The way to obtain anti-cancer drugs

 

(57) Abstract:

The invention relates to medicine. Solutions hydroxycarboxylic acids obtained from natural raw materials in the form of humic substances, treated with tetrachloroplatinate potassium under the action of ultrasound with radiated power of 40 W/cm2with a frequency of 22 kHz for 4-8 minutes Humic substances can be obtained by treating humic material by alkaline solutions under normal conditions. As humic material can be used composts, sapropel, peat from upland or transitional bogs, humus horizons of different soil types etc., Humic substances can also be obtained from the oxidized wood lignin by treatment with oxygen-containing gas in an alkaline medium at a temperature 17020oWith the pressure of 1.9-2.5 MPa within 1-3 hours and subsequent cooling of the reaction mixture, separating the solid phase from the solution, and acidification of the latter to a pH of 2-3. The invention allows to expand the Arsenal of anticancer agents derived from available raw materials. 8 C.p. f-crystals.

The invention relates to the field of production of medicines, in particular the production of anticancer agents representing integrated the s platinum.

Anticancer drugs containing chelating platinum, causing disturbance of the genetic apparatus of tumor cells, has strong anti-tumor effect, resulting attract the attention of specialists.

Platinum drugs have a broad spectrum of antitumor activity. The most studied drug in this class of anticancer agents - CIS-dichlorodiammineplatinum (MDC) - active against tumors of different origin: spontaneous transplantable, induced by viruses and chemical carcinogens. The main disadvantage of the MDC to its high toxicity. Tests on animals and in the clinic showed that it acts mainly on the kidneys, bone marrow and the gastrointestinal tract (Biological aspects of coordination chemistry, ed K. B. Yatsymirsky, Kiev, "Naukova Dumka". 1979, pp. 149-180).

Other known antitumor agent, the so-called oxaliplatin, contains a complex compound of tetravalent platinum, CIS-diamminedichloroplatinum, and has activity in oral administration, the lack of nephrotoxicity, the growth inhibition of metastasis, high breadth of therapeutic action (U.S. Pat. RF 2086261, class a 61 K 45/05, publ. the changes of bivalent platinum, effective in the treatment of malignant tumors of the testis and ovary, breast cancer, dissimilitudes melanoma. Platin derived from platinochloride acid and hydroxylamine in three stages through the formation of intermediate chloroplatinite alkali metal, its interaction with hydroxylamine in the presence of alkali metal salts at room temperature in a weakly acidic aqueous medium. The product was then purified by recrystallization from dilute hydrochloric acid. ("Platinum", leaflet, NGO Mediachance", order 2178).

Also known is a method of obtaining antitumor agents (ed. St. USSR 1701323 And 61 To 45/05, publ. B. I. 48, 1991), in which water-containing DNA (high molecular weight natural organic compound and the sodium chloride, the solution is mixed with an aqueous solution of tetrachloroplatinate potassium. Before mixing in the last add ammonium chloride, potassium chloride and potassium acetate, each solution is heated to the melting temperature of DNA. In a solution containing DNA and sodium chloride, add sodium citrate. The method allows to obtain a tool that combines high antitumor activity with a strong immunomodulatory effect.

Research razlichie in the biological properties of platinum complexes: antitumor activity and side effects. Analysis of available data shows that small changes in the molecular structure of the complex can cause a radical change in biological activity. The existence of a relationship between the structure of complex compounds and antitumor activity stimulates the search for new, containing platinum drugs is highly radioactive and non-lethal.

The present invention is to develop a method that allows to obtain from the available natural raw materials for new and effective means of containing platinum and having antitumor activity.

The problem is solved in that a method for obtaining anti-cancer drugs based tetrachloroplatinate potassium. In accordance with the invention with a solution of tetrachloroplatinate potassium treated with an aqueous solution containing humic substances, when this processing is performed under the action of ultrasound with a radiated power of 40 W/cm2with a frequency of 22 kHz for 4-8 minutes Humic substances can be obtained obrabotka humified material under normal conditions the solutions of alkalis, which can be added urea and various chelating agents, such as Trilon b In p is P CLASS="ptx2">

As humified material can be used sapropels, humus horizons from different types of soils, composts, peat from bogs and transitional mires.

Humic substances can also be obtained by oxidation of wood lignin, while wood lignin in aqueous-alkaline suspension oxidize oxygen-containing gas at a temperature 17020oC and a pressure of 1.9-2.5 MPa within 1-3 hours After cooling the reaction mixture to separate the solid phase from the solution, which represents the non-oxidized particles source humified material. In the solution are the salts of humic acids, i.e. humic substances. Then from the acidified solution of humic substances produce humic acid, which, after neutralization process tetrachloroplatinate potassium.

Processing tetrachloroplatinate potassium expediently carried out at a temperature of 405oC.

Possible treatment tetrachloroplatinate potassium ultrasonic radiation power 40,00,5 W, the frequency of sound vibrations 22,00,5 kHz for 1-25 minutes Choice time ultrasonic treatment depends on the composition of humic acids and selected experimentally.

Suitable aqueous-alkaline SSPM2and frequency of 22 kHz for 6-10 minutes In this case, increasing the number of active paramagnetic centers in the substance, which leads to a further increase in the biological activity of the final product.

Lignin, which is part of the wood, is a valuable medicinal raw materials, stocks of which are practically unlimited. Medicinal properties of lignin comprehensively reviewed in the monograph (Levanova VP, Medical lignin. Ed. by N. A. Belyakov.: SP(b) 1992. p. 136). Although lignin and preparations on its basis in medicine up to the present time were regarded as sorbents, many researchers in addition to the sorption properties noted antiseptic, hypocholesterolemic, and other properties.

As wood lignin product of acid hydrolysis of wood, can be used chelators on the basis of lignin, such as "Polifan", "Lignosol" etc.

"Polifan" - nonspecific enterosorbent (Reg. 80/1211/3) is a brown powder without smell and taste, humidity 65%, consists mainly of lignin and contains not more than 20% residual polysaccharides (hydrocellulose).

"Lignosol" (paste Politeama) VFS 42-2203-93.

In the social studies, when the oxidation of lignin in terms of the proposed method does not generate harmful substances such as polycyclic aromatic hydrocarbons, nitrosamines and polychlorinated dicyclo-p-dioxins.

The resulting products are concentrated liquid dark brown color, containing from 0.05 to 1.00 % of platinum with a specific taste and smell.

It is well known that the process of humification (the formation of humic substances) is global and the resulting humic substances (otherwise humic acid, which is a mixture of humic and fulvic acids) are characterized by similar spectra in the infrared region, regardless of how they are derived.

Antitumor activity proposed funds due to its nature. Organic compounds are included in it, are characterized by a large number of covalently-active links. Whereupon it reacts with the nucleophilic centers of protein molecules. In this case violated the translation and transcription of nucleic acids. The presence of ions of platinum substantially enhances the antitumor therapeutic effect.

Mechanismamaryl mechanism of antitumor action is its effect on the hypothalamus and the thyroid gland and as a consequence the activation of the endorphin system.

Antitumor activity of the obtained product was evaluated for its effect on tumor growth in cattle (cows of black-motley breed). The latter is due to the fact that the metabolism (metabolism) in cattle similar to the metabolism of a person and gives representative results.

The following examples illustrate how the proposed method of producing anti-cancer drugs and illustrate its antitumor activity.

In the experiments described in examples 2-6 below, processing humified materials (sapropel, peat, soil) water-alkaline solution, is carried out under normal conditions, i.e. at a temperature of 20oC and a pressure of 760 mm RT. Art. as a result received a suspension containing humic substances dissolved and the insoluble residue.

Tetrachloroplatinate potassium for better interaction with humic substances used in aqueous solution.

EXAMPLE 1

The original aqueous alkaline suspension of lignin (mark "Polifan", reg. 80/1211/3) - non-specific enteral sorbent is oxidized by oxygen in the air.

The composition suspension

Sturdily in the reactor with mechanical stirring at a temperature of 1605oC at a pressure of 2.5 MPa for 1 h, the air Flow rate was 5 l/min

The reaction mass is then cooled to room temperature and the solution filtered to separate the precipitate. The filtrate, which represents an alkaline solution containing humic substances, acidified with sulfuric acid to pH 2-3. Filtering allocate precipitate in the form of gel humic acid, washed with distilled water, and then water-alcohol mixture to establish a pH of 6.0-6.5 and dried at 105oWith until smooth. The obtained humic acid is treated with a 5% solution of ammonia at the rate of 1 g of humic acid in 80 ml of the indicated solution, thermostatic in a boiling water bath to remove excess ammonia, filtered through filter paper and add 30% vol. of distilled water. In the resulting solution, which represents the salts of humic acids related to humic substances, contribute, based on 1 g of salt of humic acid, 0.27 wt.% tetrachloroplatinate potassium and create a process developed acoustic cavitation under the action of ultrasound with radiated power of 40 W/cm2and frequency of 22 kHz for 4 minutes Then the solution volume was adjusted with water to 100 ml.

The resulting product is a aq is the solution used for animal testing to determine its antitumor activity. The results are given below in example 7. To identify the obtained substances specified above solution was subjected to analysis.

The elemental composition of dry selected product in terms of organic matter, wt. %: 54% N 12% N 2%, (S+0) 32% (by difference). The substance decomposes without melting, starting with 168oC.

The results of the study infrared Fourier spectra show that in the resulting product are similar in intensity of the bands 1700 cm-1and 1600 cm-1characteristic of carboxyl groups, an intense band in the region of 1200 cm-1wide on the structure of the strip with the local maxima 3400, 3200, 3100 and 2600 cm-1and strip 2926, 2815, 1460 cm-1and strip 2955 and 2870 cm-1characteristic of the methylene groups.

The resulting product has paramagnetism. In the product there are symmetric EPR signals with q-factor 2,0000,001, close to the value for a free electron (q=2,00) and width H=6,10,1 OE. The concentration of PMC is located at (2,50,4)X1018per gram,

The organic portion of the product contains a 2.9 to 3.4 mEq of COOH-groups in 1 g of the product and 6.0-6.4 mg-EQ phenolic hydroxyl in 1 g of the product.

EXAMPLE 2

Lacustrine sapropel with Kali.

To 200 g of lake sapropel with a humidity of 95% was added 5.6 g sodium hydroxide and brought the total amount of the mixture to 1 liter, after which the mixture which was within 5 min and left for 6 hours, the Process was carried out under normal conditions. Upon expiration of the specified period was separated by filtration residue. The filtrate, which represents an alkaline solution containing humic substances, acidified with phosphoric acid to pH 1-2. The precipitation (gel humic acid) is separated by filtration, washed with distilled water, and then water-alcohol mixture to establish a pH of 6.0-6.5 and dried at 105oC to constant weight. The obtained humic acid is treated with a 5% aqueous solution of ammonia at the rate of 1 g of humic acid in 80 ml of the indicated solution, thermostatic in a boiling water bath to remove excess ammonia, filtered through filter paper and add 30% vol. of distilled water. In the resulting solution, representing a solution of salts of humic acids related to humic substances, contribute, based on 1 g of humic acid, 0.2 wt. % tetrachloroplatinate potassium and create a process developed acoustic cavitation under the action of ultrasound with radiated power of 40 W/cm2and Castelnovo product in terms of organic matter, wt.%: With 60% N 6% N 2%, (S+O) 32% (by difference). The substance decomposes without melting, starting with 168oC.

The results of the study infrared Fourier spectra show that in the resulting product are similar in intensity of the bands 1700 cm-1and 1600 cm-1characteristic of carboxyl groups, an intense band in the region of 1200 cm-1wide on the structure of the strip with the local maxima 3400, 3200, 3100 and 2600 cm-1and strip 2976, 2815, 1460 cm-1and strip 2955 and 2870 cm-1characteristic of the methylene groups.

The resulting product has paramagnetism. In the product there are symmetric EPR signals with q-factor 2,0000,001, close to the value for a free electron (q=2,00) and width H=6,10,1 OE. The concentration of PMC is located at (2,50,4)1018per gram.

The organic portion of the product contains from 3.0 to 3.6 mEq of COOH-groups in 1 g of the obtained product and 6.0 to 6.5 mEq phenolic hydroxyl 1,

EXAMPLE 3

Was carried out similarly to example 2, with vermicompost with content of organic substances in an amount of 23% on dry substance was subjected to alkaline treatment with 0.1 M sodium hydroxide solution. 10 g of vermicompost (in terms of absolutely dry sample) for the. the process was carried out under normal conditions. The filtrate, representing a solution containing humic substances, acidified with sulfuric acid to pH 1-2, and provided humic acid. Further processing was produced in the same way as shown in examples 1 and 2, except that a solution of salts of humic acids contributed 0.17 wt.% tetrachloroplatinate potassium per 1 g of humic acid and heated to 40oC.

The elemental composition of dry selected product in terms of organic matter, wt.%: With 57% N 7% N 2%, (O+S) 34% (by difference).

The organic portion of the product contained a 3.2 to 3.8 mEq of COOH groups in 1 g and 6.2 -6,7 mg-EQ phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances.

EXAMPLE 4

Was carried out similarly to example 2, with the peat from the bog with the organic matter content of 73% on dry substance was subjected to alkaline treatment of 0.2 m solution of sodium hydroxide. 5 g of dry peat filled 0.2 M solution of caustic potash, and then left for 6 h, after which the filtered precipitate was separated. The process was carried out under normal conditions. Fu made the same way as shown in examples 1 and 2, except that the processing salts of humic acids by tetrachloroplatinate potassium was conducted at 45oC.

The elemental composition of dry selected product in the calculation of the organic matter, wt.% With 51% N 12% N 2%, (O+S) 35% (by difference).

The organic portion of the product contains 3,4-4,0 mEq of COOH-groups in 1 g and 6.3-6.9 mg-EQ phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances.

EXAMPLE 5

Was carried out similarly to example 2, with 500 ml of lake sapropel with a humidity of 90% and a dry matter content of 31% was added 500 ml of distilled water, 5.6 g sodium hydroxide, 6 g of urea and 37 g of the trylon B. After stirring for 1 h, the Process was carried out under normal conditions. The precipitate was separated by filtration. The filtrate, representing a solution containing humic substances, acidified with sulfuric acid to pH 1-2. Further processing was produced in the same way as shown in examples 1 and 2, except that the solution of humic substances contributed 0.17 wt.% tetrachloroplatinate potassium per 1 g of humic acid and heated to 40oC.

The organic portion of the product contains of 3.0-3.4 mEq of COOH-groups in 1 g and 6.0-6.4 mg-EQ phenolic hydroxyl 1,

Studies of infrared spectra, and determination of the content of COOH-groups and phenolic hydroxyl showed that the obtained humic substances.

EXAMPLE 6

Was carried out similarly to example 2, to 100 g of the humus horizon of soil (a horizon And from ordinary Chernozem) with the content of total carbon 7% was added 500 ml of distilled water, and then 1.12 g sodium hydroxide, 6 g of urea and 7.4 g of trylon B.

After stirring for 10 min the mixture was stirred under normal conditions 6 h and the precipitate was separated by filtration. The filtrate, representing a solution of humic substances, acidified with sulfuric acid to pH 1-2. Further processing was produced in the same way as shown in examples 1 and 2, except that a solution of salts of humic acids contributed to 0.2 wt.% tetrachloroplatinate potassium per 1 g of humic acid and heated to 40oC.

The elemental composition of dry selected product in terms of organic matter, wt.%: With 56% N 8% N 3%, (O+S) 33% (by difference).

The organic portion of the product contains 3,4-4,0 mg-Opredelenie content of COOH-groups and phenolic hydroxyl showed it is derived humic substances.

EXAMPLE 7

The preparation obtained in example 1, was tested for non-specific immunotherapy of leukemia in cattle.

The experience was used cow black-motley breed at the age of 5-7 years of one of the enterprises of the Leningrad region. All animals were housed under standard conditions of a loose-housing. The diet and care of animals was similar to the overall herd both in experience and in control.

The preparation was stored in glass bottles 10, 20, 25, 30, 50, 100, 200 ml. of simultaneous processing of a large number of cattle were taken vials of medication to 500 ml. Bottles tightly closed in a sterile screw-top tubes of neutral plastic or rubber plugs. Sterilization of the drug was carried out by autoclaving. Keep the medication in a place protected from light. Shelf life depends on the ambient temperature, at a temperature of -5o...-10oWith up to 2-3 years. Before use a vial with the drug or the vial was kept in warm water with a temperature of 37oC for 5-10 sec. Then sterility ampoules were opened and got into the syringe for injection.

The first group (Experience): 12 cows of black-motley breed with the clinical form of leukemia respond positively on REED-test and Hematology research.

The second group (Positive control) 12 cows with clinical form of leukemia. All animals respond positively on REED-test data and hematological studies. This group were not exposed to non-specific immunotherapy.

The third group (Negative control). 12 cows of black-motley breed clinically healthy, reacting negatively on REED-test and Hematology research.

All three groups of animals were on the one yard on leash content with the same conditions of feeding and care. During the experiment the animals in the experiment and the control were tested on three tests:

the determination of the presence of clinical signs of disease;

serological diagnosis using REED-test;

hematological examination of the peripheral blood in all animals.

Clinical examination of the animals was carried out in the presence of veterinarians of management and employees of the St. Petersburg veterinary Institute.

All animals to the experimental group and in predtopochnyh. Especially were enlarged inguinal and nademanee lymph nodes, which palpation were uniformly increased. Signs of pain on deep palpation was observed. Percussion of the spleen was noted the expansion of its borders.

The basis for monitoring the development of the leukemic process was taken a clinical pattern lakskogo process Rice, 1975, Under this scheme during the development of metastases in the lymph nodes come proliferative hyperplastic processes. Lymph nodes with this increase in volume, especially when the clinical examination. This symptom is the main clinical sign of disease manifestations. Therefore, the process of increasing or decreasing the volume of the lymph nodes can be considered respectively as the deterioration or improvement of the nature of the disease leukemia.

Nonspecific immunotherapy of leukemia was performed in several cycles according to the following scheme.

Typically, the test drug was administered intramuscularly every 6 hours in 20 ml dilution 1:100 for 36 days. Then followed a break 35-40 days.

In the course of treatment was determined by the magnitude of the inguinal and nadumannij lymph nodes of each cow. Froze in which all animals were observed reduction of lymph nodes to normal size. In parallel to the positive experience of 12 cows with similar clinical form of leukemia increased in the amount of lymph nodes remained unchanged. 35-40 days after the end of the first cycle nonspecific active immunotherapy in individual animals, the first experimental group was again observed in lymph nodes.

All the animals of the experimental group 30-35 days was held the 2nd re-cycle nonspecific active immunotherapy: within 36 days each animal every 6 days received 20 ml of the drug in a dilution of 1:100. After the second course in all animals of the experimental group had reached a stable remission. All animals disappeared clinical symptoms improved General condition: cows had willingly turned up the food, increased milk yield. Marked characteristic clinical signs of the onset of remission of leukemia. Animals were active, developed the luster of the skin, did not become emaciation.

In the control analysis of a blood on a study on REED-test in 60% of animals had a negative result.

1. The way to obtain anti-cancer drugs based tetrachloroplatinate potassium, characterized in that the solution of tetrachloroplatinate potassium obrabatyvaemomu radiation 40 W/cm2with a frequency of 22 kHz for 4-8 minutes

2. The method according to p. 1, characterized in that humic substances receive treatment humified material alkaline solutions under normal conditions.

3. The method according to p. 2, characterized in that the humified material is treated with an alkaline solution in the presence of urea and complexone.

4. The method according to p. 2 or 3, characterized in that as humified material used peat from upland or transitional bogs or sapropel, or compost, or humus horizons of different soil types.

5. The method according to p. 4, characterized in that the processing tetrachloroplatinate carried out at a temperature of 405oC.

6. The method according to p. 1, characterized in that humic substances derived from oxidized wood lignin.

7. The method according to p. 7, characterized in that humic substances produced by oxidation of wood lignin in alkaline oxygen-containing gas at a temperature 17020oWith the pressure of 1.9-2.5 MPa within 1-3 hours and subsequent cooling of the reaction mixture, separation of the solid phase from the solution, and acidification of the latter to a pH of 2-3.

8. The method according to p. 8, characterized in that before oxidation Dreux is m2with a frequency of 22 kHz for 6-10 minutes

9. The method according to p. 8 or 9, characterized in that the processing tetrachloroplatinate carried out at a temperature of 405oC.

 

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