reducing accordingly the level of TNF and ostrofsky proteins, which leads to smoothing of the symptoms of intoxication. Thus there is also activation of suie microbicide system cells and the relief of the inflammatory process.

Drug in each of the obtained variants is not toxic and its use in a range of dosages of 20-2000 mg/day does not cause allergic reactions and other side effects.

Of particular importance has high biological activity and prolonged effects of mixtures of alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, including potassium salt, which can significantly reduce the dose of appropriate medication and increase the intervals between its techniques, for example, compared with the intervals between doses of the drug in the form of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (prototype).

The drug, made in the form of mixtures of chemically pure and mixtures medication alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, can be used in oral administration in the form of powders and tablets or encapsulated aqueous solutions, as well as in therapeutic water treatments or oral (inhalation), or gynecological or wrestling, or anal irrigation and klezmania respectively in the form of powders or encapsulated aqueous solutions, or liposomes; drug, made in the form of the, as in the above procedures, and intramuscular injecting.

While embodiments of the medicinal product having the above properties, differ in duration and spectrum, and and pharmacokinetic parameters, which allows to assign a schema to the desired treatment using the selected variant of the medicinal product and the form of its application. Such treatment can be carried out with due consideration of specific options, as well as the possibility of transition from one version of a drug or form of its application to another variant of a drug or other pharmaceutical form without the negative effects caused by the radical change of appointments per patient. This may be relevant when considering the economic aspects, as the cost of the drug depends on the complexity of the procedure of its receipt.

Of particular importance is the stability during long-term storage of aqueous solutions included in medication medication chemically pure and high purity alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. So, for example, solutions of all is that in closed glass vessels over a year without changing its physical-chemical properties, while in control experiments relevant commercial and technical solutions of salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and their mixtures under the same storage conditions, it was getting dark already after 3-5 days. Such resistance declared drugs in aqueous solutions confirms the possibility of their application in the form adopted by the pharmaceutical industry appropriate dosage forms.

While the absence of allergic reactions and toxicity of the medicinal product, made in the form of mixtures of drug alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, allows us to recommend their use as well as prophylactic agents, for example, for the prevention of respiratory (inhalation upper respiratory tract or gargling with an aqueous solution of a medicinal product) and other diseases.

A preliminary study of the biological activity, namely the immunomodulating action of mixtures of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in the above combinations were performed on infected supercritical doses of microbial cells Salmonella, typhoid fever (S. Tehimurium) laboratory mice selected as the test groups. While the t test biological objects from destruction, and using the drug in variants containing the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione and appropriate mixtures of salts found their prolonged therapeutic effect.

The proposed method of manufacture of a medicinal product is a high-tech low-waste process and even waste-free production, producing variants of a drug of a different degree of chemical purity, including medication, which significantly expands the possibilities of their use in cases of prolonged storage in aqueous solutions.

The invention is confirmed by the examples.

Example 1.

Patient G., 42.

Complaints paroxysmal cough, fatigue during exercise, frequent fever.

When entering tapped dry rales on the right.

Completed the treatment drug.

The first 3 days once daily intramuscular injections of 50 mg of potassium (respectively medication purity) salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in 1 ml of water for injection, and then assigned to oral intake within 7 days of the mixture of potassium and sodium (respectively copper is Oseni components 3 times a day, one hour after a meal.

10 days after the start of treatment recommended continuing the above-mentioned mixture of potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in tablets of 25 mg once a day for 5-7 days.

After 2 weeks of treatment when the patient's examination of rales no, the General condition is satisfactory.

Example 2.

Patient T., aged 27.

Assumes that the disease is a complication after recently migrated flu.

High (up to 39.6oC) temperature for 10 days, frequent bouts of debilitating cough, General weakness. Previously assigned treatment (injection of kanamycin and oral sulfadimethoxine recommended (M. D. Mashkovsky. Drugs.- M.: Medicine, 1985, so 2, S. 286) regimen) did not help.

When entering a state of moderate severity, listen moist rales.

Diagnosis: bilateral pneumonia.

The treatment drug.

The first 5 days after the day intramuscularly injection of potassium (respectively medication purity) salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 300 mg in 3 ml water for injection, with 7 to 10-day injection of the corresponding potassium salt mixed with asorrow is a given week, a mixture of potassium and sodium (respectively medication chemically pure) salts of 5-amino-2,3-dihydro-1,4-phthalazinedione tablets 50 mg in equal shares and ascorbic acid powder 50 mg three times a day before meals.

On the fifth day of treatment temperature is normalized.

During the examination after the treatment, the condition is satisfactory, wheezing is not listening. The RG-no marks.

Example 3.

Patient P., aged 60.

Operated in July 2000 for cancer of the rectum. A course of chemotherapy. The deterioration.

In February-March 2001 treatment drug, including intramuscular injecting a mixture of potassium and sodium salts (respectively medication purity) of 5-amino-2,3-dihydro-1,4-phthalazinedione 100 mg of the mixture (the ratio of the components: 70 mg potassium and 30 mg of sodium salts) in 2 ml of water for injection once a day for 10 days, taking tablets sodium salt (respectively medication chemically pure) 5-amino-2,3-dihydro-1,4-phthalazinedione 50 mg 2 times a day an hour before meals, and also enema before going to sleep: first cleaning boiled drinking water, and then treatment, containing a solution of 150 mg of chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 50-150 ml of boiled water for 20 days.

When examining 1.5 months after treatment, the condition is satisfactory.

Example 4.

Patient C., 22 year is about-cystic breast left breast.

Biopsy: found atypical cells.

Conducted intramuscular injecting: first one day 15 injection aqueous solution of a mixture of lithium and potassium salts (respectively medication purity) of 5-amino-2,3-dihydro-1,4-phthalazinedione 200 mg of the mixture of salt (in a ratio of 50 mg lithium and 150 mg of potassium salt) in 4 ml of water for injection, and then after a ten-day break daily for one day 10 of the injection solution (respectively medication purity) the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (100 mg of salt in 2 ml of water for injection), as well as lubrication 2-3 times a day area of location of the tumor ointment composition comprising the powder of the lithium salt (chemically pure) 5-amino-2,3-dihydro-1,4-phthalazinedione and ointment base (baby oil) in the ratio of components,% vol.: 50 to 50.

Three weeks after treatment, the tumor almost not detectable, at repeated biopsy atypical cells were not found.

Example 5.

Patient P., aged 65., with 40 years suffer from diabetes mellitus.

Complaints: difficulty urinating frequent urges to urinate.

Ultrasound: marked hypertrophy of the prostate.

The diagnosis of adenoma (55-60 cm3) of the prostate.

Held the military medical high purity) of 5-amino-2,3-dihydro-1,4-phthalazinedione (the ratio of the components: 100 mg lithium and 100 mg of sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione) in 4 ml of water for injection, one injection a day. Then assigned to oral intake within 10 days of the powder mixture of 100 mg of the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (respectively medication chemically pure) with xylitol with an equal ratio of the components once a day one hour after a meal.

After the first 20 injections adenoma decreased to 40-45 cm3and after a course of reception of powder up to 28-30 cm3urination normalized, the General condition of the patient is satisfactory.

Example 6.

Patient R., 38 years.

Diagnosis: carcinoma lung (3 tbsp) with metastasis to the brain.

When a state of moderate severity.

Conducted by injecting (intramuscularly) with an aqueous solution of a mixture of lithium, potassium and sodium salts (respectively medication purity) of 5-amino-2,3-dihydro-1,4-phthalazinedione first 10 injections on two daily 325 mg of the mixture (the ratio of the components: 25 mg lithium, 100 mg of potassium and 200 mg of sodium salt) salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in 3 ml of water for injection, then every other day for 15 intramuscular injections of 150 mg of potassium salt (accordingly, medical high purity) 5-amino-2,3-dihydro-1,4-phthalazinedione.

In the course of treatment was observed poloai, the rising tone. After carrying out the indicated course of treatment based on the results of imaging metastases are not detected at ULTRASOUND examination revealed a slight decrease of the primary tumor and its capsulesare.

The implementation of the method of production of a drug (in the following embodiments) is carried out in cycles, each of which begin with the action of aqueous solutions of the corresponding hydroxides of alkali metals (Li, Na, K) on the source composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione, and finish up with the receipt of the target product, with cycles repeated to obtain, for example, the required number of the target product.

When describing the production of a medicinal product, the original product is labeled in accordance with the systematic nomenclature as 5-amino-2,3-dihydro-1,4-phthalazinedione (see, for example, chemist's Handbook.- M.-L.: Chemistry, 1965, T. II, S. 760), is a hydrazide of 3-amino-O-phthalic acid. Sometimes the sources of information for its designation use name 5-amino-2,3-dihydroartemisinin-1,4 (see, for example, the above-mentioned author's certificate USSR 130903) or rational nomenclature the product name 3-aminophthalhydrazide (see, nab is.

In Fig. 1 shows the structural formula of 5-amino-2,3-dihydro-1,4-phthalazinedione (3-amino-O-falicitated), Fig.2 shows the structural formula of N-alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (alkali metal salts (M=Li, Na, K) 3-amino-O-falicitated). In Fig.3 presents a simplified schematic of chemical-technological process of obtaining salts of alkali metals, M=Li, Na, K (alkaline salts 3-amino-O-falicitated), and their mixtures or from commercial or technical, or from chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione.

Consider the scheme of chemical technology process (Fig.3).

Diagram (Fig.3) contains the nodes(1, 2, 3, 4, 5, 6, 7, 8 and 9) characterizing the input in this process reagents, United graphs (arrows), conditionally defining the kind of impact on the reagents or their interaction.

Here indicated.

Node 1 is the original composition, which may be a commercial, technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione, and 5-amino-2,3-dihydro-1,4-phthalazinedione the above types with the addition of waste containing aqueous solutions of alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, uterine fluids and other residues react low 5-amino-2,3-dihydro-1,4-phthalazinedione.

Node 3 is an aqueous solution of a technical or chemically pure salts of the corresponding alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Site 4 - technical or chemically clean the corresponding alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Site 5 - the mother liquor after separation of the technical or chemically pure alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Node 6 is obtained in the process of technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione.

Node 7 is an aqueous solution of chemically pure salts of the corresponding alkali metal 5-amino-2,3-dihydro-1,4-phthalazinedione.

Site 8 - aqueous solution of chemically pure salts of the corresponding alkali metal 5-amino-2,3-dihydro-1,4-phthalazinedione.

Site 9 - drug chemically pure and drug purity salt of the corresponding alkali metal 5-amino-2,3-dihydro-1,4-phthalazinedione.

While terms: commercial, technical, chemically pure and of high purity is used, and the resulting compounds are well known (see, for example, concise encyclopedia of chemical.- M: Soviet encyclopedia, 1967, I. 4, S. 546-548, and Nesmeyanov, A. N., Nesmeyanov N. A. Beginning organic chemistry.- M.: Chemistry, 1969, T. 1, Dion.

Graph 1-3 - action hydroxide of the corresponding alkali metal 5-amino-2,3-dihydro-1,4-phthalazinedione.

Graph 2-3 - chromatographic purification of technical salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Graph 3-4 - deposition of technical or chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and their allocation.

Graph 4-5 - passing the mother liquor after separation of the salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Graph 4-7 - chromatographic purification of technical salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Graph 4-9 - crystallization or technical, or chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Count 5-6 - treatment of the cells with an aqueous solution of acids and the separation of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Graph 6-1 - send the selected 5-amino-2,3-dihydro-1,4-phthalazinedione in the beginning of the processing chain (cycle start).

Count 7-8 - deposition of chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and their allocation.

Count 8-9 - crystallization of chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

In addition, this scheme includes one input (node 1) and outputs: two from node 6 and one of the nodes 4, 8, and 9.

The entrance to the site 1 shows that here in this scheme (in process) enter the IP Output from node 4 shows from this node from the process display technical or chemically pure alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (intermediate composition).

The first and second outputs from node 6 show that away from the process output, respectively, of a technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione and waste - water solution of the corresponding alkali salts of organic and inorganic acids or mixtures thereof.

The outputs of the nodes 8 and 9 show that here from the process output, respectively, of chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (intermediate composition) and drug chemically pure and drug purity salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (target product).

Thus, the possibility of chemical-technological process, in other words, used as the initial composition of the types of 5-amino-2,3-dihydro-1,4-phthalazinedione, and obtained as an intermediate composition and quality of the target product alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, concentrated can be represented as follows.

Original composition: 5-amino-2,3-dihydro-1,4-phthalazinedione commercial (sold for use, for example, Ispra 5-amino-2,3-dihydro-1,4-phthalazinedione without additional purification); 5-amino-2,3-dihydro-1,4-phthalazinedione chemically pure (obtained from technical salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, in the process of obtaining of which was included adsorption chromatographic purification or who have been previously crystallized).

Intermediate composition: lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures of these salts - technical (obtained from commercial or technical 5-amino-2,3-dihydro-1,4-phthalazinedione without additional purification) and chemically pure (in the process of obtaining of which was included adsorption chromatographic purification).

Target product: mixtures of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione - drug chemically pure (obtained by crystallization of the corresponding technical salts of 5-amino-2,3-dihydro-1,4-phthalazinedione) and drug purity (obtained by crystallization of the corresponding chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione).

Presents chemical-technological process of obtaining mixtures of alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (lithium, sodium, potassium) can be arranged in the form of two alternative productions is actor (node 5) without removal of water and organic precipitants can be used for direct selection from it by the action of acid (acid) 5-amino-2,3-dihydro-1,4-phthalazinedione (node 6), which is then sent to the beginning of the production cycle (site 1), or it can be used as commercial products, and a solution of alkaline salts of simple acids, for example sodium acetate or potassium chloride, etc. may be used for separation from it of these salts in the form of marketable products (non-waste technology) or sent to treatment (biochemical, chemical or physical-chemical) or disposal (low-technology).

In another cycle, the mother liquor from node 5 (after separation of the alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, for example, by filtration or by decantation and removal of the mother liquor, for example, by distillation or evaporation, part (30-70%) of the water and almost completely organic precipitants that have been applied for the deposition of these alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione) passed at the beginning of the processing chain (node 1) or in the reaction mixture aqueous solution of alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (node 2).

It is important that the conversion of salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 5-amino-2,3-dihydro-1,4-phthalazinedione by the action of acids does not depend on taken for this purpose, alkali metal salts (lithium, sodium, potassium) or respectively azannyh) salts, and then at the same time to carry out their transfer to the 5-amino-2,3-dihydro-1,4-phthalazinedione.

Also significant is the fact that for this method, the purity of the original 5-amino-2,3-dihydro-1,4-phthalazinedione is not critical to the quality of intermediate composition and the target product, obtained as alkali metal salts or mixtures of these salts, 5-amino-2,3-dihydro-1,4-phthalazinedione can be cleaned to the desired state using the procedures of crystallization or adsorption chromatography and obtained in the form of intermediate composition (node 4) technical or chemically pure alkaline salts by ion-exchange chromatography can be transferred to other, set alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione different from the original included them cation of the corresponding metal.

This adsorption chromatographic purification (column 2-3), presented at the beginning of the production cycle for the synthesis of chemically pure lithium, sodium or potassium salts on the basis of commercial or technical 5-amino-2,3-dihydro-1,4-phthalazinedione, is not strictly mandatory, since you need to include in the production cycle, for example, when working with particularly Zagra the draw-1,4-phthalazinedione (node 4) for receiving on the basis of drug chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (node 9) crystallized or without their separation from aqueous solutions or, followed by separation by precipitation from aqueous solutions subjected to adsorption chromatography purification with the formation of chemically pure salts, which in turn can accordingly be translated in drug purity salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

To complete the material cycles (balance) chemical engineering process, except for the transfer of the mother liquor from node 5 to node 1 or 2, uterine solutions of the nodes 8 and 9 after the removal of organic precipitants and part (30-70%) of water, as well as other unused aqueous solutions containing alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, passed at the beginning of the processing chain (node 1) or in the reaction mixture an aqueous solution of alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (node 2). In nodes 1 and 2 can be transferred to other aqueous solutions of alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, and also the corresponding salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in the solid phase, for example in the form of powders or crystalline, obtained in the production cycle with the violation of technological regulations (secondary raw materials).

As in the case of the process of obtaining 5-amino-2,3-dihydro-1,4-faluting processing acids technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione (to simplify the scheme last operation graphically not reflected).

Method of production of a medicinal product, which is, as mentioned above, the cyclic chemical-technological process of manufacturing of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and their mixtures can be divided into stages.

The first stage is a procedure (options procedure) technical synthesis of 5-amino-2,3-dihydro-1,4-phthalazinedione from the appropriate technical alkali metal salts or a mixture of the corresponding salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione (purified from impurities and contaminants from the corresponding chemically pure alkaline salt (or mixture of salts) 5-amino-2,3-dihydro-1,4-phthalazinedione. (The procedure for obtaining these chemically pure salts (a mixture of salts) are discussed below). In the case of use as the source already available or commercial, or technical, or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione above the first stage is terminal and completes the cyclic process.

Embodiments of the 1-th stage shown in examples 7 and 8 (the numbering of the examples given in the description, end-to-end).

Example 7.

Variants of the synthesis of tech is about-2,3-dihydro-1,4-phthalazinedione, or any of their mixtures.

Option 1.

7-10 g technical (any of above) salt of 5-amino-2,3-dihydro-1,4-phthalazinedione dissolved in 80-150 ml deionized (demineralized or distilled water. Then to this solution is added dropwise 1-4 ml organic, for example 98% acetic acid (CH3COOH), bringing the pH of the mixture to 1-5,5. This aqueous solution precipitation 5-amino-2,3-dihydro-1,4-phthalazinedione, which is filtered, for example, through a paper filter or a SCHOTT filter and dried, for example, in a drying Cabinet 1-5 hours at a temperature of 50-100oC to constant weight.

The optimal molar ratio of salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (original composition) and acetic acid 1:(of 0.9 to 5.0). To 5-amino-2,3-dihydro-1,4-phthalazinedione 80-95%.

Option 2.

Technical alkaline salt of 5-amino-2,3-dihydro-1,4-phthalazinedione procedure option 1 of this example is mixed with an aqueous solution of inorganic, e.g. hydrochloric acid (Hcl), and accordingly carry out the procedure for allocation of technical 5-amino-2,3-dihydro-1,4-phthalazinedione. This saves the ratio of the reactants and percentage yield technical 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 3.

T is with a water solution, containing a mixture of hydrochloric and acetic acid in a volume ratio of, for example, 1:3, and carry out the appropriate procedure selection technical 5-amino-2,3-dihydro-1,4-phthalazinedione. This also saved the ratio of the reactants and percentage yield technical 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 4.

A mixture of technical alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the above ratios of the quantities of reagents using acetic acid by the procedure of option 1 of the present example was transferred to technical 5-amino-2,3-dihydro-1,4-phthalazinedione. The percentage yield 5-amino-2,3-dihydro-1,4-phthalazinedione saved.

Example 8.

Variants of the synthesis of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione or lithium, or sodium or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or any of their mixtures.

Option 1.

5-10 g any technical, for example sodium, salts of 5-amino-2,3-dihydro-1,4-phthalazinedione dissolved in 50-200 ml of distilled water and the aqueous solution is passed through the chromatic column sorbent, for example, aluminum oxide (neutral alumina by Brockmann II, Budapest, Hungary). To the filtered solution add 1-5 ml, for example, acetic acid, soumialot with water and dried. When this mass of cleaned salt and sorbent is chosen in the ratio of 1:(0.1 to 10). The output of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione (per technical salt) is 80-90%.

Here as sorbent can also be used or cellulose for chromatography, or bentonite clay with appropriate refinements ratios of the reactants and percentage yield 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 2.

7-10 g of chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by crystallization (see below) relevant technical salt, dissolved in 80-150 ml of distilled water and above (see example 7, option 1) the scheme obtain chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione. The output of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione is 80-95%.

Option 3.

A mixture of technical alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione pass through a chromatographic column filled with alumina (see also option 1 of this example) and using the acetic acid is transferred into chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione. This saves the ratio of the reactants and percentage yield of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione.

2nd eey 5-amino-2,3-dihydro-1,4-phthalazinedione and accordingly a mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione) from the reaction mixture, formed in the interaction of commercial 5-amino-2,3-dihydro-1,4-phthalazinedione or received in the previous step, or technical, or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione, with an aqueous solution of hydroxide of a given metal or mixture of hydroxides of the specified metals. In addition, the procedures held on the 2nd stage, related procedures associated with the transfer using ion-exchange chromatography of some alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (obtained in the intermediate composition) in other specified salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Embodiments of the 2-th stage shown in examples 9-12.

Example 9.

Variants of synthesis of technical or lithium, or sodium, or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 1.

Technical or lithium, or sodium, or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione prepared by mixing or commercial 5-amino-2,3-dihydro-1,4-phthalazinedione, or technical 5-amino-2,3-dihydro-1,4-phthalazinedione obtained in accordance with the procedure described in example 7, with an aqueous solution of the corresponding hydroxide, made using deionized or distilled the agents choose in a molar ratio of 5-amino-2,3-dihydro-1,4-phthalazinedione and metal hydroxide as 1:(0,85-3,0), and the mass ratio of 5-amino-2,3-dihydro-1,4-phthalazinedione and water is 1:(3,0-6,0).

The reaction solution is filtered, for example, using filter paper or a SCHOTT filter. Then, for deposition of the resulting salt, add, for example, acetone or isopropyl alcohol (mass ratio of 5-amino-2,3-dihydro-1,4-phthalazinedione and precipitator 1:(10-30)), after which the reaction mixture is cooled to a temperature of-1-+15oC and maintained at this temperature for 1 to 15 hours. The precipitation of the corresponding salt of 5-amino-2,3-dihydro-1,4-phthalazinedione filtered, and then respectively dried.

The precipitated salt before drying washed with cooled to 5-10oWith ethyl alcohol.

Output technical alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the optimal mode of procedure reaches 80-95%.

Option 2.

Technical lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion-exchange chromatographic column filled with ion exchange resin KU-2-cs in Li+-form 0.5 to 2 molar aqueous solution of technical sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione made using deionized or distilled water. While ml is the transmission rate of the solution through the column chosen in the range of 0.1-1.0 ml/min.

The resulting aqueous solution of the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione evaporated to 30-70%, and then the remaining solution was added acetone or isopropyl alcohol, the reaction mixture cooled down to a temperature of-1-+15oC and maintained at this temperature for 1-10 hours. The precipitation of the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione filter, for example, SCHOTT filter and dried.

Output technical lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 80-85%.

Option 3.

Technical lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get ion exchange chromatography of technical potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in accordance with the procedure of option 2 of this example.

Output technical lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 70-80%.

Option 4.

Technical sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion-exchange chromatographic column filled with ion exchange resin KU-2-cs in PA+form, the technical solution of the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in accordance with the procedure of option 2 of this example.

Output technical sodium salt of 5-amino-2,3-digitouch in accordance with the procedure of option 2 of the present example, by passing through the ion-exchange chromatographic column filled with ion exchange resin KU-2-cs in+-form solution of technical sodium salt.

Output technical salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 70-85%.

Example 10.

Variants of the synthesis of chemically pure or lithium, or sodium, or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 1.

Chemically pure or lithium, or sodium, or potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by mixing commercial 5-amino-2,3-dihydro-1,4-phthalazinedione or technical 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by the procedure described in example 8, with an aqueous solution of the corresponding hydroxide, in accordance with the procedure described in example 9 (option 1).

Next, the reaction mixture was passed through a chromatographic column filled with adsorbent such as alumina, in accordance with the procedure described in example 8 (option 1).

Then after filtering to the solution of salt, for her deposition, add acetone or isopropyl alcohol in accordance with the procedure described in example 9 (option 1).

This saves the corresponding ratios of the reactants and optimalnyh modes of conduct of the relevant processes is 80-90%.

Option 2.

Chemically pure lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get ion exchange chromatography of chemically pure sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione according to the procedure described in example 9 (option 2).

The output of chemically pure lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 80-92%.

Option 3.

Chemically pure lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get ion exchange chromatography of chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione according to the procedure described in example 9 (option 3).

The output of chemically pure lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 70-85%.

Option 4.

Chemically pure sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion-exchange chromatographic column filled with ion exchange resin KU-2-cs in Na+-form solution of chemically pure potassium salt by the procedure described in example 9 (option 2).

The output of chemically pure sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 80-95%.

Option 5.

Chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion-exchange chromatographic column, C is d, example 9 (option 2).

The output of chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 80-90%.

Option 6.

Chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion-exchange chromatographic column filled with ion-exchange resin KU-2-cs in+-the form of an aqueous solution of technical sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione in accordance with the procedure described in example 9 (option 2).

Next, the reaction mixture is technical potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione pass through a chromatographic column filled with a sorbent, such as aluminum oxide, in accordance with the procedure described in example 8 (option 1).

Then after filtering to the solution of salt for her deposition add acetone or isopropyl alcohol in accordance with the procedure described in example 9 (option 1).

The output of chemically pure potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione 70-85%.

Example 11.

Ways to obtain technical or mixtures of lithium and sodium, or lithium, and potassium, or potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as technical mixture of lithium, sodium and potassium with potassium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, and a mixture of technical lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by mixing commercial 5-amino-2,3-dihydro-1,4-phthalazinedione or technical 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by the procedure described in example 7, with an aqueous solution of deionized or distilled water mixture of hydroxides respectively lithium and sodium, lithium and potassium, sodium and potassium, along with a corresponding aqueous solution of a mixture of hydroxides of lithium, sodium and potassium in accordance with the procedure described in example 9 (option 1).

For the interaction of 5-amino-2,3-dihydro-1,4-phthalazinedione with mixtures of hydroxides of alkali metals, their number is selected based on the mass ratio hydroxides, such as lithium hydroxide and sodium as (0,1-2):1, hydroxides of lithium and potassium as (0,2-1,5):1, hydroxides of sodium and potassium as (0,1-3): 1 and hydroxides of lithium, sodium and potassium, respectively, as(0,5-1,5): 1: (0,2-3), moreover, the overall proportions of the reagents and conditions for reaction corresponds to those shown previously.

Option 2.

A mixture of technical lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, and a mixture of l is accordance with the procedure example 9 (option 2), when passing through the ion exchange column in Li+-the form of an aqueous solution respectively technical sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or technical potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione at speeds of more than 1.0 ml/min.

Option 3.

A mixture of technical sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get ion exchange chromatography according to the procedure described in example 9 (option 2), when passing through the ion exchange column in PA+-the form of an aqueous solution of technical sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or by passing through an ion exchange column To+-the form of the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione at speeds of more than 1.0 ml/min.

Example 12.

Obtaining mixtures of chemically pure or lithium and sodium, or lithium, and potassium, or sodium and potassium, and mixtures of chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

A mixture of chemically pure or lithium and sodium, or lithium, and potassium, or sodium and potassium, and mixtures of chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-talaga 5-amino-2,3-dihydro-1,4-phthalazinedione or technical 5-amino-2,3-dihydro-1,4-phthalazinedione, obtained in accordance with the procedure described in example 7, with aqueous solutions (deionized or distilled water), respectively, mixtures of the hydroxides of lithium and sodium, lithium and potassium and sodium and potassium and mixtures of the hydroxides of lithium, sodium and potassium.

Next, the reaction mixture was passed through a chromatographic column filled with adsorbent such as alumina, in accordance with the procedure described in example 8 (option 1).

Then after filtering to the solution of salt for her deposition in accordance with the procedure described in example 9 (option 2) add acetone or isopropyl alcohol.

The ratio of reagents and conditions for carrying out reactions in this match earlier.

the 3rd stage is the processing of intermediate composition that is allocated in the form of technical or chemically pure alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixture of salts of the corresponding alkali metal 5-amino-2,3-dihydro-1,4-phthalazinedione to obtain the target product, moreover, this processing is crystallization from water or bicarbonate buffer solutions previously obtained alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and their subsequent mixing or mixtures of alkaline is the form medication form mixtures of alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Variants of this step is shown in examples 13-14.

Example 13.

Options for obtaining medical chemically pure or lithium, or sodium, or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, mixtures of drug chemically pure or lithium and sodium, or lithium, and potassium, or sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as the mixture of drug chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 1.

Drug chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, a mixture of drug chemically pure lithium and sodium, lithium and potassium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as the mixture of drug chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by crystallization from water technical lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, received in turn in accordance with the procedure described in example 9, and respectively by crystallization from water technical mixture of lithium and sodium, lithium and potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, obtained by the procedure described in example 11.

Appropriate salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or a mixture of the corresponding salts of 5-amino-2,3-dihydro-1,4-phthalazinedione at a temperature of 45-80oTo dissolve in deionized water, or distilled water, or pre-boiled for 0.1-2 hours deionized water or distilled water. The mass ratio of salt and water 1:(2-12).

Then the aqueous solution is filtered through a paper filter or through a SCHOTT filter, cooled to a temperature of-1-+15oC and maintained at this temperature for 0.5-24 hours (for best deposition of salts crystallization solution can occasionally (1-5 times/min) shake). The precipitation of the corresponding salts or mixtures of salts filtered and dried.

The release of drug chemically pure salts is 60-90%.

It should be borne in mind that the procedure of receiving medical salts in accordance with existing requirements should be in the box, filled or cleaned from dust, air, or inert gas (nitrogen or argon).

Option 2.

Drug chemically pure sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione receive in accordance eve salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, obtained in accordance with the procedure described in example 9 (options 1 and 4), from the corresponding bicarbonate buffer solutions made in deionized or distilled water. During crystallization of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione use sodium bicarbonate (Panso3) buffer solution, and crystallization of the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione respectively potassium bicarbonate (knso3) buffer solution. The ratio of water (l) and bicarbonate (g) (0,2-1,5):(0,1-0,7), pH buffer solution of 7.5 to 10.0.

In addition, in this case, before drying the salts washed with cooled to 10-15oWith ethanol.

The release of drug chemically pure sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 70-95%.

Option 3.

The mixture of drug chemically pure lithium and sodium, lithium and potassium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as the mixture of drug chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by mixing appropriate medication chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione. When etimer 14.

Options for obtaining drug purity or lithium, or sodium, or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, mixtures of drug purity or lithium and sodium, or lithium, and potassium, or sodium and potassium, as well as the mixture of drug purity lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

Option 1.

Medical high purity lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, a mixture of drug purity lithium and sodium, lithium and potassium, sodium, and potassium, as well as the mixture of drug purity lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by crystallization from deionized or distilled water, or pre-boiled for 0.1-2 hours deionized or distilled water is chemically pure lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by the procedure described in example 11, and by crystallization from above water mixtures of chemically pure lithium and sodium, lithium and potassium, sodium, and potassium, as well as mixtures of lithium, sodium and the ore 12 and example 13 (option 1).

The release of drug purity alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione is 60-95%.

Option 2.

Medical high purity sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by crystallization in accordance with the procedure described in example 13 (options 1 and 2), from the corresponding bicarbonate buffer solutions of chemically pure accordingly, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione obtained by the procedure described in example 10.

For the preparation of the corresponding buffer solutions use deionized or distilled water.

The release of drug purity sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione 70-97%.

Option 3.

A mixture of medical high purity lithium and sodium, lithium and potassium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, as well as the mixture of drug purity lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione receive in accordance with the procedure described in example 13 (option 3) from the appropriate medical high purity alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

ywaniem remove previously introduced organic precipitants and 30-70% of water, and of the remaining after obtaining the target product mother liquor respectively remove 30-70% water and the remaining part of the fallopian solutions are mixed with the original composition or introduced into the reaction mixture obtained in the subsequent production cycle, and repeat the process of obtaining drugs.

Another option processing remaining after separation of intermediate composition or the target product uterine solutions is to use them to obtain using acids or mixtures of acids 5-amino-2,3-dihydro-1,4-phthalazinedione, which in turn is used in the subsequent production cycle. This operation (obtaining 5-amino-2,3-dihydro-1,4-phthalazinedione) given in the description of the 1st stage. Here it is necessary to specify that remaining after obtaining 5-amino-2,3-dihydro-1,4-phthalazinedione the solution discharged from the loop.

Studies of the chemical and physico-chemical characteristics of the initial and intermediate compounds and target products, as well as relevant characteristics of the intermediate composition and destination of the product under different drying showed the following.

As a feedstock in the synthesis of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione used in the fine Chemicals, 1999-2000, p. 99), and technical and chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione synthesized from alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in accordance with the proposed method.

The identity and purity of the synthesized 5-amino-2,3-dihydro-1,4-phthalazinedione confirmed by the experimental results of the elemental analyses and by comparison of temperature (5-amino-2,3-dihydro-1,4-phthalazinedione) melting with reference data.

Elemental analysis of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione. Found, %: 54,06; N. Of 3.96; N 23,59. C8H7N3O2. Calculated, %: C 54,23; N. Of 3.95; N 23,72.

Thus, from the experimental data of elemental analysis, it follows that the content of the basic substance is synthesized chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione exceeds 99% and sootvetstvetstvovat accepted standards (see , for example, Nesmeyanov, A. N., Nesmeyanov N. A. Beginning organic chemistry. -M.: Chemistry, 1969, T. 1, S. 26), and according to elemental analysis the technical purity of 5-amino-2,3-dihydro-1,4-phthalazinedione is within 96-98,5%.

The melting point of the synthesized chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione is (331-332)oSince, according to paragraph 5-amino-2,3-dihydro-1,4-phthalazinedione 328-331oC. the Sample is mixed melting of chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione and commercial drug (Aldich) is (328-331)oWith that also meets the standards (see, for example, the Total workshop on organic chemistry. Translated from the German Ed. by A. M. Costa.- M.: Mir, 1965, S. 85).

As an intermediate structure in the implementation of this method has been chemically pure (containing more than 99% of the basic substance) and technical (containing 96-98,5% of the basic substance) salt of 5-amino-2,3-dihydro-1,4-phthalazinedione and mixtures thereof. These salts were allocated depending on the conditions of drying in the form of corresponding crystalline or anhydrous powders. The presence of water in the resulting preparations was determined, based on comparison of the experimental data of elemental analysis calculated, and by Fisher (see, for example, GOST 24614-81. "Liquids and gases that interact with the reagent Fisher". Coulometric method for the determination of water.).

During the synthesis of the lithium and sodium salts in the case of deposition from the aqueous reaction medium with acetone or isopropyl alcohol and when they are drying at room temperature for 10-14 hours they receive in the form of crystalline with two malokupitan to obtain mono - or trihydrates or fractional, for example half, their content of water of crystallization. For example, chemically pure crystalline lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione, contain two molecules of water, found, %: C 43,97; N 4,58; N 19,11; Li 3,20; N2O 16,50. With8H6N3O2Li2H2O. Calculated, %: C 43,83; N. Of 4.57; N 19,17; Li 3,19; N2O 16,44.

For chemically pure crystalline sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione, contain two molecules of water, found, %: C 40,91; N 4,28; N 17,79; Na 9,82; N2O 15,39. With8H6N3O2PA2H2O. Calculated, %: 40,85; N 4,25; N 17,87; Na 9,78; H2O 15,32.

Potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in the above conditions emit mainly in the form of monohydrate (in some cases it is possible to obtain and di - and trihydrate). Maintaining potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione on the air longer than a specified earlier time (over 12 hours) usually leads to spontaneous fracture of crystalline and obtaining these salts in the form of powders in anhydrous form.

For chemically pure anhydrous powder of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione found,%: the data about the stability of the crystalline alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione should it's easier just destroyed the crystalline potassium salts, then sodium and, finally, lithium.

For complete destruction of crystalline lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and mixtures thereof sufficiently carrying out drying at a temperature of 60-70oC for 2-5 hours (until constant weight). This procedure was applied to obtain anhydrous powders of salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

For example, chemically pure anhydrous powder of the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione found, %: C 52,32; N 3,15; N 22.84 to; Li 3,76. C8H6N3O2Li. Calculated, %: 52,46; N Is 3.27; N 22, 95mm; Li 3,83. For chemically pure anhydrous powder of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione found, %: C 48,21; H 2,95; N 21,0; Na 11,50. With8H6H3O2PA. Calculated, %: 48,24; N 3,01; N 21,10; Na 11,55.

The conditions of drying of the target product. A mixture of medication alkaline salts in the form of crystalline hydrates with different amount of water of crystallization or as anhydrous powders meet the above conditions to obtain the corresponding intermediate composition.

It should be borne in mind that the temperature after the destruction of the crystalline lithium, sodium in the open air at room temperature in air-dry conditions contain no more than 1-2% of water.

Chemical individuality salts of 5-amino-2,3-dihydro-1,4-phthalazinedione was proved by thin-layer chromatography on plates Culyfol UV-254.

The manifestation of the chromatograms was performed by annealing these records over a gas burner, and iodine.

In the case of testing of chemically pure and high purity salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (aqueous solution) on the chromatogram had a single spot with Rf 0.32 in the h-C4H9HE : WITH2H5HE : NH3(25% solution) 3:1:1, and in the h-C4H9HE : WITH2H5HE : NH3(25% solution) 1:1:1 single spot with Rf of 0.65.

In the study of the structure of salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (hydrazides 3-amino-ortho-phthalic acid) by the method of nuclear magnetic resonance in nuclei of protons (NMR1N) obtained the following data.

An NMR spectrum1H salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (D2O), M. D.: 6.74 d7.10 d [1H,,3JH-H7.8 Hz], 7.31 t(the protons in nitrogen).

The spectrum of the NMR1H confirms the structure of the hydrocarbon and heterocyclic fragments salts of 5-amino-2,3-dihydro-1,4-feneley selectivity).

Therefore, to determine the position of the metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione (hydrazides 3-aminophthalic acid) and study of the structure and spatial organization of salts was conducted by x-ray diffraction analysis on the example of the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione (3-aminophthalhydrazide potassium), obtained as crystalline.

These x-ray analysis showed that the studied object is a crystalline 3-aminophthalhydrazide potassium (hydrated potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione) with three molecules of water of crystallization [C8H6N3O2]-To+3H2O.

It was found that this salt is the potassium cation is linked by a chemical bond with the nitrogen atom number 2 (in accordance with previously adopted numbering) are considered salt of 5-amino-2,3-dihydro-1,4-phthalazinedione and respectively received other alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione are 5-amino-2-N-metal-3-hydro-1,4-phthalazinedione.

These x-ray analysis (the coordinates of the atoms, bond length and valence angles) of the potassium salt of 5-amino-2,3-dihydro-1,4-what Oli shown in Fig.4. It was found that the crystals of the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione [C8H6N3O2]-K+3H2About (C8H12KN3O5M=269.31) are monoclinic, space group P21/c at T=110 K:=10.7388(10), b=14.2207(19), C=7.3793(15),=99.594(3)oV= 1111.2(3), Z=4, dc=1.610 mg/cm3F(000)=560,=0.493 mm-1.

The analysis of the content of C, H and N elemental analysis) 5-amino-2,3-dihydro-1,4-phthalazinedione (the hydrazide 3-aminophthalic acid) and its salts was carried out on elemental analyzer EA-1108 firm "Carbo Erba (Italy).

The analysis of alkali metals (Li, Na and K) in the respective salts were performed on emission spectrometer with inductively coupled plasma) IRIS firm "Termo Jerrall ash (USA).

Melting point substances were determined in a capillary tube on the unit of measurement temperature (BIT) at a speed of temperature rise of 1o/min (at temperatures above 300oC).

the pH was recorded by direct potentiometric method the pH 150" (MSU) or using indicator paper.

An NMR spectrum1H was filmed on the instrument Bruker AC-200 (200 MHz), chemical with the systematic shifts integrated intensity of signals and data dual magnetic resonance.

X-ray diffraction analysis performed on the automated diffractometer Bruker SMART CCD 1000.

Claims

1. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized in that it comprises a mixture of lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. %: sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - 1,0-98,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

2. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized in that it comprises a mixture of lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. % of: potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - 1,0-98,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

3. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized in that it contains a mixture of nitramino-2,3-dihydro-1,4-phthalazinedione - 1,0-98,0; potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

4. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized in that it comprises a mixture of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione when the ratio of components, wt. %: sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - 1,0-85,5; potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - 1,0-55,0; lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione - rest.

5. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized in that it contains a mixture or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and drinking water or water for injection in the following ratio of components, wt. %: the mixture of these alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione - 0,5-25,0; water - the rest.

6. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized by the fact that he Seva and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and filler in the form of five - or setiathome alcohol, for example xylitol, or carbohydrate, such as glucose, and/or vitamin, such as vitamin C, with the following ratio of components, wt. %: the mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione - 5,0-50,0; filler - rest.

7. Drug with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect, characterized by the fact that it is made in the form of a solution mixture or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and filler in the form of five - or setiathome alcohol, such as xylitol, or carbohydrate, such as glucose, and/or vitamin, such as vitamin C, or drinking water or water for injection in the following ratio of components, wt. %: the mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione - 0,25-25,0; filler - 0,25-25,0; water - the rest.

8. The drug according to any one of paragraphs. 1-7, characterized in that said mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione made in the form of salts or technical, or chemically pure salts, or salts of high purity, or drug chemically pure salts, Il is spent in any of paragraphs. 1-4, including the impact of an aqueous solution of alkali metal hydroxide to the original composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione, followed by precipitation using an organic solvent, the resulting impact of intermediate composition in the form of alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, and obtaining the target product, characterized in that the drugs are repetitive cycles, each of which on the source composition containing commercial or technical, or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione, or mixtures thereof, affect aqueous solution of alkali metal hydroxide or mixture of hydroxides of alkali metals, and the intermediate composition correspondingly in the form of technical or chemically clean the corresponding salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixture of such salts, and then this intermediate composition is dissolved in water or in a suitable bicarbonate buffer solution and treated by cleansing away impurities, to obtain the target product, respectively, in the form of chemically pure, or drug chemically pure or purity, or medical special cestodaria after getting dried, moreover, the remaining after the allocation of intermediate composition or the target product uterine solutions processed and received after this processing residue and remainder of uterine fluids or removed from the loop, or a mix or original composition, or the reaction mixture obtained in the subsequent production cycle.

10. The method according to p. 9, characterized in that for the interaction with 5-amino-2,3-dihydro-1,4-phthalazinedione choose aqueous solutions of hydroxides or lithium, or sodium, or potassium, or an aqueous solution of a mixture of hydroxide or lithium and sodium, or lithium, and potassium, or sodium and potassium, or lithium, sodium and potassium.

11. The method according to p. 9, characterized in that the target product is obtained, respectively, or in the form of a mixture of lithium and sodium, or a mixture of lithium and potassium, or a mixture of sodium and potassium, or a mixture of lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

12. The method according to p. 9 or 11, characterized in that for the interaction of 5-amino-2,3-dihydro-1,4-phthalazinedione individual hydroxides of alkali metals or mixtures of these hydroxides their number is chosen in the ratio of their moles, equal to 1: (0,85-3,0), and upon receipt of the mixtures lities the draw-1,4-phthalazinedione the amount of the hydroxide or lithium and sodium, or lithium and potassium, or potassium and sodium, or lithium, potassium and sodium chosen in the ratio of their masses equal to: (0,1-2): 1, (0,2-1,5): 1, (0,1-3): 1, and(0,5-1,5): 1: (0,2-3) respectively.

13. The method according to p. 9, characterized in that the purification of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione of impurities is carried out using adsorption chromatography was carried out by passing in the appropriate chromatographic column of aqueous solutions of these salts through the layer of sorbent, such as a layer or aluminium oxide, or cellulose for chromatography, or bentonite clay, and the mass of the alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and sorbent is chosen in the ratio of 1: (0.1 to 15).

14. The method according to p. 9, characterized in that the selection of intermediate composition - technical or chemically pure alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures of these salts are produced by introducing into the reaction mixture obtained after the interaction, respectively, commercial, technical or chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione with an aqueous solution of alkali metal hydroxide or mixture of hydroxides, acetone or isopropyl alcohol, cooling this reaction mixture to a temperature of (-1)-(+15)oWith the development of intermediate composition - technical or chemically pure alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione carry out the crystallization of the corresponding received an alkaline salt or a mixture of alkaline salts and receive, respectively, chemically pure or high purity product.

16. The method according to p. 9, characterized in that the processing of the first intermediate composition using ion-exchange chromatography conduct a full or partial ion exchange, and then spend the adsorption chromatography was carried out or crystallization obtained after carrying out this procedure, the alkaline salt or a mixture of alkaline salts.

17. The method according to p. 15 or 16, characterized in that technical or chemically pure alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione crystallized or in the air, after which receive, respectively, chemically pure or high purity alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or, for example, in Boxing under conditions of high sterility, for example, in the atmosphere of purified air or inert gas and then receive respectively medication chemically pure or medical high purity alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures thereof) is conducted by dissolving in water or in aqueous solutions of the corresponding hydrocarbons with 45-80oC, cooling the aqueous solution to a temperature of (-1-+15)oC and keeping it at this temperature for 0.5-24 hours

19. The method according to any of paragraphs. 15-19, characterized in that the number of intermediate composition (alkali salts of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures thereof) during crystallization from water or bicarbonate buffer solutions chosen in the ratio of their masses is equal to 1: (2,0-12).

20. The method according to any of paragraphs. 15-19, characterized in that the crystallization of intermediate composition in the form of potassium or sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione carried out from aqueous buffer solutions, respectively, of potassium bicarbonate or sodium bicarbonate.

21. The method according to any of paragraphs. 15-20, characterized in that during crystallization from water or bicarbonate buffered aqueous solutions used or deionized (demineralized, or distilled water.

22. The method according to p. 21, characterized in that the water previously subjected to boiling for 0.1-2 hours

23. The method according to p. 9, characterized in that the processing of the intermediate composition or the target product after their allocation in the form of alkaline salts, or a mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione composition or the desired product in the form of alkaline salts, or a mixture of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione after their separation to produce a dry powder or in an oven at 60-70oC for 2-5 h, or beginning on air, for example, at room temperature or in the flow of the chilled 4-15oWith an inert gas such as argon or nitrogen, and then, for example, in an oven at 60-70oC for 2-5 hours

25. The method according to p. 9 or 23, characterized in that the drying of intermediate composition in the form of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione to anhydrous powder and in the form of lithium or sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione to crystalline with two moles of water of crystallization was performed at room temperature for 10-14 hours

26. The method according to p. 9, characterized in that remaining after separation of intermediate composition or the target product uterine solutions processed by exposure to an aqueous solution of acid or mixture of acids to obtain a precipitate in the form of 5-amino-2,3-dihydro-1,4-phthalazinedione.

27. The method according to p. 9 or 26, characterized in that the aqueous solution of the acid or mixture of acids, respectively, using an aqueous solution or organic, e.g. acetic or propionic, or inorganic, for example, sulfuric or hydrochloric or phosphoric acid, or an aqueous solution of a mixture of these organic and neola solution by exposing the corresponding acid or a mixture of the corresponding acid as a precipitate from the mother liquor technical salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or mixtures of these salts produce technical 5-amino-2,3-dihydro-1,4-phthalazinedione, and from the mother liquor chemically pure salt, or from the mother liquor drug chemically pure salts of 5-amino-2,3-dihydro-1,4-phthalazinedione, or mixtures of these salts, or high purity salt, or medical high purity salt of 5-amino-2,3-dihydro-1,4-phthalazinedione, or mixtures of these salts produce chemically pure 5-amino-2,3-dihydro-1,4-phthalazinedione.

29. The method according to p. 9, characterized in that remaining after separation of intermediate composition or the target product mother liquor recycle by distillation or evaporation.

30. The method according to p. 9 or 29, characterized in that when processed by distillation or evaporation remaining after isolation of the intermediate composition of the mother liquor removed previously introduced organic precipitator and 30-70% of water, and when the corresponding processing remaining after separation of the desired product, the mother liquor is removed 30-70% of water.

31. The method according to any of paragraphs. 9, 12, or 16, characterized in that a lithium salt or a mixture of lithium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of sodium salt of 5 - amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cat is eating this column of water with simultaneous control of acidity (pH) of the obtained solution.

32. The method according to any of paragraphs. 9, 12, or 16, characterized in that a lithium salt or a mixture of lithium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), for example through the ion exchange column filled with resin KU-2-cs" Li+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

33. The method according to any of paragraphs. 9, 12, or 16, characterized in that the sodium salt or the mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get using ion-exchange chromatography by passing an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione through ion-exchange resin (cation-exchanger), for example, through ion-exchange column filled with resin KU-2-cs" in Na+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

34. The method according to any of paragraphs. 9, 12, or 16, characterized in that the potassium salt or a mixture of potassium and sodium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get through inoome the C ion-exchange resin (cation-exchanger), for example, through ion-exchange column filled with resin KU-2-cs"+form, and by washing the column with water with simultaneous control of acidity (pH) of the obtained solution.

35. The method according to any of paragraphs. 9, 12, 16, 31 or 32, characterized in that the lithium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through a column of ion exchange resin in the Li+-the form of an aqueous solution of sodium or potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione a speed of 0.1-1.0 ml/min.

36. The method according to any of paragraphs. 9, 12, 16 or 33, characterized in that the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through a column of ion exchange resin in the Na+-the form of an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione speeds (0.1 to 1.0) ml/min

37. The method according to any of paragraphs. 9, 12, 16 or 34, characterized in that the potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through a column of ion exchange resin in To the+-the form of an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione a speed of 0.1-1.0 ml/min.

38. The method according to any of paragraphs. 9, 12, 16, or 31 and 32, characterized in that the mixture of lithium and sodium, lithium and potassium salts of 5-amino-2,3-dia, respectively, sodium or potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione at speeds of more than 1.0 ml/min.

39. The method according to any of paragraphs. 9, 12, 16, 33 or 34, characterized in that the mixture of sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione get by passing through the ion exchange column in Na+-the form of an aqueous solution of potassium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione or by passing through an ion exchange column To+-the form of an aqueous solution of sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione at speeds of more than 1.0 ml/min.

40. The method according to any of paragraphs. 9, 12, 16 or 31-39, characterized in that when carrying out ion-exchange chromatography using 0.5 to 2.0 molar solutions of alkaline salts of 5-amino-2,3-dihydro-1,4-phthalazinedione in water.

41. The method according to any of paragraphs. 9, 12, 16 or 31-39, characterized in that the working volume of the column for chromatography choose based 300-2000 cm31 mol passed through this column alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione.

42. The method according to p. 9, characterized in that a mixture of lithium and sodium, lithium and potassium, sodium, and potassium, and lithium, sodium and potassium salts of 5-amino-2,3-dihydro-1,4-phthalazinedione is produced by mixing the components in the specified proportions.

 

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