The agent with antiviral activity, based on compounds of silver and gold with diazinon and method thereof

 

(57) Abstract:

The invention relates to medicine. Water-soluble antiviral drug based on compounds of silver and gold with N, N1-tetramethylthiuram nitrate at a molar ratio of 1:1:2 and correspond to the composition: FROM32H36N9O9S2Cl Ag-Au. It is heated to 80-95oWith aqueous solution of N,N1-tetramethylpyrazine chloride add the silver nitrate at a molar ratio of 1: 1. The precipitate is filtered off. To the solution at 80-95oWith add aqueous silver nitrate solution, then the aqueous solution of gold compounds in the form of gold trichloride or three-hydrate soloconsolidation acid, ethyl alcohol at a molar ratio of 2:1:1:1 respectively. The resulting solution is sent for drying. The invention allows to realize the purpose of the tool and to simplify the process of obtaining it. 2 S. p. f-crystals, 5 PL.

Water-soluble antiviral drug based on silver compounds and gold compounds with N,N'-tetraethylthiuram nitrate (methylene blue in nitrate form) at a molar ratio of 1:1:2 and correspond to the composition: C32H36N9O9S2Cl medicines, to the field of pharmaceutical chemistry and medicine. The invention relates also to method of obtaining these funds. The invention can be used for the treatment of mixed viral-bacterial infections, including HIV.

Goal - the creation of highly effective antiviral drugs, in particular for the treatment of mixed infections, including HIV.

The essence of the invention. The proposed new antiviral agent-based compounds silver nitrate and gold compounds with N,N'-tetraethylthiuram nitrate (methylene blue in nitrate form) at a molar ratio of 1:1:2 and correspond to the composition: C32H36N9O9S2Cl Ag-Au (PL. 1a).

A way to get a new water-soluble antiviral drugs, lies in the fact that the synthesis is carried out at a temperature of 80-95oC and a molar ratio of N,N'-tetramethylpyrazine nitrate, silver nitrate, gold compounds and ethanol 2:1:1:1, while in the water first to dissolve methylene blue (N,N'-tetramethylpyrazine chloride), translated in nitrate form by adding silver nitrate at a molar ratio of 1: 1, followed filebased aqueous solution of silver nitrate, then an aqueous solution of compounds of gold in the form of gold trichloride or three-hydrate soloconsolidation acid and ethyl alcohol at a molar ratio of 2:1:1:1, and send the resulting solution of the target product for drying.

The positive effect of the method of production of new medicines, claimed us, compared to the prototypes (see below Patent Austrian and German Patent) that is excluded stage crystallization of the product and does not require careful filtering from the impurities of silver chloride remaining in a small amount due to the formation of colloidal form, as the recommended method of use of a medicinal product does not provide intravenous and designed for use by medical rectal enemas (finished dosage form powder in vials) or in the form of intersolubility gelatin capsules.

The invention relates to water-soluble drugs with a broad spectrum antiviral and antibacterial action, cytostatic activity in anaerobic conditions in the presence of the ABOVE-N (the reduced form of adenine dinucleotide).

The invention relates also to the method according to the La production of finished dosage forms of drugs with a broad medical spectrum, superior in vivo by the action of azidothymidine - AZT (domestic drug timated), most modern antibiotics, cytostatics type of cisplatin and other.

Both of the proposed object - drug and how to obtain it, United by a common creative idea aimed at improving the technology of production and reproducible physico - chemical properties of drug substances and finished dosage forms.

Known commercial drug called Alahram firm Merck (produced in Germany from about 1916 to 1945 and received by imports in the former USSR in the interwar period), which falls under the force since 1914 Patent Austria N 69476 and called up to 1920 German Silber methylene blau and patented in 1922 in Germany drug on the basis of HAuCl4or AuCl3with methylene blue as described in German Patent N 347376.

Also known from these patents ways of getting these medicines. These patents us selected as the closest analogues are the prototypes of our new medicines and how to obtain it.

Known compounds of these medicines and how they get Holota in the same drug under patent in Germany amounts to about 30 wt.%, and claimed in us a new medicinal product total weight content of these metals is 27-28 wt.%.

The technology of the new medicinal product is easy chemical synthesis, hardware production schemes, including the state effective drying of the reaction mass to powder, the process control of chemical synthesis method relaxometry on ions Cl-, NO3-Ag+.

A method of obtaining complex AgNO3since methylene blue is implemented in the following technological operations.

1. Dissolve in warm water methylene blue (chloride) to a concentration of 9-10 weight. % and the addition of an aqueous solution of AgNO3with a concentration of 20-25 wt.% when the molar ratio of the reagents methylene blue: AgNO3= 1:1.

2. Filters the resulting warm solution and separating the precipitate AgCl.

3. Heating the obtained filtrate to boiling and mixing it with a solution 9-10 wt.% AgNO3when the molar ratio of nitrate methylene blue, obtained after filtration and AgNO3= 1:1.

4. Evaporation of the solution to 1/20 of the original volume.

5. Filtration of the precipitated crystals of the target Priceline precipitated AgCl.

8. Evaporation of the solution on a rotary evaporator.

9. Drying of the precipitated crystals.

A method of obtaining complex with methylene blue ion drug gold implements the following technological operations.

1. An alcoholic solution of HAuCl43H2O with a concentration of 35-40 wt.% mixed with an alcoholic solution of 9-10 wt.% methylene blue at a molar ratio of reactants is 1:1.

2. The reaction mass is heated nearly to boiling.

3. Evaporation of the solution to 1/20 of the original volume.

4. Cooling of the solution and crystallization.

5. Drying of the crystals.

The inventive method of obtaining a new medicinal product is described as an example of a specific implementation of the

Example.

In the dark glass reaction apparatus equipped with a polymer stirrer, addition funnel and a bubbler for inert gas purge, download 373,9 g of methylene blue in the form of 9-10 wt.% an aqueous solution heated to a temperature of 80-95oC and at this temperature, add 169,9 g AgNO3at 25 weight. % aqueous solution at room temperature. Filtered the reaction mass from the fall in the ot on the anhydrous silver nitrate. The resulting solution is mixed with heated nearly to boiling with aqueous-alcoholic solution at room temperature HAuCl43H2O with a concentration of 35 wt.% the number 196,9 g calculated on the base material in the form of three-hydrate. Then the resulting reaction mass is maintained at a temperature of 80-90oC for 30 minutes. The resulting aqueous solution of the target product are evaporated to dryness on a rotary evaporator.

Note. Aqueous-alcoholic solution of HAuCl43H2O contains to 23.03 g of ethyl alcohol, calculated on anhydrous.

When the above-described method, the loss of precious metals is not more than 0.01 wt.% downloaded from drugs in terms of metals.

Investigation of the anti-HIV activity of preparations NN 1,2

Evaluation of the cytotoxicity of the compounds.

The cytotoxicity of these compounds was evaluated on the culture of human T lymphocytes person (line MT-4). From initial solutions of the investigated compounds were prepared by serial 10-fold dilution on the basis of the nutrient medium RPMI-1640 (from 0.1% to 0,00001%) and appropriate dilutions were made in 200 μl into the wells of 96-well plates (three for each dilution) for the screening of cells. The seeding concentration is t 0.01% to 0,000001%. Cells were cultured in 96-well tablets for cell culture company "Costar" (USA) in growth medium (medium RPMI-1640 with the addition of 10% serum fetal cow, 0,06% L-glutamine, 100 µg/ml gentamicin) at 37oC and 5% CO2within 4 days.

At the end of incubation was estimated percentage of viable cells in the cell Goryaeva after dyeing Trifanova blue. Built a dose-dependent curve and determine the concentration of compounds that causes death of 50% of the cells - CD50(see tab. 1)

Evaluation of anti-HIV activity of the compounds.

To assess anti-HIV activity of the compounds of the cells it-4 (concentration of 2106cells/ml) were infected with HIV-1 strainTHE ECRSwith a multiplicity of infection of 0.2-0.5 infectious units per cell. After adsorption of virus for 1 hour at 37oC infected and control cells (without virus) was diluted growth culture medium before seeding concentration 5105cells/ml and added into wells of 96-well culture plates. Then into the appropriate wells contributed solutions of the investigated compounds (three wells for each dilution) and then cultured as described above. The reference drug is used in azidothymidine (AZT) - WPI is pensii ranged from 0.01% to 0,000001%.

The inhibiting effect of the compounds was evaluated on the 4th day of cultivation by the JRC of the virus on the basis of the degree of protection of infected cells from death due to virus infection. This was determined by the percentage of viable cells count in the camera Goryaeva after dyeing Trifanova blue. On the basis of the obtained results was calculated quantitative characteristics of inhibition of reproduction of HIV: ID50- the concentration, 50% inhibitory products of a virus or causing 50% protection of the cells; IS the index selectivity - the ratio of the toxic dose of the compounds of CD50its effective dose ID50.

The results of these studies.

In the result of the experiments to study drug NN 1, 2 cytotoxic doses, which accounted for drug N 1 CD50=0,0001%, for the preparation of N 2 CD50=0,0005%.

In the study of anti-HIV activity of these drugs was found that the drug is N-1 at a concentration of 0,00001% significantly reduces the JRC of the virus, i.e., protects 76% infected cells from death due to infection (see table. 2). The percentage of viable cells in other samples with drugs almost everywhere is not exceeded, and in some samples the g/ml in this experiment provided 100% protection of infected cells (proportion of viable cells in the sample 92,15%).

For a more complete characterization of anti-HIV activity presents drugs was the quantitative assessment of viral P24 antigen by ELISA (see tab. 3).

According to the presented in the table. 3 experimental data to evaluate the extent of inhibition of the accumulation virousspecificakih protein P24 investigational drugs NN 1, 2 in the culture of cells MT-4 both drugs exhibit a pronounced anti-HIV activity in the concentration range from 0.01 to 0.0001%. The reference drug AZT inhibits the reproduction of HIV in 92% at a concentration of 0.1 µg/ml.

On the basis of studies have defined all the necessary quantitative characteristics of inhibition of reproduction of HIV in culture cells MT-4: ID50CD50, IS presented in table. 4.

It should be noted that both drugs have low selectivity indexes - 5 and 7, but in the case of the preparation N 1 manifests itself in contrast to the drug N 2 significant protective effect (IS=10).

If necessary, you can Refine the quantitative characteristics choose to experiment, not 10, but, for example, 2-fold dilution of the initial drugs.

1. Water-soluble agent having anti-Christ. Ohm at a molar ratio of 1:1:2 and correspond to the composition: FROM32H36N9O9S2ClAgAu.

2. The method of obtaining water-soluble agents that have antiviral activity on p. 1, namely, that it is heated to 80-95oWith aqueous solution of N,N1-tetramethylpyrazine chloride add the silver nitrate at a molar ratio of 1:1 followed by filtration of the precipitate of silver chloride and filtered solution of nitrate N,N1-tetramethylpyrazine at 80-95oWith the newly added aqueous silver nitrate solution, then the aqueous solution of gold compounds in the form of gold trichloride or three-hydrate soloconsolidation acid, ethyl alcohol at a molar ratio of 2:1:1:1 respectively and the resulting solution is sent for drying.

 

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