Method for virus controlling using substance based on 2,8-dithioxo-1h-pyrano[2,3-d;6,5-d']dipyrimidine and 10-aza- analogs thereof (variants)

FIELD: medicine, virology.

SUBSTANCE: invention relates to method for virus controlling using substance based on 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and 10-aza- analogs thereof. Claimed method includes sharing said substances together with integrase inhibitor, reverse transcriptase inhibitor, ore protease inhibitor in various ratio (variants).

EFFECT: method for virus inhibiting of increased effectiveness.

7 cl, 8 tbl, 8 ex

 

The invention relates to medicine and can be used to influence a variety of viruses, particularly retroviruses.

The problem of exposure to causative agents of diseases caused by retroviruses, particularly HIV, is one of the primary goals of modern medicine. Today for HIV infection using mainly two classes of drugs: nucleoside reverse transcriptase inhibitors and protease inhibitors. The use of these drugs can significantly reduce the level of viral load, however, continued in a separate cell replication leads to the emergence of strains resistant to the action of drugs data types (Perelson et al, Nature, 1997, 387: 123-124). Moreover, the human immunodeficiency virus is able to develop resistance against the action of almost all currently used antiviral drugs (Schmit at al, J. Infect. Dis, 1996, 174:962-968).

There is a method of exposure to causative agents of viral diseases through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d'] dipyrimidine and their 10-Aza-analogues. This method is described in patent RU 2246496 and adopted for the prototype of the present invention. However, this method is not effective in cases where the emergence of resistant forms of the virus.

The present invention provision is about the task of creating a more effective way of influencing the causative agents of viral diseases, especially with the emergence of resistant forms of the virus.

According to the first variant of the invention this problem is solved due to the fact that the method of exposure to the virus through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d'] dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group: O, NH, N-Alkyl;

R1 is selected from the group: H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar.

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group:6H5, Aryl;

R3 is selected from the group: H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, in addition use a protease inhibitor; in addition, you can use the inhibitor of integrases; in addition, you can use analog reverse transcriptase inhibitor.

According to the second variant of the invention this problem is solved due to the fact that the method of exposure to the virus through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group: O, NH, N-Alkyl;

R1 is selected from the group: H, Is H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar.

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group:6H5, Aryl;

R3 is selected from the group: H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, optionally use the inhibitor of integrases; in addition, you can use analog reverse transcriptase inhibitor.

According to the third variant of the invention this problem is solved due to the fact that the method of exposure to the virus through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group: O, NH, N-Alkyl;

R1 is selected from the group: H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar.

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group:6H5, Aryl;

R3 is selected from the group: H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, optionally use the nucleoside reverse transcriptase inhibitor; in addition, you can use a protease inhibitor.

The best activity environments the substances of General formula A1*M have the following derivatives:

Table 1
RoomXR1R2R3
IaOHEWith6H5Cl
IbOHEC6H4-4-NO2Cl
IiaOClC6H4-4-NO2Cl
IIIOHEC6H4-4-NO2NH2
IVOClC6H4-4-NO2NH2
VONH2C6H4-4-NO2NH2
VINHNH2C6H4-4-NO2NH2
VIINHHEC6H4-4-ClNH2
VIIIOHEC6H4-4-NO2NHCH3
IXOHEC6H4-4-NO2N(CH3)2
XOheC6H4-4-NO2
XIOOHWith6H4-4-NO2N
XIIOOHWith6H4-4-NO2HE

In the group of most active were also complexes A1*M:

XIII - Complex salt composition: {Ib (1 mol), XII (1 mol), NH3(1 mol)}

XIV - Complex salt composition: {III (1 mol), XII (1 mol), NH3(1 mol)}

XV - Complex salt composition: {XI (1 mol), XII (1 mol), NH3(1 mol)}

The implementation of the method is illustrated below by examples

Example 1. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with a protease inhibitor (saquinavir) (claim 1 of the patent claims).

The effectiveness of the method was evaluated for the protection of the cells. The level of inhibition of reproduction of the virus was determined to protect T-lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by: 1) indirect immunofluorescence assay (ELISA) with polyclonal polerowanie anticorodal from HIV-infected and b is selected AIDS (antibody titer is 1:1000000). In the tests used a dilution of 1:40. 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal substrate. The results are shown in table 2.

Table 2
Substance (from table 1)Concentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
the protease inhibitor5.070
0,2540
Ib + saquinavir0,5+0,2590
XIV5,0100
0.560
XIV + saquinavir0,5+0,05100

Example 2. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with inhibition proteases (saquinavir) and the integrase inhibitor - a substance No. 51 in US patent No. 6638921 B1 (claim 2).

The effectiveness of the method was evaluated for the protection of the cells. The level of oppression/reproduction of the virus was determined by the protection of T lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27 Cells, infected with the virus, were analyzed by: 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 3.

Table 3

The inhibition of the reproduction of the HIV virus
Substance (from table 1)Concentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
Protease inhibitor5.0100
0,0230
The integrase inhibitor5.070
0,12525
Ib + Saquinavir + integrase Inhibitor0,5+0,02+0,12570
XIV5100
0.130
XIV + protease Inhibitor + integrase Inhibitor0,1+0,02+0,125100

Example 3. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-p is sooner[2,3-d; 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with the nucleoside reverse transcriptase inhibitor (azidothymidine), protease inhibitor (saquinavir) and integrase inhibitor (substance No. 51, US 6638921B1) (p.3 claims).

The effectiveness of the method was evaluated for the protection of the cells. The level of inhibition of reproduction of the virus was determined to protect T-lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 4.

Table 4

The inhibition of the reproduction of the HIV virus
Substance (1)Concentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
AZT5.0100
0,0230
Protease inhibitor50 70
0,0610
The integrase inhibitor0,570
0,12525
Ib + AZT + protease Inhibitor + integrase Inhibitor0,5+0,02+0,06+0,12590
XIV5100
0.130
XIV + AZT + protease Inhibitor + integrase Inhibitor0,1+0,02+0,06+0,125100

Example 4. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with integrase inhibitor (substance No. 51, US No. 6638921 B1 (4 claims).

The effectiveness of the method was evaluated for the protection of the cells. The level of inhibition of reproduction of the virus was determined to protect T-lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 5.

Table 5

The inhibition of the reproduction of the HIV virus
SubstanceConcentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
The integrase inhibitor5.070
0,2540
Ib + integrase Inhibitor0,5+0,2590
XIV5,0100
0.560
XIV + integrase Inhibitor0,5+0,05100

Example 5. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with the nucleoside reverse transcriptase inhibitor (azidothymidine) and integrase inhibitor (substance No. 51, US No. 6638921 B1), (5 claims).

The effectiveness of the method was evaluated for the protection of the cells. The level of inhibition of reproduction of the virus was determined to protect T-lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-deg. of infection is the R and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 6.

Table 6

The inhibition of the reproduction of the HIV virus
SubstanceConcentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
AZT5.0100
0,0230
The integrase inhibitor5.070
0,12525
Ib + AZT + integrase Inhibitor0,5+0,02+0,2590
XIV5100
0.130
XIV + AZT + integrase Inhibitor0,1+0,02+0,125100

Example 6. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, as well as their complexes and salts together with the nucleoside reverse transcriptase inhibitor (azidothymidine) (item 6 of the claims).

The effectiveness of the method was assessed by protecting cells during completion of the m adding test substances and azidothymidine. The level of inhibition of reproduction of the virus was determined by the protection of T lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 7.

Table 7

The inhibition of the reproduction of the HIV virus
SubstanceConcentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
AZT5.0100
0,0550
Ib + AZT0,5+0,0580
XIV5100
0.560
XIV + AZT0,5+0,05100

Example 7. The impact on the human immunodeficiency virus derived 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d']dipyrimidine and their 10-Aza-analogues, and their to the of ElexV and salt together with a protease inhibitor (saquinavir) and nucleoside reverse transcriptase inhibitors (azidothymidine) (7 claims).

The effectiveness of the method was evaluated for the protection of the cells. The level of inhibition of reproduction was determined by the protection of T lymphoblastoid cells infected MT4 vaccinated liquid culture HTHIV27. Cells infected with the virus, were analyzed by 1) indirect ELISA with polyclonal polerowanie anticorodal from HIV-infected and AIDS patients (titer antibodies in ELISA is 1:1000000). In the tests used a dilution of 1:40; 2) competitive ELISA with monoclonal antibodies (MonAb) to P24 HIV and polyclonal background.

The results are shown in table 8.

Table 8

The inhibition of the reproduction of the HIV virus
Substance (1)Concentration, mg/lThe level of inhibition of virus reproduction (in %)
Ib5.070
0,520
AZT5.0100
0,0230
Protease inhibitor5.070
0,0610
Ib + AZT + protease Inhibitor0,5+0,02+0,0690
XIV5100
0.130
0,1+0,02+0,06100

The claimed method (options) allows the impact of early replication integration of viral DNA into the human genome, thus inhibiting the replication of the virus; they can be used as agents that inhibit the virus life cycle depends on the integrases, similar to HIV integrases.

The claimed method of exposure to viruses can be used to treat or prevent infections caused by HIV or other viruses, the life cycle which will certainly depend on integrase, traditional way. The specific conditions of treatment using the inventive method effects on viruses can be developed from the existing Arsenal of tools and techniques. The claimed method can be combined with known pharmaceutically tested methods of exposure to viruses. In addition, the inventive method can also be combined with the method of the use of any pharmaceutically tested auxiliary medicinal product traditionally used in vaccines for introduction in the amount effective to extend the period of preventive actions against viral infections such as HIV infection. Used in the application method can be used as the basis for the creation of effective methods of prevention of viral infections, the key HIV mammals. When using the inventive method with the simultaneous use of methods based on the introduction of other antiviral drugs that act on different targets in the viral replication cycle, the antiviral action of these substances potentiated by, for example, if jointly entered antiviral drug acts on the virus during the early stages of its life cycle, such as entry into the cell, reverse transcription and integration of the viral DNA into cellular DNA. This drugs such as didanosine (ddI), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT) polysulfated polysaccharides, sT4 (soluble CD4) - which block the attachment or adsorption of the virus to the host cells and other substances that block the binding of the virus to CD4 receptors and respectively with bearing CD4 T-lymphocytes. Together may be implemented methods based on the introduction of other inhibitors of reverse transcription of retroviruses, such as derivatives of AZT, substantially reducing or destroying the viral infection and the symptoms it caused. The inventive method effects on viruses lets you simultaneously use the means providing for the introduction of such antiviral drugs such as ganciclovir, dideoxycytidine, trinacria phosphonoformate, affinity, ribavirin, acyclovir, alpha interferon, trim otritsat, diribonucleoside, reverse transcriptase inhibitors - TIBO, nevirapine or delavirdine, inhibitors undressing virus, inhibitors of TRANS-activating proteins, such as tat or rev, or inhibitors of viral protease. The inventive method allows to simultaneously apply different inhibitors of HIV integrases immunodeficiency virus.

The claimed method effects on viruses detects a synergistic effect of inhibition of HIV replication, as it provides exposure to various sites of viral replication. Such exposure to viruses can significantly reduce the dosage of anti-retroviral drugs to achieve the desired effect. Achieved a reduction or complete elimination of side effects used antiviral drugs. The claimed method reduces the possibility of forming a resistance to the drugs, at the same time minimizing induced toxicity.

The claimed method of exposure to viruses can also be combined with methods of treatment of viruses through the introduction of various inhibitors of HIV protease, such as saquinavir, indinavir, nelfinavir, ritonavir and amprenavir to enhance therapeutic effect and prevention of various mutations of the virus. The proposed method effects on viruses has shown good results when simultaneously applied to the and inhibitors of the reverse transcriptase of retroviruses, causing a significant synergistic effect, thereby preventing, greatly reducing or completely eliminating viral infection.

The method of exposure to the virus can be combined with the simultaneous introduction of immunomodulators, such as bropirimine, anti-human antibodies to alpha-interferon, IL-2, GM-CSF, methionine-enkefalina, alpha-interferon, diethylthiocarbamate, tumor necrosis factor (TNF), naltrexone, recombinant erythropoietin (REPO); antibiotics, isocyanato pentamidine (pentacarinat) or vaccines for the prevention or combating infection or disease associated with HIV infection, such as AIDS and AIDS-associated complex (ARC).

In the case of joint use of the proposed method effects on viruses and other ways you can implement them in sequence or simultaneously.

Although the present invention focuses primarily on the impact on the human immunodeficiency virus, it can also be used to affect other viruses life cycle depends on similar integrases. These viruses include, but are not limited to other pathogenic retroviruses, such as simian immunodeficiency virus, HTLV-1 and HTLV-2.

The inventive method effects on viruses includes the use of any acceptable excipient, adjuvant, tra is of sporter. Pharmaceutically acceptable salts, pharmaceutically acceptable excipient, adjuvant, conveyor, which can be used in the claimed method may include (but are not limited to exchange ions, alumina, aluminum stearate, lecithin, serum proteins, buffer solutions such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixture of glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, Na2HPO4, K2HPO4, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl perridon, polyethylene glycol, carboxymethylcellulose sodium, wax, polyethylene-polypropylene block polymers, polyethylene glycol and lanolin.

When implementing the proposed method introduced drugs can be in the form of an aqueous solution and in the form of an oil suspension. This suspension may be created by conventional known manner, using any suitable detergents and other auxiliary substances (tween-80). A sterile preparation can be in the form of a solution, or in suspension; the solvent or liquid Foundation for suspension can be any non-toxic acceptable parenteral substance, such as, for example, 1.3-butanediol. Acceptable vehicles and solvents can be mannitol, water, ringer's solution istoricheskii solution of sodium chloride. To create oil solution you can use fixed vegetable oils that are traditionally used to create oil solution or suspension. For this purpose any suitable neutral non-volatile oils, including synthetic mono - and diglycerides, fatty acids. To create forms for injection is quite suitable oleic acid and glycerides, olive or castor oil, especially their polyoxyethylene derivatives, as they are natural pharmaceutically acceptable vegetable oils. These oil solutions or suspensions may also include as stabilizers and detergents long-chain alcohols, such as Ph. Helv., or others similar to it.

The inventive method of exposure to viruses can be the basis for developing specific treatments for animals and people, based on oral administration of capsules, tablets, aqueous solutions and suspensions. In the case of tablets as filler typically use lactose and corn starch. Definitely add technological additives such as magnesium stearate. If the drug for oral administration in the form of capsules, as fillers used lactose and corn starch. If the product has the form of a water suspension, the effective substance also add emulsifiers and one hundred is ilistory. At desire it is possible to add substances which impart a sweet taste, pleasant aroma, and color.

The claimed method of treatment for viruses in case of creation on its basis of the methods of implementation in the body of animals or humans implies the possibility of introducing substances in the form of suppositories for rectal use. As fillers can be included substances such as cocoa butter, beeswax and polyethylene glycols.

The inventive method the impact on the virus during its implementation in the body of animals or humans allows a local application, is particularly useful when impacts require parts of the body to which it can be applied topically. In the case of local application on the skin of the implementation of the method should be combined using a suitable ointment bases. Ointment base in the local application can include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, a mixture of polyoxyethylene and polyoxypropylene, emulsifying wax and water.

The inventive method the impact on the virus during its implementation in the body of animals or humans the possibility of creating such dosage forms for external use as nasal sprays or inhalers. Such forms can be created using existing technologies used for the production of such forms. In the operation of the liquid phase can be used saline solution, this stabilizer can serve as benzyl alcohol or any suitable substance, activator suction can be forcarbon, to improve the dissolution and dispersion can be used any known in the production of such pharmaceutical forms excipients.

The inventive method the impact on the viruses can also be used in laboratory research, which requires the binding of integrase, especially HIV integrase. In laboratory practice, the method can be used to block the integration of the molecules of the target DNA by the integrase or the creation of such polymeric compounds, as a binding substrate for use in affinity chromatography. These or other variants of the proposed method is quite affordable at the level of modern science.

1. The method of exposure to the virus through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d'] dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group of O, NH, N-Alkyl;

R1 is selected from the group of H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar,

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group6H5, Aryl;

R3 is selected from the group H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M or from outstay, or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, wherein optionally use a protease inhibitor.

2. The method according to claim 1, characterized in that the additional use of an inhibitor of integrases.

3. The method according to claim 2, characterized in that the additional use of nucleoside reverse transcriptase inhibitors.

4. The method of exposure to the virus through the use of substances on the basis of 2,8-dicicco-1H-pyrano[2,3-d : 6,5-d'] dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group of O, NH, N-Alkyl;

R1 is selected from the group of H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar,

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group6H5, Aryl;

R3 is selected from the group H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, wherein optionally use the inhibitor of integrases;

5. The method according to claim 4, characterized in that the additional use of nucleoside reverse transcriptase inhibitors.

6. The method of exposure to the virus through the use of washes the VA on the basis of 2,8-dicicco-1H-pyrano[2,3-d; 6,5-d'] dipyrimidine and their 10-Aza-analogues, including derivative of the specified group of General formula A1*M

where X is selected from the group of O, NH, N-Alkyl;

R1 is selected from the group of H, HE, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar,

N(Alkyl)2, SH, S-Alkyl, S-Ar, S-Hetaryl;

R2 is selected from the group6H5, Aryl;

R3 is selected from the group H, Cl, O-Alkyl, NH2, NH-Alkyl, NH-Ar, S-Hetaryl;

M is absent or selected from the group of cations Na, K, Li, ammonium, or any other pharmacologically acceptable cation; or a complex pharmacologically acceptable cation, wherein optionally use the reverse transcriptase inhibitor.

7. The method according to claim 6, characterized in that it further using a protease inhibitor.



 

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21 cl, 2 tbl, 11 dwg, 9 ex

FIELD: veterinary science.

SUBSTANCE: the suggested preparation for preventing and treating respiratory and gastrointestinal infectious diseases of bacterial and viral etiology in farm animals contains tetracycline (oxytetracycline) (8-10%-solution) at the quantity of about 10-15 vol.%, polyethylene glycol (15-20%-solution) - about 10-15 vol.%, polyvinyl pyrrolidone (15-20%-solution) - about 10-20 vol.%, ethylene diamine tetraacetate (0.01-0.02%-Versen's solution) - about 10-15 vol.%, and, also, trypsin (0.01-0.25%-solution) - the rest. As for the method for preventing and treating the above-mentioned diseases, it deals with a single intramuscular injection of the present preparation for farm animals (predominantly, for piglets) at the dosage of about 0.5-1.0 ml/animal. The suggested preparation is of immunostimulating properties and provides efficient therapy of respiratory and gastrointestinal diseases of bacterial and viral etiology.

EFFECT: higher efficiency of prophylaxis and therapy.

2 cl, 6 tbl

FIELD: veterinary science, infectious diseases.

SUBSTANCE: invention relates to the development of dry cultural virus vaccine against plague in small ruminant animals that possesses high immunogenicity, harmlessness, areactogenic properties for sheep and goats and low cost. Virus vaccine comprises lyophilized virus-containing material prepared on base of the strain "45G37/35-K" and protective medium in the volume ratio 1:1. As protective medium virus vaccine comprises medium of the following composition, wt.-%: enzymatic peptone, 9.8-10.2; lactose, 1.8-2.2, and distilled water, the balance. Vaccine is harmless, shows highly immunogenic properties and stable in storage.

EFFECT: improved and valuable properties of vaccine.

2 cl, 3 ex

FIELD: veterinary, in particular agents for prophylaxis and treatment of viral avian influenza.

SUBSTANCE: invention relates to application of birch bark extract as agent for prophylaxis and treatment of viral avian influenza.

EFFECT: antiviral agent of increased effectiveness.

7 tbl

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: medicine, in particular surgery, oncology.

SUBSTANCE: claimed method includes immunotherapy, namely on day before operation reaferonum-EC-lipint in dose of 1000-15000 U/kg is perorally administrated to patient. Then in postoperative period blood sampling, extracorporal incubation of leucocytes with imunofan, and intravenous drop administration are carried out. Further for 5 days after operation reaferonum-EC-lipint is perorally administrated to patient dose of 1000-15000 U/kg one time per day. Method of present invention may be used in treatment of patients after radiotherapy in postoperative period. Furthermore method makes it possible to decrease of therapy time by 1.6 times, to reduce total accident number by 2.3 times and decrease of mortality by 2 times.

EFFECT: improved method for rectal cancer treatment.

3 ex, 1 tbl

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel derivative of variolin B of the general formula (I) or their pharmaceutically acceptable salts possessing antitumor activity. In the general formula (I) radical R1 means aromatic group representing aromatic group representing phenyl optionally substituted with nitro-group, amino-group or alkyl-substituted amino-group, or aromatic group represents 5-6-membered heterocycle with two nitrogen atoms or sulfur atom as heteroatoms optionally substituted with (C1-C12)-alkyl, -OH, unsubstituted amino-group or amino-group substituted with (C1-C4)-acyl, phenyl-(C1-C4)-alkyl wherein phenyl group can be substituted with -OR1, or (C1-C12)-alkylthio-group, (C1-C12)-alkyl- or phenylsulfonyl, (C1-C12)-alkyl- or phenylsulfinyl or -OR1 wherein R1 is chosen from (C1-C12)-alkyl or phenyl; R2 represents hydrogen atom; R3 represents oxo-group when a dotted line is between nitrogen atom to which R2 is bound and carbon atom to which R3 is absent, or R2 is absent when R3 represents optionally protected amino-group wherein a substitute is chosen from (C1-C4)-acyl, phenylsulfonyl and (C1-C4)-alkylphenylsulfonyl when a dotted line forms a double bond between nitrogen atom to which R2 is bound and carbon atom to which R2 is bound; R4 represent hydrogen atom. Also, invention relates to a method for synthesis of compounds of the invention and to intermediate substances for their realization. Also, invention relates to a pharmaceutical composition based on variolin B derivatives.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 5 sch, 1 tbl, 50 ex

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