Means for inhibiting the reproduction oblachennyh viruses, method thereof, pharmaceutical composition and method of inhibiting viral infections

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to the creation of a means for inhibiting reproduction enveloped viruses. The invention lies in the fact that the proposed group of inventions, joint General inventive concept includes a method of obtaining compounds, the development of the pharmaceutical compositions and methods of treatment using them, means on the basis of fullerenelike anions to inhibit the activity of enveloped viruses in the treatment of diseases caused by these viruses. The choice of such quantitative ratios of components and reaction conditions provide polyaddition products. When carrying out the synthesis of a number of amino acids must exceed the number of fullerene more than 50 times. A method of inhibiting the reproduction of enveloped viruses in the treatment of diseases caused by HIV/AIDS, herpes infections, viral hepatitis C. the Invention produces a product under the proposed method, which has unlimited solubility in water, bioavailability, high efficiency effects on infected cells, low which can be used in the pharmaceutical industry. 4 C. and 1 C.p. f-crystals.

The invention relates to pharmaceutical industry and relates to the creation of a means for inhibiting reproduction enveloped viruses.

The present invention relates to compounds and their pharmaceutically acceptable salts, causing the inhibition of the reproduction enveloped viruses such as human immunodeficiency virus (HIV) type 1, herpes simple (Herpes simplex virus (HSV), type 1, hepatitis C virus (HCV) genotype 1B.

Currently, studies are underway on the development of therapies and methods of treatment of viral infections, particularly those caused by HSV, HCV, HIV/AIDS and associated with AIDS complex (KCC). AIDS patients, the immune system stops functioning, suffer from numerous opportunistic infections, such as Pheumocystis carinii and Candida albicans, as well as HSV, HCV, cytomegalovirus (CMV) or certain types of tumors (Kaposi's sarcoma), which are the direct cause of death. A method of treatment of AIDS is unknown, and current therapy in most cases is applied without sufficient evidence of effectiveness and has adverse side effects.

HIV is characterized by a high genetic and, therefore, antigenic variability. PCs on antigenic properties and nucleotide sequences. There is difference between the strains in different climatic zones. This complicates chemotherapy, immunotherapy and vaccine prevention of AIDS.

Problems in the treatment of AIV infections arise from the ability of these viruses to persist in a latent or dormant form. When primary infection subsides or retreats, the virus mainly remains in a latent form in sensory nerve ganglia, which nerveroot place of primary infection. Defines the period of latency is unknown, in addition, this period can be broken by overheating, cooling, solar radiation, hormonal and emotional disabilities or immunosuppressive means, leading mainly to repeated infections.

Most anti-virus tools used so far for the treatment of HSV infections were substances that interfere with the synthesis of viral DNA. These substances include idoxuridine, cytosine, arabinose, adrenalised and triptorelin. These substances interfere in similar functions in the host cell, which causes cellular toxicity and, consequently, the impossibility of systematic use in humans. Currently, the main drug for the toxicity. However, poor solubility and the emergence of drug-resistant viruses restricts the use of this tool.

Chemotherapy of AIDS associated currently with the creation and use of reverse transcriptase inhibitors and HIV protease inhibitors.

Inhibitors of HIV reverse transcriptase have or nucleoside nature: zidovudine (AZT, Retrovir), Epivir (FTC, lamivudine), videx (ddI, didanosine), civil (ddC, zalcitabine), stavudine, zerit (d4T, stavudine), abacavir (ABC, Ziagen), Combivir (zidovudine+Epivir), Trizivir (abacavir+Epivir+zidovudine), or a non-nucleoside: delavirdine (rescriptor), nevirapine (viramune), efavirenz (sustiva), or nucleotide: TDF, Viread. In Russia, registered domestic product phosphatid. These drugs are toxic to the microorganism, as they intervene in the genomic structure. Reverse transcriptase performs the synthesis of viral DNA during the whole period of the disease, therefore, inhibitors revertase HIV must be used for life.

HIV protease inhibitors currently several drugs: saquinavir (invirase), indinavir (Crixivan), ritonavir (norvir), nelfinavir (viracept), APV (agenerase), Kaletra (lopha glycoproteins leads to the inability of HIV virions to join the CD4+cell.

Currently, there is the term “third line therapy for characteristics of patients with HIV/AIDS, from which the pathogen was resistant to at least one drug from each class of drugs, or any treatment by using two different modes of treatment have been ineffective. Such highly active antiretroviral therapy (HAART) also indicate the terms "mega-HAART" or "Giga-HAART". The third line therapy includes the use of four simultaneous antiretroviral drugs with different mechanisms of blocking the reproduction of HIV nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors. While difficult to predict possible negative interactions of different medications, resulting in dramatically increased the likelihood of side effects and complications. In such cases, the continuous monitoring of the concentration of drugs in blood serum, which is an expensive procedure. The need to complement therapeutic course of drugs that inhibit the activity of causative agents of opportunistic infections, further complicating the healing process.

Known drugs allow controlee can cure or at least to provide the best protection against the deadly virus continues and is connected with the search for new compounds, able to inhibit the reproduction of the virus by means of known mechanisms, and develop new approaches to problem solving.

Expanding the range of drugs for patients with HIV/AIDS. Currently undergoing clinical trials are the following drugs: FTC, DAPD (nucleoside analogues), capravirine, TMC-120 (non-nucleoside). Attention is drawn to the new protease inhibitors: atazanavir (Sripada), tipranavir, mozenavir. Conducting research to create drugs completely new classes: inhibitors integrase (S-1360), and fusion inhibitors (pentatonic (T-20 or Fuzeon)), T-1249, PRO-542, and inhibitors of receptors chemokines (SCH-C and PRO-140). However, the test results are ambiguous. Thus, the drug SCH-C caused an increase of the QT interval in the ECG of healthy subjects when using the maximum dose, which is an indication of possible cardiac complications. Fusion inhibitors are polypeptides: T-20 consists of 36 residues of the natural amino acids, T-1249 - 39. The use of these drugs is limited to intravenous, as a result of taking in some patients treated with T-20, formed subcutaneous nodules, occasionally noted subcutaneous infection and what stavitelyami enveloped viruses. Infection of a host cell enveloped viruses initially based on the interaction of different receptors on the surface of the host cell with the glycoproteins of the virus. Then the viral and cellular membranes fuse, and the contents of the virion flows into the cytoplasm of the host cell. Interference in the formation of the viral envelope protein could prevent the primary interaction of virus and host cell and subsequent merger, and to inhibit the formation of virions. In patent No. 2196602 it is shown that under the action of salts filerenameoperations and butyric acids was the suppression of the replicative activity of the CMV due to inhibition of late structural protein gB.

Particularly noteworthy are the high-polymeric polyanionic natural compound - composition, dextrans, polysaccharides, etc. These little toxic compounds that can adsorb the virus particle and serve xenobiotics “trap” of HIV virions. These substances prevent the formation of syncytium, but the direct effects of these drugs on virus infectivity has not been established (European application 04065512 and 0467185). It is suggested that from sulphonated polyurea (patent No. 2160746) mol. weight of Directors contact with the virus and/or cell membrane and thereby interrupts the ability of the virus to replicate.

Known drugs, mainly suppress one of the specific functions of the virus. In the patent (WO 95/19949, C 07 C 49/223, 1995) was first shown the ability to impact one connection on two targets: the protease and reverse transcriptase of HIV. In patent No. 2196602 for the first time a method of inhibiting two viruses: HIV and CMV. Inhibition was carried out by the mechanism of blocking the active site on the molecule protease and reverse transcriptase, and late structural protein of CMV gB man. In both patents used compounds - derivatives of fullerene.

Recently, the biological activity of fullerenes attracts attention due to the possibility of using them in the fight against viruses. The main obstacle to the creation of therapeutic drugs is associated with the insolubility of fullerenes in water, which makes their direct introduction into an organism of the man.

Known methods for producing water-soluble fullerene due to the formation of adduct with polyvinylpyrrolidone (Kiselev O. I. et al. //Mol. Materials. 1998. V. 11. P. 121; discovered on L. B. et al. //Ibidem. 2000. V. 13. P. 41). Shown its effectiveness against influenza a - and b-type.

The products resulting from such modifications are unstable compounds with disabilities storage.

It is promising to obtain water-soluble fullerene derivatives by chemical joining of different radicals. Analogs of the present invention are compounds and methods for their preparation, are described in patents WO 95/19949, C 07 C 49/223, 1995, the Russian Federation No. 2196602, the Russian Federation No. 2124022.

Known compound containing a water-soluble fullerene derivative with the General formula C60-X=HOC(O)(CH2)2C(O)NH(CH2)2(publ. WO 95/19949, C 07 C 49/223, 1995). As deputies are any alkalemia or aryl-alkalemia substituents, in particular those which are substituted by nitrogen or oxygen containing from 1 to 20 carbon atoms. However, this compound has a low solubility in water of 1 mg/ml, and the method of its production complex.

In the patent of the Russian Federation No. is now and dipeptide derivatives of fullerene. As the amino acid derivative of fullerene used sodium salt filerenameoperations and fullerenelike acids.

The closest in technical essence and the achieved result is the compound N-(monohydro)-fullerenechromophor acid HC60NH(CH2)5COOH (RF patent No. 2124022).

To obtain the solution of fullerene in o-dichlorobenzene add an aqueous solution of potassium salt of aminocaproic acid and 18-crown-6. The reaction mass is stirred for 6-8 hours at 60C. Then the solvent is distilled off, the residue is treated with saturated solution of potassium chloride and the remainder of the fullerene derivative is washed with water. The yield of the desired product quantitatively. The obtained N-(monohydro)-fullerenechromophor acid is soluble in dimethylsulfoxide, dimethylformamide, pyridine.

The disadvantages of this synthesis are: reaction conditions of interaction of fullerene WITH60and potassium salts of aminocaproic acid in two-phase system lead to an increase of the process time, in addition, used as a solubilizer 18-crown-6 has a high cost.

The yield of the target product is not more than 5% of the mass of spent sin is and is what fraction of the product is in the form of water-insoluble compounds.

In all the previously described patents were obtained products monopolisation fullerene and amino acids and peptides. However, fullerenes have a large number of equivalent reaction centres by the number of double bonds, which enables the formation of addition polymerisation products.

The present invention is to obtain a product with the highest possible number of substituted groups, providing a high solubility.

To achieve the objectives of the proposed group of inventions combined to form a single inventive concept: a means of representing the connection fullerenelike anions, method thereof, pharmaceutical composition comprising the specified tool and method of inhibiting the reproduction of enveloped viruses.

As a result of interaction of fullerene with the salt of the amino acids in the medium of organic solvent in the presence of polyalkylated received fullerenelike anions of General formula 1.

C60Hn[NH(CH2)mC(O)O-]n,

where C60- fullerene nucleus

NH(CH2)mC(O)O-am the ASS="ptx2">n is an integer from 2 to 12, preferably from 4 to 6, most preferably 6.

The molecular weight associated with the value of n and m of the compounds obtained and equal to, respectively:

n equal to 6, and m is equal to 5, fullerenechromophor anion C60H6[NH(CH2)5C(O)O-]6equal to 1500 g/mol.

To obtain the solution of fullerene in o-dichlorobenzene (toluene or other organic solvent) contribute the amino acid in the form of salts (potassium or sodium), then add a solubilizer. The order of entering into reaction medium amino acids and a solubilizer is not important, you can make them as complex, pre-mixing. As a solubilizer use different polyalkyloxy: glycols mol. mass of from 150 to 400, and above 400 (e.g., PEG-1500), and polyethylene glycols having a free end groups, but with substituted (for example, polyethylene glycol dimethyl ether mol. weight 500).

To increase the rate of reaction add any strong reducing agent (alkali metals).

The ratio of the fullerene and amino acids increased more than 50 times. When the ratio is less than 50 times out the connection with less rastvorimosti in the desired pharmaceutically acceptable salt, especially sodium or potassium, can be performed by treating the acid with a suitable base or by adding a salt of the weak volatile acid. In particular, it is not soluble in water fullerenelike acid into the preferred pharmaceutically acceptable salts such as sodium salt, which is soluble in water. The salt of the weak volatile acid by treatment of a solution of a salt of an alkali metal and a weak volatile acid. When the concentration of the solution by evaporation or lyophilization of a weak acid is removed and fullerenelike acid are in the form of their alkali metal salts. Examples of salts of alkali metals and weak volatile acids are sodium and potassium carbonate or bicarbonate.

The yield of the target product is more than 200% in a single fullerene. Target product according to this invention is characterized by the constancy of the composition, the content of the target product of the basic substance is at least of 87.8%.

The compounds of formula 1 - dark-brown crystalline substance, unlimited water-soluble salt form and practically insoluble in water and in acid form. In acid form, they have limited restartresource.

The unique structure of the obtained compounds is the presence in the molecule of several carboxylic groups, which, depending on the pH of the medium, or are in salt or acid form, showing the buffer properties. the pH of education full salt - 7,9; pH education full acid to 4.0, the acid due to the low solubility in water, it forms micelles, colloid and precipitates.

the pH of the transition of the claimed compounds in the dissolved state (education of the true solution) - 5,0-6,0. The formation of 1-2 substituted salt.

At pH 5,0-7,9 due to hydrolysis of salts with various degrees of substitution are in dynamic equilibrium.

TLC was performed on silica gel 60F254firm Merck. The best results in separation of the components were obtained with systems eluents: tO-benzene-N2O 4:1:1 (I) and 4:1:1,5 (II).

(I) the system was found 3 spots with Rfof 0.68, 0.37 to and at the start, in the system (II) - 3 spots with Rf0,82, of 0.71 and 0.47 - last belongs to the polar component. Test with ninhydrin showed absence in the composition of the product components in the product with the primary amino group.

The data obtained indicate that shared TLC substances pendletones. This can occur when the incomplete hydrolysis of salts fullerenelike acids. The width of the chromatographic spots (areas) of each component indicate chemical (structural) homogeneity of the substance.

Were studied1H and13C-NMR spectra of solutions of compounds of formula 1 in deuteromony solvents with different Salvaterra ability. Spectra are taken at 20 ° C on the unit WM-200 operating frequency 200,13 MHz1N and 50,32 MHz13C.

13C-NMR (D2O): 25,2 (CH2CH2C(O)O-), 25.4MM (CH2(CH2)2C(O)O-), 26,8 (CH2C(O)O-), 69,5 (CH2NH), 130-160 (C60), 183,7 (C(O)O-).

1H-NMR (CD3OD): 1,16 d (1H, J=6.0 Hz, -NH-), 1,26; 1,45 and 1,65 (3M, 1W, 2W, 3W, respectively, -(CH2)3-), 2,18; of 2.23 (2s, 0,2 H, -NH...), 2.34 t (2N, J=7,2 Hz, -CH2C(O)O-), 2,94 of user.T. (0.4 H, J=6.0 Hz, J=1.8 Hz, -NCH2-), 3.6 m (1H, J=1.8 Hz, J=6.0 Hz, C60N).

1H-NMR (, DMSO-d6): 1,02 d (0,4 H, J=6.0 Hz, -NH-), 1,22; 1.32; and of 1.52 (3M, 6N, -(CH2)3-), 1,90; 2,08 (2C, 0.3 nm each, -NH...), 2.20 (2H, J=7.2 Hz, -CH2C(O)O-), 2,68 square (2H, -NCH2-), 7,46 m; 8,17 s (0.5 H each, C60N), 12,08 ush.(1H, -C(O)OH)).

1H-NMR (D2O): 1,25 m 1,49 m (2H, 4H, respectively, J=7.8 Hz, J=6,9 Hz, -(CH2)3-), of 1.88 l (0,1 N, J=1,6 Hz, -NH...), 1,89 l (0,1 N, J=5.5 Hz, -NH...), 2,05 d (0,="ptx2">The following properties of the proposed compounds due to the presence of fullerene nucleus in the molecule. The abundance of isolated multiple bonds can be considered fullerenealuminum system. For him, the most typical connection on the double bond. It easily attaches nucleophiles and free radicals, which makes possible the use of such substances as antioxidants.

The technical result of the invention is that a new class of compounds fullerenelike anions of General formula 1 by nucleophilic attachment to the fullerene amino acids in several double bonds with two or more amino acids.

The compounds possess new properties:

- unlimited solubility in water,

- high bioavailability,

- high efficiency effects on infected cells,

- low toxicity.

It is shown that the antioxidant properties of the claimed compounds slightly depends on their concentration. When the concentration is increased 40 - fold from 5 to 200 μg/ml of the antioxidant activity increased with 22,78 to 32,21%. Thus, compounds even at low concentrations are the maximum is G, hepatitis C.

The compounds of formula 1 in a concentration of 1 µg/ml provided the full protection of human lymphoblastoid cells MT-4 from viral cytopathic effect (JRC) of HIV-1, taken in a dose of 100 JRS50up to 7 days of observation after infection of cell cultures. At a concentration of 10 μg/ml is the disappearance of the virus (antigen P24 in the culture medium. At these concentrations of the cytotoxic effect of the drug on the cells was not found.

The compounds of formula 1 at a concentration of 10 μg/ml provided the full protection of transplantable cells cultures of monkey kidney (VERO) and culture of fibroblasts of the human embryo (M-21) from cytodestructive action of herpes simplex virus (HSV-1), taken in a dose of 100 JRS50after 48 hours after infection of cell cultures. During the same time in the control infected cell cultures, not affected by the proposed compounds was 100% cell death.

The compounds of formula 1 at a concentration of 10 μg/ml, made at the time of infection, provided complete protection transplantable cell culture adenocarcinoma adrenal human SW-13 from cytodestructive steps of hepatitis C virus (genotype 1B), taken in a dose of 100 Zdeno complete absence of residual infectivity of the virus on day 3 after infection of cells with the compounds at a concentration of 100 µg/ml at a concentration of 10 μg/ml infectious titer of progeny virus (EID50) fell from 4.8 lg in control of up to 1.5 lg.

Has the effect of inhibition of proliferation of human tumor cells under the influence of these compounds.

Installed inhibitory concentration (IC50) of the drug on tumor cells of human MT-4 and ner 2, 100 μg/ml Shows that the concentration of the drug has an effect on biochemical processes in the cell culture, causing a marked inhibition of cell proliferation and inhibition of protein synthesis.

The presence of the drug in the culture medium at a concentration of 100 μg/ml alters the metabolism of the cells of the ner 2, resulting in inhibition of protein synthesis. Already after 1 day of exposure observed the disappearance of two proteins, mol. mass of 90 kDa and 50 kDa. After 3 days of observation in the control cultures marked the emergence of a new protein with a mol weight of about 100 kDa, the presence persisted for 6 days. In culture under the influence of the drug, the synthesis of this protein was absent.

It was shown that the compounds of formula 1 are associated with albumin (maximum concentration of 240 μg/ml) and in this form are easily transported to various organs is ereference fabric, showed that the drug penetrates all bodies. Most intensively in the liver, spleen, kidneys and lungs. Proposed connection unlike other poorly water-soluble derivative of fullerene little penetrates the gland and the brain and does not cause neurotoxicity.

These compounds have a sufficiently low molecular weight to pass through the excretory cell membrane. Having unlimited ability to dissolve in water, connection quickly eliminated from the body. The study of the excretion of the drug showed that for three days with urine output 52-54% of the injected dose; the rate of excretion of intravenous and rectal routes of administration are the same.

The effect of the drug on the enzymatic system of biotransformation of xenobiotics in the liver of rats was assessed by the change in the activity of enzymes: the ferment aldehyddehydrogenase as a part, NADPH cytochrome C reductase, N-demethylase, Ineligibility obtained from nadditionally fraction of the liver, and the content of P450 and B5 in a rectal animal drug in two doses of 0.3 and 3.0 mg/kg Not established dose-dependent effect on the activity of the studied enzymes and the content of P450 and B5 in the liver of rats after a single injection of the drug in techenie 1 day after drug administration compared with the control, placebo-treated and non-treated animals.

The compounds of formula 1 have no immunotoxic effects. When used in doses up to 15 mg/kg of the claimed compounds do not have a mutagenic effect on warm-blooded animals. LD50for nonlinear mice was intravenously for females is 83 mg/kg for males and 114 mg/kg intraperitoneal - 688 mg/kg for females and males, intragastric - >2700 mg/kg by rectal - >450 mg/kg

Pharmaceutical forms of drugs of the compounds of formula 1 can be made in a form for oral or parenteral appointment for treatment or prophylaxis of viral infections and conditions under which shows the use of antioxidants and antidotes.

Compounds mixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, suppositories, ointments, injectable solutions, etc., Compositions comprising the compounds of formula 1 contain about 0.1-90% by weight of active compound, most preferably 0.5 to 10%.

Compounds of the present invention can be used orally, parenterally (including subcutaneous injections, intravenous, intramuscular, vnutrigodovye injection or infusion is ielemia media stimulants and auxiliary agents.

Such pharmaceutical compositions can be produced in the form of orally applied suspensions or tablets; nasal sprays; sterile injectables, for example in the form of a sterile aqueous or oily suspension for injection, or candles.

For oral administration in the form of a suspension compositions prepared according to methods widely known in the field of preparation of pharmaceutical formulation and may contain microcrystalline cellulose for maintenance of weight, alginic acid or sodium alginate as a suspending agent, methylcellulose as an amplifier viscosity and sweetening agents and/or fragrances, known in this area. In the form of tablets immediate allocation of such compositions may contain microcrystalline cellulose, calcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrators, diluents and lubricants known in this field.

When applied as nasal aerosols or by inhalation, such compositions are prepared by methods well known in the field of pharmaceutical formulations, and they can be produced in VI is now, promoters adsorption to enhance bioremediate, and/or other solubilizing or dispersing agents known in this field.

Solutions or suspensions for injection can be formulated according to known methods, using non-toxic, parenterally applicable diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution or isotonic sodium chloride solution or suitable dispersing or wetting and suspendida agents, such as sterile, soft, sustainable oils, including synthetic mono - or diglycerides or fatty acids, including oleic acid.

At rectal administration in the form of candles such compositions can be prepared by mixing the drug with such a non-irritating excipients as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but sigalda and/or dissolve in the rectal cavity emitting medicines.

The proposed connection can be used to treat infections caused by HIV, HSV, hepatitis C.

The treatment of infectious diseases by influencing the pharmaceutically prkci) and affects different stages of viral replication. It is shown that the treatment is accompanied by a reduction of stress effect on the introduction of the drug, increased antioxidant protection of the organism against infection, excretion of toxins. Intoxication characteristic for the flow of a number of viral infections and determines the severity of the disease.

Calculated data showed that the levels of dosages of about 0.1-250 or 2500 mg/day may be used for treatment or prevention of the above conditions, and oral dosage is 2-5 times higher. However, it should be borne in mind that a particular level of dosage and frequency of medication for each individual patient will depend on a number of factors, including the activity of the specific compound, the metabolic stability and length of action, allocation rate, the patient's age, body weight, General health, sex, drug combination.

The possible combinations of the compounds of formula 1 with other antiviral agents, immunomodulators, anti-infective agents or vaccines in various combinations with any pharmaceutical composition intended for the treatment.

1. Means for inhibiting the reproduction enveloped viruses, characterized by t is="ptx2">WITH60Hn[NH(CH2)mC(O)O-]n,

where C60- fullerene core;

NH(CH2)mC(O)O-- aminocarbonyl anion;

m is an integer from 1 to 5, preferably 3 or 5, most preferably 5;

n is an integer from 2 to 12, preferably from 4 to 6, most preferably 6.

2. The method of obtaining funds for inhibition of reproduction enveloped viruses, characterized by the fact that the solution of fullerene in o-dichlorobenzene make the amino acid in the form of potassium or sodium salt, then add a solubilizer selected from the group of polyalkyleneglycol: glycols mol. mass of from 150 to 400 and above, and dimethyl ethers of polyethylene glycols, the ratio of the fullerene and acid increased more than 50 times, and the synthesis is carried out at a temperature of 60-80C.

3. Pharmaceutical composition for inhibiting reproduction enveloped viruses, characterized in that it contains means under item 1 in an effective amount and a pharmaceutically acceptable fillers.

4. Pharmaceutical composition for inhibiting reproduction enveloped viruses under item 3, characterized in that it is made in pill form, to the tion enveloped viruses, characterized by the fact that the use of the pharmaceutical composition according to paragraphs.3 and 4 for the suppression of viruses in the treatment of HIV and AIDS, herpes infections, viral hepatitis C.

 

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< / BR>
where (a)-g) R=H; h) R=OMe; a) X=7-hydroxy-2-methyl-1,4 - naphthoquinone-5-yl; b) X= 7-hydroxy-2-methyl-6-etoxycarbonyl-1,4-naphthoquinone-5-yl; C) X=3-hydroxy-9,10-anthraquinone-1-yl; g) X= 8-hydroxy-3-trimethyl-siloxy-2-etoxycarbonyl-and 1,1, 4,4-Tetra-hydro-9,10-anthraquinone-1-yl; d) X=8-hydroxy-3-oxo-1,2,3,4-tetrahydro-9,10-anthraquinone-1-yl; (e) X=3-hydroxy-2-taxicab-Nile-4,4-dihydro-9,10-anthraquinone-1-yl; g) X= 3,8-dihydroxy-2-etoxycarbonyl-4,4-dihydro-9,10-anthraquinone-1-yl; C) X= 3-hydroxy-2-etoxycarbonyl-4,4-dihydro-9,10-anthraquinone-1-yl, possessing anti-HIV activity
The invention relates to biotechnology, in particular to a technology for primary protease inhibitor type Konitza of the bodies of cattle, and can be used in biochemistry, cell and molecular biology, as well as in the medical industry as a substance to obtain drugs

The invention relates to medicine, surgery, anesthesiology and critical care medicine and can be used for postoperative pain management of patients with pancreatic necrosis after omentoplasty with multiple programmed rehabilitation by relaparotomy
The invention relates to medicine, namely to the development of new dosage forms for oral administration
The invention relates to pharmaceutical compositions, in particular to pharmaceutical compositions comprising an inhibitor illegitimates (ARI) and angiotensin-converting enzyme (ACE), which is applicable for the prevention and treatment of complications of diabetes

The invention relates to medicine, in particular to Hematology and proteins used as anticoagulants, in particular to modified forms of Factor VII, inhibiting the coagulation of blood and tissue factor

-interleukin" target="_blank">

The invention relates to compounds of General formulaand-

< / BR>
< / BR>
where n = 0, 1, or 2, m and m' = 1 or 2; R11is

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or

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R2'= R2= H, R3is-CH2Ar or 5-15 membered non-aromatic monocyclic group which may contain from 0 to 2 endocycles nitrogen atoms; R4is a branched (C1-5) alkyl group; R5choose from a group comprising-C(O)R7, -C(O)OR9, -C(O)C(O)R7; R7selected from the group: phenyl, naphthyl, isoquinoline, and phenyl may be substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or - N(H)C(O)(C1-6)-alkyl, R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl; R12and R13independently selected from the group comprising-R7-C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group, f is -interleukin (ICE), method of inhibiting ICE activity, methods of treating or preventing IL-mediated diseases

The invention relates to medicine, namely to methods of treatment relating to the improvement of regional myocardial blood flow during postischemic reperfusion, as well as prevent or minimize damage to the tissue associated with postischemic perfusion

The invention relates to medicine, namely to ophthalmology, and for the prevention of recurrence of erosion and ulceration of the cornea on the eye ended with the healing of burn wounds with bilateral burns after keratoplasty about ulceration of the cornea of one eye
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