Preventive and therapeutic method for treating infectious and other diseases by applying immunoeffective compounds

FIELD: medicine.

SUBSTANCE: method involves making patient contact with effective quantity of one or several compounds. Pharmaceutical composition comprises one or several compounds applicable in absence of exogenous antigen for treating or alleviating the cases of infectious, autoimmune diseases and allergy.

EFFECT: enhanced effectiveness of treatment or prophylaxis.

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The system of innate immunity coordinates the inflammatory response to pathogens through the system, which distinguishes "self" from "foreign" through receptors that recognize classes of molecules, synthesized exclusively by microorganisms. These classes are sometimes referred to as associated with pathogen molecular profiles (the AGENCY), and include, for example, lipopolysaccharide (LPS), composition, lipoteichoic acid and bacterial lipoproteins (BLP).

LPS is a common component of the outer cell wall of gram-negative bacteria that is recognized by the system of innate immunity. Although the chemical structure of LPS is already known, but the molecular mechanism of LPS recognition by proteins and/or cells serum is only beginning to be elucidated. A number of recent publications family of receptors called Toll receptor type (TLR)was associated with a strong innate immune response to LPS and other microbial components. TLR is a membrane protein with a single transmembrane domain. The cytoplasmic domains consist of approximately 200 amino acids and exhibit similarities with the cytoplasmic domain of the receptor of IL-1. The extracellular domains are relatively large (550-980 amino acids) and can contain multiple binding sites of ligands.

The importance of TLR in the immune response to LPS has been demonstrated specifically for men is our least for the two receptor type Toll-Tlr2 and lr4. Thus, experiments on transfection of human embryonic kidney cells showed that Tlr2 person sufficient to impart reactivity to LPS (Yang et al., Nature 395: 284-288 (1998); Kirschning et al., J. Exp, Med. 11: 2019-97 (1998)). Apparently, for a strong response to LPS requires LPS-binding protein (LBP) and CD 14, which binds LPS with high affinity. Direct binding of LPS with Tlr2 was observed with relatively low affinity, suggesting that the binding of LPS with Tlr2 and/or activation in vivo may contribute auxiliary proteins.

Important lr4 in the immune response to LPS has been demonstrated in connection with the positional cloning of mutant lines of mice lps. It was identified two mutant allele of lps: predominantly allele in mice lines SN/ / HeJ and second, the recessive allele from C57BL/10ScN and C57BL/10ScCr. Mouse homozygous for mutant alleles of the gene lps susceptible to infection by gram-negative bacteria, but are resistant to LPS caused septic shock. Locus Ips from these mice cloned, and it has been shown that these mutations are associated with changes in gene lr4 in both cases (Portorak et al., Science 383: 2085-2088 (1998); Qureshi et al., J. Exp. Med. 4: 615-625 (1999)). In these works concluded that lr4 needed to respond to LPS.

Biologically active endotoxic part of the structure of LPS is lipid A - phosphorylated, multiple acylated fatty and acid disaccharide of glucosamine, which serves to secure the entire structure in the outer membrane of gram-negative bacteria. Previously, we reported that the toxic effects of lipid a can be reduced by selective chemical modification of lipid a with the formation of compounds of monophosphorylated a (MPL adjuvant, Corixa Corporation, Seattle, WA). Methods of obtaining and applying immunostimulant MPL and close to the structure of the compounds as adjuvants for vaccines and other applications already described (for example, see US Patent No. 4436727; 4877611; 4866034 and 4912094; 4987237; Johnson et al., J. Med. Chem. 42: 4640-4649 (1999); Ulrich and Myers, in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds., Plenum: New York, 495-524, 1995). In particular, these and other works have shown that adjuvant MPL and related compounds have significant adjuvant activity humoral and/or cellular immunity to antigens in their application as part of a vaccine along with protein and carbohydrate antigens.

Molecule synthetic mono - and disaccharides, which are similar in structure with the immunostimulant MPL and called aminoalkylindole (AGF) is described, for example, in US Patent No. 6113918; US Patent No. 6303347 and WO 98/50399, published on 12 October 1998, These compounds substantially retain the properties of the adjuvant with the inclusion in the composition of the vaccine compositions and have friends or a better toxicity profile compared with monophosphoryl is the home of A. Describes the use of these compounds in combination with antigens in the composition of the vaccines (US Patent No. 6113918) and in the absence of antigen as monotherapy (WO 01/90129, published on November 29, 2001).

Cyclic aminoalkylindoles (cyclic AGF) is described in PCT Patent Application no PCT/US01/24284. These cyclic AGF are effective immunoaffinity molecules that enhance humoral and cellular responses to antigens of the vaccine. Applied to the present invention, the term "cyclic AGF" means such azacyclonol or (azacyclonol)Alkylglucoside, in which 2-deoxy-2-amino-β-D-glucopyranose (glucosamine) is connected glycosidic bond with azacycloheptane or (azacyclonol)alkyl group (the aglycone).

The present invention provides a monotherapy, which was compiled and entered in the absence of exogenous antigens for prophylactic and/or therapeutic treatment of diseases and conditions of animals and plants, such as infectious diseases, autoimmune diseases and allergies. Monotherapy of the present invention includes one or more of the AGF. These and other aspects of the invention will become clear upon reference to the following detailed description and the accompanying drawings.

Disclosure of inventions

In one aspect the present invention provides methods of treatment, clothe treatment or substantial prevention of diseases or conditions in animals by injecting an effective amount of the compounds of formula I:

and its pharmaceutically acceptable salts, where X is-O - or-NH-, Y represents-O - or-S-; a R1, R2and R3independently from each other represent a (C2-C20)acyl groups, including saturated, unsaturated and branched acyl group; R4represents-H or-RO3R7R8where R7and R8independently from each other presents N or (C1-C4)aliphatic group; R5is-H, -CH3or RHO3R9R10where R9and R10independently from each other selected from - H or (C1-C4)aliphatic groups; R6independently selected from among H, HE, (C1-C4)oxyaliphatic groups, RHO3R11R12, ORO3R11R12, -SO3R11, -OSO3R11, -NR11R12, -SR11, -CN, -NO2, -CHO, -CO2R11and-CONR11R12where R11and R12independently from each other selected from H or (C1-C4)aliphatic groups; provided that one of the groups R4and R5contains phosphorus and that, when R4presents RHO3R7R8, R5is not RHO3R9R10if this *1-3and ** represents a chiral centers; and the indices n, m, p and q independently from each other mean a whole h the SLA from 0 to 6, provided that the sum of p and m is from 0 to 6.

In some embodiments of the compounds of the present invention contain-O -, when X and Y, R4means RHO3R7R8, R5and R6represented by N, and the indices n, m, p and q are integers from 0 to 3. In a more preferred embodiment R7and R8presents - N. In one of the incarnations n=1, m=2, and p and q=0. In other embodiments, R1, R2and R3presents (C6-C14)-, (C6-C12)or (C6-C8)acyl groups, and in the preferred embodiment (C6-C12)acyl groups. In the next incarnation *1-3located in the R-configuration, Y is in the Equatorial position, and ** are in the S-configuration.

To illustrative embodiments include N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-tetradecyltrimethylammonium]-3-O-[(R)-3-tetradecanoylphorbol]-β-D-glucopyranoside and its pharmaceutically acceptable salts (formula II)

[N-(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron]-β-D-glucopyranoside and its pharmaceutically acceptable salt (formula III) and

[N-(R)-3-decanolactone canol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β -D-glucopyranoside and its pharmaceutically acceptable salts (formula IV).

In certain illustrative aspects of the invention, the above methods are used for the treatment, relief or substantial prevention of infectious diseases, autoimmune diseases and allergies.

In other aspects the present invention provides pharmaceutical compositions comprising one or more of the above compounds in a suitable filler, made and/or entered in the absence of exogenous antigens.

The implementation of the invention

The preferred prophylactic and therapeutic use

The present invention in a broad sense relates to prophylactic and therapeutic methods of treatment of certain diseases and other medical conditions by introducing one or more of the described compounds or pharmaceutical compositions comprising one or more of such compounds. Although the use of some cyclic compounds AGF as adjuvants in combination with exogenous input antigens in the vaccine composition has already been described, as is their use in some other applications, however, the present invention presents new therapeutic ways in which these compounds are preferably in estudia in monotherapeutic applications that is, without the introduction of exogenous antigen.

In one aspect the present invention provides methods of treating, alleviating and/or substantial prevention of infectious diseases in eukaryotes, especially in animals, preferably humans. Given the importance of TLR mediated signaling pathways in the innate immune response to microbial infection, the ability to electoral incentives such paths with minimal toxicity is a powerful approach to possible ways of preventive and/or therapeutic treatment against a range of pathogens.

The described methods are applicable against almost any type of pathogens, including bacteria, viruses, parasites and fungi. For example, the invention is applicable to preventive and/or therapeutic treatment of bacterial infections caused by various species of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Staphylococcus, Streptococcus, Chlamydia, Mycoplasma, Bacillus, and many others. Illustrative viral diseases that can be treated in accordance with the invention include diseases caused by, for example, influenza virus, adenovirus, parainfluenza virus, rhinovirus, respiratory syncytial virus (RSV), herpes viruses, cytomegaloviruses, hepatitis viruses, such as hepatitis b and C, the other Examples of fungi include, for example, Aspergillus, Candida albicans, Cryptococcus neoformans, Coccidioides immitus and other

In one illustrative embodiment of the invention provides methods of treatment, in particular immunocompromising patients who have acquired the infection or at risk of developing infections, such as nosocomial bacterial or viral infection. About 2 million of the 40 million people coming to the hospital every year, acquire a nosocomial infection during hospital stay and about 1% of them, that is about 400,000 patients acquire nosocomial pneumonia, with more than 7000 of them die. It makes nosocomial pneumonia is the leading cause of death among hospital-acquired infections. Thus, this embodiment fills a significant need for effective preventive approach to the treatment of nosocomial infections.

In one related embodiment the present invention provides methods of preventive treatment immunocompromised patients, e.g. HIV-positive patients who have already acquired pneumonia or at risk of developing pneumonia or due to opportunistic infections or due to reactivation of suppressed or latent infection. In 1992, only USA registered about 20,000 cases, and then the Pneumocystis carinii in patients with AIDS. In addition, 60-70% of AIDS patients infected with P. carinii at one time or another during illness. Thus, the present invention in this embodiment provides an effective means of prevention for this at risk population.

In another related embodiment, the methods of the present invention are used for treatment of other patient populations or immunocompromising or/and at risk of acquiring infectious diseases, including, for example, patients with cystic fibrosis, chronic obstruction of the respiratory tract and other immunocompromising patients and/or placed in the hospital.

The following aspect of the invention described compounds are used in methods of treatment, relief or substantial prevention of allergic diseases and conditions, such as sinusitis, chronic rhinosinusitis, asthma, diffuse neurodermitis and psoriasis. This approach is based, at least in part on the ability of these compounds to activate the production of target cells those cytokines that can compete with stereotypicality cytokine responses, allergic-type, characterized by production of IL-4 or hypersensitivity to the effects of IL-4. Some of the compounds described in this invention, leads to the expression of IFN-; and IL-12 antigen-presenting and processormask cells, and other cells, which leads to down-regulation (downregulation) of cytokines associated with allergic reactions, such as IL-4, 5, 6, 10 and 13.

The following aspect of the invention compounds are used in methods of treatment of autoimmune diseases and conditions. Connection to this embodiment, as a rule, choose from among those that can be antagoniste, to inhibit or otherwise negatively modulate one or more of the Toll receptor type, in particular lr2 and/or lr4, so that the autoimmune reaction associated with this condition is reduced or prevented. To illustrate how this embodiment can be used in the treatment of diseases such as chronic inflammation of the intestine, rheumatoid arthritis, chronic arthritis, multiple sclerosis and psoriasis.

Not wanting to limit ourselves to any one theory, it can be assumed that the effectiveness of the above-described prophylactic and therapeutic applications based at least in part on the participation of these compounds in the modulation of the activity of the receptor type Toll. In particular, it is assumed that lr2, lr4 and other Toll receptor type are specific activation, competitive inhibition or any other influence non-toxic producing the data and mimetics LPS, disclosed in the present invention. Accordingly, the methods of the invention provide a powerful and selective approach to the simulation of mechanisms of innate immunity in animals without causing toxic effects often associated with natural bacterial components, which usually stimulate these mechanisms.

Illustrative compounds of cyclic AGF

For illustrative compounds used in the above prophylactic and therapeutic applications include compounds of formula I:

and their pharmaceutically acceptable salts, where X is-O - or-NH-, Y represents-O - or-S-; a R1, R2and R3independently from each other represent a (C2-C20)acyl groups, including saturated, unsaturated and branched acyl group; R4is-H or-RO3R7R8where R7and R8independently from each other presents N or (C1-C4)aliphatic group; R5is-H, -CH3or RHO3R9R10where R9and R10independently from each other selected from-H and (C1-C4)aliphatic groups; R6independently selected from among H, HE, (C1-C4)oxyaliphatic groups, -PO3R11R12, ORO3R11R12, -SO3R11, -OSO3R , -NR11R12, -SR11, -CN, -NO2, -CHO, -CO2R11and-CONR11R12where R11and R12independently from each other selected from H or (C1-C4)aliphatic groups; provided that one of the groups R4and R5contains phosphorus and that, when R4presents RHO3R7R8, R5is not RHO3R9R10if this *1-3and ** represents a chiral centers; and the indices n, m, p and q independently of one another denote integers from 0 to 6 provided that the sum of p and m is from 0 to 6.

Although hexopyranoside in the formula I presented in glucoraphanin, other glycosides also included in the scope of the invention. For example, glycopyranoside, including other hexopyranoside (ALLO-, ultra-, manno-, holo-, IDO-, galacto-, talo), are included in the scope of the invention.

In the above General formula 3'-stereogenic centers, which is the accession of the normal fatty acid residues and which are indicated as *1, *2and *3are R - or S-configuration, preferably in the R-configuration. The absolute stereochemistry of the carbon atoms in the cyclic aglycone to which are attached R6and glucosamine, directly or indirectly (marked as **), may be represented by R - or S-configuration. In the above General formula, Y may ahadiths in the Equatorial or axial position, preferably Equatorial. All stereoisomers, enantiomers, diastereoisomers and their mixtures are considered as included in the scope of the present invention.

In illustrative embodiments of the present invention X and Y denote-O-, R4is phosphono, R5and R6mean N, and the indices n, m, p and q are integers from 0 to 3, more preferably from 0 to 2. In the example of the preferred embodiment n=1, m=2, and p and q equal to 0. In this embodiment of the compounds of this invention are represented by 2-pyrrolidinyl-β-D-glucosamine-4-phosphates of General formula V:

In another illustrative embodiment of the present invention R1, R2and R3in the formula III are tetradecanoyl residues and 3'-stereogenic centers (*1-3), according to which they attach, are in the R-configuration, Y is in the Equatorial position, and the absolute stereochemistry of the stereogenic center pyrrolidine (**) presents the S-configuration.

Other illustrative of the embodiments include N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-tetradecyltrimethylammonium]-3-O-[(R)-3-tetradecanoylphorbol]-β-D-glucopyranoside and its pharmaceutically acceptable salts (formula II)

[N(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron]-β -D-glucopyranoside and its pharmaceutically acceptable salt (formula III) and

[N-(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glucopyranoside and its pharmaceutically acceptable salts (formula IV).

Compounds of the present invention can be obtained by the methods described in Johnson et al., Bioorg. Med. Chem. Lett. 9: 2273, 1999, and PCT/WO 98/50399 and are there links. In General, the methods of synthesis described in the above sources, applicable in a broad sense to produce compounds with different acyl groups and substituents. For example, some compounds applicable in the present invention, are described in U.S. Provisional Application No. 60/223056 and International Application PCT/USO 1/24284. In General, to obtain these compounds in a broad sense, applicable methods of synthesis described in the above sources and in the present invention and other methods of synthesis are known in this area. For example, upon receipt of compounds with different acyl groups and overrides the experts in this field should understand that described in the above references converging methods can be modified by using other alleluya reagents or can come from commercial the key available materials with the attached corresponding acyl groups.

The term "acyl" refers to those groups which are derived from organic acids during removal of the hydroxyl portion. Accordingly, the acyl may mean, for example, acetyl, propionyl, butyryl, decanoyl and pivaloyl.

"(C2-C20)acyl" means an acyl group containing from 2 to 20 carbon atoms. Similarly, (C6-C14)-, (C6-C12)-, (C9-C12)- and (C6-C8)acyl means a group containing from 6 to 14, from 6 to 12, from 9 to 12 and from 6 to 8 carbon atoms, respectively. The term "acyl" also covers acyl group containing typical substituents, such as hydroxy-, keto - and other

The term "aliphatic" by itself or as part of another substituent means, unless otherwise specified, unbranched or branched hydrocarbon chain or cyclic hydrocarbon group, including groups containing both cyclic and chain, which may be fully saturated or mono - or polyunsaturated, containing a specified number of carbon atoms (for example, C1-C4means from 1 to 4 carbon atoms). Examples of saturated hydrocarbon radicals include such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, cyclopropylmethyl, methylene, ethylene and n-butylene. Unsaturated alkyl gr is PAP this is a group that contains one or more double bonds and/or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 1-PROPYNYL and 2-butadienyl.

The term "accelerations" refers to those groups that contain an aliphatic group, connected with the rest of the molecule through an oxygen atom.

Each of the above terms (e.g., "aliphatic", "acyl"may include substituted and unsubstituted forms of the indicated groups. Preferred substituents for each type of groups is presented below.

The substituents in the aliphatic groups can serve a number of groups selected from-OR', =O, -S, -NR',=N-OR', -NR'r R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)R NR'r", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'r C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'r R',- CN and NO2the number which varies from 0 to (2m'+1), where m' = this is the total number of carbon atoms in such radical. R', R" and R"' independently of one another denote hydrogen and unsubstituted (C1-C4)aliphatic group. When R' and R" are attached to the same nitrogen atom, they can be connected to the nitrogen atom with the formation of 5-, 6 - or 7-membered ring. For example, -NR'r R" may include 1-pyrrolidinyl and 4 morpholinyl. From the above discussion of substituents should be understood that the terminology is "aliphatic" may include groups such as haloalkyl (for example, CF3and CH2CF3) and the like.

The terms "halo" or "halogen" by themselves or as part of another substituent means, unless otherwise stated, a fluorine atom, chlorine, bromine or iodine. In compounds with multiple halogen halogen substituents may be the same or different.

The term "pharmaceutically acceptable salt" includes such salts of the active compounds, which are obtained by relatively nontoxic acids or bases, depending on the particular substituents in the compounds described in this invention. In the case where the compounds of the present invention contain relatively acidic functional groups, their salts with bases can be obtained by adding the desired base, in an appropriate inert solvent or without it. Examples of pharmaceutically acceptable salts formed with bases include salts of sodium, potassium, calcium, ammonium, organic amines, magnesium and the like. In the case where the compounds of the present invention contain relatively basic functional group, and their salts with acids can be obtained by adding the desired acid, in an appropriate inert solvent or without it. Examples of pharmaceutically acceptable salts formed with an acid and, include salts of inorganic acids such as hydrochloric, Hydrobromic, nitric, carbonic, one-deputizing coal, phosphate, one-deputizing phosphate, disubstituted phosphoric, sulfuric, one-deputizing sulfur, itestosterone, phosphoric and the like acids, and salts of relatively non-toxic organic acids such as acetic, propionic, somalina, oxalic, maleic, malonic, benzoic, succinic, subernova, fumaric, almond, phthalic, benzolsulfonat, para-tolilsulfonil, citric, tartaric, methanesulfonate and the like. Also covered are salts of amino acids such as arginate and the like, and salts of such organic acids like glucuronic or galacturonic acid and the like (see, for example, S.M. Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional group that can be converted into salts formed either base or acid.

The neutral forms of the compounds can be regenerated by treating the salt with base or acid and highlight the original standard connection method. The original form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, a new rest of these salts are equivalent to the original form of connection for the purposes of the present invention.

Along with the salt forms of the present invention provides compounds in the form of prodrugs (predecessors). Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to form compounds of the present invention. Additionally, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo. For example, prodrugs can be slowly converted to compounds of the present invention, when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reagent.

Some compounds of the present invention may exist in resolutiony forms along with solvated forms, including hydrates. In General, the solvated forms are equivalent nonsolvated forms and provided that they come within the scope of this invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In General, all physical forms are equivalent for use in accordance with the present invention and provided that they come within the scope of this invention.

Some compounds Nast is asego of the invention have asymmetric carbon atoms (optical centers) or double bonds. It is envisaged that the racemates, diastereoisomers, geometric isomers and individual isomers are encompassed by the scope of the present invention.

Compounds of the present invention can also contain atomic isotopes in unnatural proportions of one or more atoms within the composition of these compounds. For example, the compounds can be labeled with radioactive isotopes, for example such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). Provides that all isotopic variations of the compounds of the present invention, radioactive and non-radioactive, covered by the scope of the present invention.

Preferred pharmaceutical compositions and their introduction

In the following embodiment of the present invention relates to pharmaceutical compositions containing one or more compounds that are injected in the absence of exogenous antigen, i.e. they are applied in monotherapeutic applications, in combination with pharmaceutically acceptable carriers and excipients. Such pharmaceutical compositions suitable for introduction into cells, tissue, animal or plant, alone or in combination with one or more means of therapy. In many such embodiments the pharmaceutical compositions according to the invention contain one or more with the of dinani, described in this invention.

The phrase "pharmaceutically acceptable" refers to molecules and compositions, not causing allergic or other adverse reactions when administered to man. In applying the present invention to "holders" or "fillers" are all solvents, dispersion media, media, coatings, diluents, antibacterial and antifungal agents, isotonic and slows the absorption of substances, buffers, solutions, media, suspensions, colloids, etc. the Use of such media and agents for pharmaceutically active substances is well known in this field. Except in those cases where traditional environment or substances incompatible with the active ingredient, its use in therapeutic compositions is provided.

Examples of carriers for preparation of pharmaceutical compositions include, for example, emulsion oil-in-water or water-in-oil, water compositions, whether or not containing organic solvents, suitable for intravenous administration, liposomes or containing detergent vesicles, microspheres, beads and microsome assay, powders, tablets, capsules, suppositories, aqueous suspensions, aerosols and other carriers known in this field.

In some embodiments the pharmaceutical compositions include one or more buffers (EmOC is emer, neutral salt buffer or phosphate-saline buffer), carbohydrates (e.g. glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, bacteriostatic, chelators type EDTA, glutathione, adjuvants (e.g., aluminum hydroxide), a substance that makes the composition is isotonic, gipotonichnaya or weakly hypertonic relative to the recipient's blood, suspendresume agents, thickening agents and/or preservatives.

For some applications, the preferred aqueous compositions, especially those that include an effective amount of one or more surfactants (detergents). For example, the composition may take the form of a micellar dispersion comprising at least one suitable detergent, for example phospholipid detergent. Examples of phospholipids include diazepammedicine, such as dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPG) and distearoylphosphatidylglycerol (DSPG); diazepamwithdrawlay, such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC); diarylphosphino acid, such as dimyristoylphosphatidylcholine acid (DMPA), dipalmitoylphosphatidyl acid (DPPA) and distearoylphosphatidylcholine acid (DSPA); and dieselpartikelfilter, such as dimyristoyl spatialanalysis (DMPE), dipalmitoylphosphatidylethanolamine (DPPE) and distearoylphosphatidylcholine (cells of the dspe). Typically, the molar ratio of detergent to mono-/disaccharides in aqueous composition is from 10:1 to 1:10, more preferably from 5:1 to 1:5, however, in the aqueous composition may be applied in any effective amount of detergent that best meets your goals.

Applied to the present invention an "effective amount" is an amount that causes the response above the level of the carrier or the negative control. As discussed above, the exact dosage of the compounds of this invention when administered to patients depends on the method of administration, the pharmaceutical compositions and patient.

Compounds and pharmaceutical compositions of the invention can be designed for almost any application, for example, injection, inhalation through the mouth or nose, rectal, vaginal or intratracheal injection, oral administration, transdermal or transmucosal applications, etc. Thus, the effects achieved using the methods and compositions of the invention, for example, can be systemic, local, tissue-specific, etc. depending on the specific requirements of a given application of the invention.

Illustrative compositions may be formulated and administered parenteral, i.e. inside the abdominal, subcutaneously, intramuscularly or intravenously. One of the notable examples of the carrier for intravenous administration includes a mixture of 10% ethanol, 40% propylene glycol (USP, USP) or polyethylene glycol 600, the rest is water for injection USP (VDI). Other preferred media include 10% ethanol USP, VDI USP 0.01 to 0.1% triethanolamine in VDI USP, 0.01 to 0.2% dipalmitoylphosphatidylcholine in VDI USP and 1-10% squalene or emulsion of oil in water for parenteral administration. Pharmaceutically acceptable solvents for parenteral administration is usually chosen so that they represented a solution or dispersion, which can be filtered through a 0.22 μm filter without loss of the active ingredient.

Illustrative examples of carriers for subcutaneous or intramuscular use include phosphate-saline buffer (PBS), 5% glucose in VDI and 0.01-0.1% triethanolamine in 5% glucose or 0.9% NaCl in VDI USP, or diluted 1:2 or 1:4 mixture of 10% ethanol USP, 40% propylene glycol, the rest is acceptable isotonic 5% glucose or 0.9% NaCl or 0.01 to 0.2% dipalmitoylphosphatidylcholine in VDI USP and 1-10% squalene or emulsion of oil in water for parenteral administration.

Examples of carriers for use through the mucous surfaces depend on the specific method, for example, orally, under the tongue, n is from, etc. Oral introduction illustrative examples include mannitol, starch, lactose, magnesium stearate, sodium saccharide, cellulose, magnesium carbonate pharmaceutical purity, etc. while the preferred mannitol. By intra illustrative examples include polyethylene glycol, phospholipids, glycols and glycolipids, sucrose and/or methylcellulose, powder suspension with a filler type of lactose or without it, preservatives type benzylaniline, EDTA. In a particularly preferred embodiment as an isotonic aqueous media used the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) at a concentration of 0.01 to 0.2% for intranasal compounds of this invention in a concentration of from 0.1 to 3.0 mg/ml

With the introduction by inhalation to preferred carriers include polyethylene glycol or glycols, DPPC, methylcellulose, powder dispersing substances and preservatives, while the preferred glycol and DPPC. In many cases, it is preferable that the connection was in aerosol form when introduced by inhalation. For example, you can use disposable delivery device, spray, breath-activated powder inhaler, spray dispenser-inhaler (MDI) or any other of the numerous spray delivery devices that are available in it is field. In addition, you can use fumigation tent or direct introduction through an endotracheal tube. Intratracheal or nasopharyngeal introduction effective for some indications.

Specialists in this field should understand that the preceding description is illustrative rather than comprehensive. In fact, this area is known for many other methods of making compositions and pharmaceutically acceptable fillers and media solutions, and develop appropriate schemes dosage and treatment for the use of certain compositions of the present invention in various modes of treatment.

Compounds can be evaluated in a variety of formats analyses, including those described in this invention to identify compounds with characteristics that best corresponding to the specific application of the invention. For example, you can use animal models to identify and evaluate the profile of allocation of cytokines in the systemic circulation after administration of the compounds of cyclic AGF. In addition, there are different models in vitro and in vivo to assess changes in one or more aspects of the immune response to various antigenic components in order to identify compounds that are most suitable for development of specific in representing the EPEC immune response. For example, you can handle the connection target cells, such as macrophages, dendritic cells or Langerhans cells in vitro and to measure cytokine production. In addition, you can use the matrix of gene expression to identify specific pathways activated or inhibiting certain cyclic AGF.

It should be borne in mind that, if desired, as described in this invention compounds can be introduced in combination with other drugs such as antimicrobial, antiviral and antifungal compounds or drugs, different drugs based on DNA, drugs based on RNA-based drugs polypeptides, and/or with other immunoelectron. So, you can turn almost any other components, provided that the additional components do not cause significant adverse effects upon contact with the target cells or host tissues. Thus, the compositions can be entered together with the various other substances, necessary or desirable for particular embodiments of the invention.

As an illustration, pharmaceutical compositions of the invention can include or be used together with DNA encoding one or more therapeutic proteins, antisense RNA, ribozymes, etc. of the DNA can be in any of a number of delivery systems known vannoy region, including systems for the expression of nucleic acids, bacterial and viral expression systems. In this area there are many known methods of gene delivery, such as those described in Rolland, Crit. Rev. Therap. Drug Carrier Systems 15: 143-198, 1998, and are there links. Suitable expression system, a nucleic acids contain the necessary DNA sequences for expression in the patient (such as a promoter and signal termination). In the preferred embodiment the DNA is introduced using a viral expression system (e.g., vaccinia virus or other poxvirus, retrovirus, or adenovirus), which usually involves the use of non-pathogenic (defective), replication competent virus. Suitable systems are disclosed, for example, in Fisher-Hoch et al., Proc. Natl. Acad. Sci. USA 86: 317-321, 1989; Flexner et al., Ann. N.Y. Acad. Sci. 569: 86-103, 1989; Flexner et al. Vaccine 8: 17-21, 1990; U.S. Patent No. 4603112, 4769330 and 5017487; WO 89/01973; U.S. Patent No. 4777127; GB 2200651; EP 0345242; WO 91/02805; Berkner, Biotechniques 6: 616-627, 1988; Rosenfeld et al., Science 252: 431-434, 1991; Kolls et al., Proc. Natl. Acad. Sci. USA 91: 215-219, 1994; Kass-Eisler et al., Proc. Natl. Acad. Sci. USA 90: 11498-11502. 1993; Guzman et al., Circulation 88,2838-2848,1993; and Guzman et al., Cir. Res. 73: 1202-1207, 1993. Methods for incorporating DNA into such expression systems are well known in this field.

DNA can be "naked", as described, for example, in Ulmer et al., Science 259: 1745-1749, 1993, and in the review of Cohen, Science 259: 1691-1692, 1993. The uptake of naked DNA can be increased by coating the DNA onto biodegradable beads, which effect is active are transported into the cells. It should be borne in mind that the pharmaceutical composition according to the invention may include polynucleotide, and the protein component.

In the compositions of this invention can include any of a number of additional Immunostimulants. For example, cytokines such as GM-CSF, interferons or interleukins for more specific modulation of the immune response. Thus, in some embodiments the composition may include additional components to enhance the induction of high levels of cytokines type Th-1 (e.g., IFN-γ, TNF-α, IL-2 and IL-12). Alternatively, or in addition to this can be desirable, high levels of cytokines type Th-2 (e.g., IL-4, IL-5, IL-6 and IL-10) for certain therapeutic applications. The levels of these cytokines can be easily determined by standard methods. Cm. an overview of the family of cytokines: Mossmann and Cofftnan, Ann. Rev. Immunol. 7: 145-173,1989.

Examples of compositions for application to induction of cytokines type Th-1 include, for example, the combination of CpG-containing oligonucleotides (in which the CpG dinucleotide is not methylated), as described, for example, in WO 96/02555, WO 99/33488 and U.S. Patent No. 6008200 and 5856462. Immunostimulatory DNA sequences are also described, for example, Sato et al., Science 273: 352, 1996. Other suitable Immunostimulants include saponins such as QS21 (Aquila Biopharmaceuticals Inc., Framingham, MA), GPI-100 (Marciani et al., Vaccine 18: 3141, 2000; U.S. Paent No.6,080,725) and related derivatives other saponins and their mimetics.

Other examples of Immunostimulants that can be used in combination with the present invention include Montanide ISA 720 (Seppic, France), SAF (Chiron, California, United States), ISCOMS (CSL), MF-59 (Chiron), adjuvants series SBAS (SBAS-2 or SBAS-4 firm Smith-Kline Beecham, Rixensart, Belgium) and immune Enhanzyn™ (Corixa, Hamilton, MT). Immunostimulants on the basis of esters of polyoxyethylene described BW 099/52549A1.

Further, the invention disclosed in the following non-limiting examples.

EXAMPLES

Example 1. Getting triethylammonium salt of N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-tetradecyltrimethylammonium]-3-O-[(R)-3-tetradecanoylphorbol]-β-D-glucopyranoside (triethylammonium salts of the compounds of formula (II)

(1a) a solution of 2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-tetradecanoate the deletion]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichloroethane-carbylamine)-β-D-glucopyranoside (1,05 g, 0.81 mmol) in anhydrous 1,2-dichloroethane (10 ml) was added molecular sieve 4 Å (0.5 g), anhydrous CaSO4(2.2 g, 16 mmol) and N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidineethanol (0.40 g, 0.75 mmol). This mixture was stirred 1 hour at room temperature, was treated with Hg(CN)2(1,02 g of 4.05 mmol) and boiled under reflux for 16 hours in the dark. The reaction mixture was cooled, diluted with CH 2Cl2and filtered. The filtrate is washed with 1 N aqueous KI solution, dried with Na2SO4and concentrated. After flash chromatography on silica gel (gradient elution, 15-20% EtOAc/hexane) received 0,605 g (43%) of N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-tetradecanoylphorbol]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside as an amorphous solid.

(1b) the Solution obtained in the previous PA compound (0.50 g, 0.29 mmol) in Asón (10 ml) at 60°were treated With zinc dust (0,98 g, 15 mmol) in three equal portions over 1 hour. The reaction mixture was cooled, treated with ultrasound, filtered through a layer of celite and concentrated. The precipitate was subjected to distribution between CH2Cl2and saturated aqueous NaHCO3and the layers were separated. The organic layer was dried with Na2SO4and concentrated. A solution of the obtained crude amerosport and (R)-3-tetradecanoate-decanoas acid (0,155 g, 0.34 mmol) in CH2Cl2mixed with powder molecular sieves 4 Å (0.25 g) for 0.5 h, then was treated with 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (0.11 g, 0.44 mmol). The resulting mixture was stirred at room the Oh temperature for 8 h, was filtered through celite and concentrated. After flash chromatography on silica gel using 50% EtOAc/hexane got 0,355 g (68%) of N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-2-[(R)-3-tetradecanoate-decanoylamino]-3-O-[(R)-3-tetradecanoylphorbol]-β-D-glucopyranoside as a colorless syrup.

(1C) the Solution obtained in the previous .1b connection (0,300 g, 0,166 mmol) in a mixture of Asón (1 ml) and tetrahydrofuran (9 ml) was subjected to hydrogenation in the presence of PtO2(0.15 g) at room temperature and a pressure of 70 psi for 18 hours, the Reaction mixture was diluted with a mixture of 2:1 CHCl3-Meon (50 ml) and was briefly treated with ultrasound. Collected the catalyst and washed with a mixture of 2:1 CHCl3-Meon, and the combined filtrate and wash water were concentrated. After flash chromatography on silica gel using CHCl3-Meon-H2O-Et3N (90:10:0,5:0,5) had a partially purified product, which was dissolved in ice-cold mixture of 2:1 CHCl3-Meon (30 ml) and washed with ice-cold solution of 0.1 N HCl (12 ml). The organic phase was filtered and liofilizirovanny of 2% aqueous solution of Et3N (5 ml free from pyrogens), receiving 0,228 g (79%) triethylammonium salt of N-[(R)-3-tetradecanoylphorbol]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-tetradecanoate is radionoviene]-3-O-[(R)-3-tetradecanoylphorbol]-β -D-glucopyranoside as a colorless powder. TPL 67-70°IR spectrum (film): 3306, 2955, 2923, 2853, 1736, 1732, 1644, 1548, 1466, 1378, 1245, 1177, 1110,1053, 844 cm-1;1H-NMR (CDCl3CD3OD): δ to 0.88 (m, 18H), 1,0-1,205 (m, H), 2,20-2,70 (m, N), 3,06 (q, 6N, J=7,2 Hz), 3,3-of 3.25 (m, H)to 4.52 (d, 1H, J=8 Hz), of 5.05 is 5.28 (m, 4H), 7,44 (d, 1H, J=9 Hz);13C-NMR (CDCl3): δ 173,3, 173,0, 170,3, 169,6, 168,6, 101,8, 100,4, 75,8, 72,5, 72,4, 70,9, 70,8, 70,3, 70,2, 69,9, 69,3, 67,9, 66,6, 56,5, 56,3, 54,5, 47,4, 45,8, 44,6, 41,4, 41,0, 39,7, 39,2, 39,0, 34,5, 34,3, 34,1, 32,0, 29,7, 29,4, 28,1, 27,3, 25,7, 25,3, 25,2, 25,1, 24,0, 22,7, 21,6, 14,1, 8,6.

The analysis is theoretically101H194N3O17P·N2About: From=68,47, N=Of 11.15, N=2,37, P=1,75; actual:=68,79, N=11,00, N=2,24, P=1,97.

Example 2. Getting triethylammonium salt of N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron-yl]-β-D-glucopyranoside (triethylammonium salt of compound III)

(2A) a solution of 2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-dodecanoate the deletion]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichloroethane-carbylamine)-α-D-glucopyranoside (1.60 g, of 1.27 mmol) in anhydrous 1,2-dichloroethane (3.2 ml) was added molecular sieve 4 Å (0.6 g), anhydrous CaSO4(1.0 g, 7,3 mmol) and N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidineethanol (0,58 g to 1.14 mmol). This mixture was stirred 1 hour at room temperature, was treated with the Hg(CN) 2(of 0.58 g, 2.3 mmol) and boiled under reflux for 6 hours in the dark. The reaction mixture was cooled, diluted with CH2Cl2and filtered through a layer of celite. The filtrate is washed with 1 N aqueous KI solution, dried with Na2SO4and concentrated. After flash chromatography on silica gel (gradient elution, 25→35% EtOAc/ hexane) received 1,72 g (82%) of N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-dodecanolide-canol]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside as a colorless oil.

(2b) the Solution obtained in the previous PA connection (1,58 g, 0,806 mmol) in Asón (40 ml) at 60°were treated With zinc dust (2.6 g, 40 mmol) in three equal portions over 1 hour. The reaction mixture was cooled, treated with ultrasound, filtered through a layer of celite and concentrated. The precipitate was subjected to distribution between EtOAc and saturated aqueous NaHCO3and the layers were separated. The organic layer was washed with saturated salt solution, dried with Na2SO4and concentrated, obtaining 1.3 g of a white solid. A solution of the obtained crude amerosport and (R)-3-dodecadodecahedron acid (0.45 g, 1.05 mmol) in CH2Cl2(20 ml) was treated with 2-this is the XI-1-etoxycarbonyl-1,2-dihydroquinoline (0,30 g, to 1.21 mmol). The resulting mixture was stirred at room temperature for 18 h and concentrated. After flash chromatography on silica gel using 40→50% EtOAc/hexane got 0,89 g (56%) of N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron]-β-D-glucopyranoside as a white foam.

(2C) the Solution obtained in the previous .2b compound (0.75 g, 0.44 mmol) in a mixture of Asón (4,5 ml) and tetrahydrofuran (45 ml) was subjected to hydrogenation in the presence of PtO2(0.45 g) at room temperature and a pressure of 70 psi for 18 hours, the Reaction mixture was diluted with a mixture of 2:1 CHCl2-Meon (35 ml) and was briefly treated with ultrasound. Collected the catalyst and washed with a mixture of 2:1 CHCl3-Meon, and the combined filtrate and wash water were concentrated. After flash chromatography on silica gel using CHCl3-MeOH-H2O-Et3N (gradient elution: 96:4:0,3:0,3→90:10:0,5:0,5) had a partially purified product (0.51 g), which was dissolved in ice-cold mixture of 2:1 CHCl3-Meon (50 ml) and washed with ice-cold aqueous solution of 0.1 N HCl (20 ml). The organic phase was filtered and concentrated. The obtained white wax liofilizirovanny of 2% aqueous solution of Et3N (70 ml, free from pyrogens)to give 0.54 g (78%) treat lemmonii salt of N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron]-β -D-glucopyranoside as a white powder. TPL 146-151°IR spectrum (film): 3292, 3100, 2958, 2922, 2852, 1739, 1731, 1659, 1651, 1644, 1562, 1555, 1468, 1455, 1433, 1377, 1339, 1310, 1253, 1238, 1183, 1160, 1107, 1080, 1047, 960, 856, 722 cm-1;1H-NMR (CDCl3CD3OD): δ 0,88 (m, 18 H), 1,0-2,10 (mH), 2,20-of 2.75 (m, N), 3.04 from (q, 6H, J=7.2 Hz), 3,3-4,3 (mH), of 4.45 (d, 1H, J=8.5 Hz), 5,0 is 5.28 (m, 4H);13C-NMR (CDCl3): δ 173,9, 173,4, 173,2, 170,6, 170,1, 169,2, 101,4, 75,5, 74,0, 70,8, 70,7, 70,2, 68,5, 60,5, 56,6, 53,6, 47,4, 45,6, 40,9, 39,6, 38,8, 34,5, 34,3, 34,2, 34,1, 31,9, 29,7, 29,6, 29,5, 29,4, 29,4, 29,3, 29,2, 27,3, 25,2, 25,0, 23,6, 22,7, 21,6, 14,0, 8,3.

Mass spectrometry MALDI: theoretically for [M+Na]+1590, 1900, in fact, 1590, 1866. The analysis is theoretically95H182O17R·3H2O:=66,20, N=10,99, N=2,44; actual:=Collected 66.36; H=10,69, N=2,15.

Example 3. Getting triethylammonium salt of N-[(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-1(R)-3-technologietransfer]-β-D-glucopyranoside (triethylammonium salt of compound (IV)

(3A) a solution of 2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-technologietransfer]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside (1.70 g, 1.38 mmol) in anhydrous 1,2-dichloroethane (3.5 ml) was added molecular sieve 4 Å (0.6 g), anhydrous CaSO4(1.2 g, 8,8 mmol) and N-[(R)-3-technologietransfer]-(S)-2-pyrrolidineethanol (0,60 g of 1.24 mmol). This mixture AC is stirred 1 hour at room temperature, was treated with Hg(CN)2(to 0.63 g, 2.5 mmol) and boiled under reflux for 6 hours in the dark. The reaction mixture was cooled, diluted with CH2Cl2and filtered through a layer of celite. The filtrate is washed with 1 N aqueous KI solution, dried with Na2SO4and concentrated. After flash chromatography on silica gel (gradient elution, 25→40% EtOAc/hexane) received 1,82 g (80%) of N-[(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-3-O-[(R)-3-technologythere-canol]-6-O-(2,2,2-trichloro-1,1-dimethylethoxysilane)-2-(2,2,2-trichlorocarbanilide)-β-D-glucopyranoside as a colorless oil.

(3b) the Solution obtained in the previous PA connection (1,67 g of 1.02 mmol) in Asón (50 ml) at 60°were treated With zinc dust (3.33 g, 51 mmol) in three equal portions over 1 hour. The reaction mixture was cooled, treated with ultrasound, filtered through a layer of celite and concentrated. The precipitate was subjected to distribution between EtOAc and saturated aqueous NaHCO3and the layers were separated. The organic layer was washed with saturated salt solution, dried with Na2SO4and focused, getting to 1.25 g of a white solid. A solution of the obtained crude amerosport and (R)-3-technologytechnology acid (0,53 g of 1.33 mmol) in CH2Cl2(20 ml) education is atively 2 ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (0,38 g, 1.53 mmol). The resulting mixture was stirred at room temperature for 18 h and concentrated. After flash chromatography on silica gel using 40→50% EtOAc/hexane got to 1.23 g (74%) of N-[(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-diphenylphosphino-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glucopyranoside as a white foam.

(3C) the Solution obtained in the previous .3b compound (1.07 g, 0,654 mmol) in a mixture of Asón (6.5 ml) and tetrahydrofuran (65 ml) was subjected to hydrogenation in the presence of PtO2(0.66 g) at room temperature and a pressure of 70 psi for 18 hours, the Reaction mixture was diluted with a mixture of 2:1 CHCl3-Meon (50 ml) and was briefly treated with ultrasound. Collected the catalyst and washed with a mixture of 2:1 CHCl3-Meon, and the combined filtrate and wash water were concentrated. Received waxy solid liofilizirovanny of 2% aqueous solution of triethylamine, receiving ˜1 g crude triethylammonium salt as a white powder. After flash chromatography on silica gel using CHCl3-MeOH-H2O-Et3N (gradient elution: 96:4:0,3:0,3→88:12:1:0,6) has been partially purified product (0.84 g), which was dissolved in ice-cold mixture of 2:1 CHCl3-Meon (168 ml) and washed with ice-cold solution of 0.1 N HCl (67 ml). Organic f the zu was filtered and concentrated. The obtained white wax liofilizirovanny of 2% aqueous solution of Et3N (70 ml, free from pyrogens), receiving 0,79 g (79%) triethylammonium salt of N-[(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glucopyranoside as a white powder. TPL 121-122°IR spectrum (film): 3287, 3093, 2961, 2913, 2850, 1745, 1738, 1732, 1716, 1666, 1660, 1651, 1644, 1635, 1565, 1556, 1538, 1470, 1455, 1434, 1416, 1378, 1337, 1311, 1248, 1184, 1104, 1081, 1021, 964, 721 cm-1;1H-NMR (CDCl3CD3OD): δ to 0.88 (m, 18H), 1,0-2,05 (mH), 2,20-of 2.75 (m, N), 3.04 from (q, 6H, J=7.2 Hz), 3,3-4,3 (mH), of 4.45 (d, 1H, J=8.5 Hz), 5,0 is 5.28 (m, 4H);13C-NMR (CDCl3): δ 173,7, 173,4, 173,2, 170.5, 170,1, 169,1, 101,4, 75,6, 74,0, 70,8, 70,2, 68,7, 60,4, 56,6, 53,8, 47,4, 45,6, 41,0, 39,6, 38,9, 34,5, 34,3, 34,2, 34,1, 31,9, 29,7, 29,6, 29,5, 29,4, 29,4, 29,3, 29,2, 27,3, 25,3, 25,0, 23,7, 22,7, 21,6, 14,1, 8,4.

Mass spectrometry MALDI: theoretically for [M+Na]+1506,0961 actually 1506,1008. Analysis in theory for C89H170N3O17P:=67,43, N=10,81, N=2,65; actual:=67,26, N=10,85, N=2,47.

Example 4. A sample introduction Listeria monocytogenes in mice

This example presents the experiments to assess the induction of nonspecific resistance by the method of sample introduction Listeria monocytogenes in mice, which was performed using the compounds obtained in examples 1, 2 and 3. Mice (5 per group) were injected intravenously with 1 mg of cyclic AGF or MPL, dissolved in 0.2% triethanolamine is (tea). After 2 days, the mice were injected intravenously ˜105cells of Listeria monocytogenes serotype 10403 (the original culture obtained from Jory Baldridge, Washington State University, Pullman, WA). 2 days after injection, the mice were killed and determined the number of colony forming units (CoE) in the spleens of mice sowing 10-fold serial dilution of homogenates of spleen on agar plates with trypticase the hydrolyzate of soybean. Expected degree of protection produced by AGF or MPL, subtracting the average number of bacteria per 1 spleen (log10 value) in the group of mice treated with this compound, the average number of bacteria per 1 spleen (log10 value) in the control group, which as a simulation was injected solvent (0.2% tea) before sample introduction L. monocytogenes.

From all investigated compounds was the most active compound from example 3, which induced protection to the extent comparable with MPL (˜0.9 log10 units). The compound from example 2 induced a slightly lesser degree of protection, while the compound of example 1 was the least active (0.7 and 0.2 log10 units, respectively).

Example 5. Protection against lethal infection with influenza virus through prevention of the introduction of cyclic AGF

This example presents the experiments on the evaluation of the protection against lethal infection with influenza virus in mice treated with cyclic AGF. Mice BALB/c mice (10 per group)were injected in the nose 20 μg of the compounds of examples 1, 2 and 3, or MPL 48 hours before lethal intranasal infection with influenza virus a/HK/68 (5 doses LD50). The protective effect was evaluated by survival, clinical symptoms (ruffled fur, hunched posture and difficulty in breathing) and to prevent weight loss in 21 days after infection.

As in the case of models with the introduction of Listeria, the compounds of examples 2 and 3 provided a high degree of protection compared to the control solvent. The survival rate was 60% in mice treated with the compound from example 3, 40% of mice treated with the compound from example 2, and 30% of mice treated with MPL. Not survived, none of the mice treated with compound 1. These data show that the compound of example 3 provides the greatest protection, followed by the compounds of examples 2 and 1.

All cited publications and patent applications included in the present invention by reference in its entirety. Although this invention is described in sufficient detail with engaging illustrations and examples to facilitate understanding, however, in light of the provisions of this invention, the experts in this field should understand that it can be made certain changes and modifications, without deviating from the spirit and scope of the appended claims.

1. The way of relief or significant warnings info the ment of the disease, autoimmune diseases or allergic condition in a patient, comprising contacting the patient with an effective amount of one or more compounds of the following formula:

or their pharmaceutically acceptable salts, where X is selected from the group consisting of-O-and-NH-;

R1, R2and R3independently from each other selected from the group consisting of (C2-C20)acyl groups,

if this *1, *2, *3and ** represents a chiral centers.

2. The method according to claim 1, in which X is represented by-O-.

3. The method according to claim 1, in which each of R1, R2and R3presents (C6-C14)acyl group.

4. The method according to claim 1, in which each of R1, R2and R3presents (C6-C12)acyl group.

5. The method according to claim 2, in which each of R1, R2and R3presents decanolide balance.

6. The method according to claim 2, in which each of R1, R2and R3presents dodecanolide balance.

7. The method according to claim 2, in which each of R1, R2and R3presents tetradecanoyl balance.

8. The method according to claim 2, in which *1, *2and *3located in the R-configuration.

9. The method according to claim 2, in which the atom On between the glucosamine residue and the aglycone is in Equatoria enom position.

10. The method according to claim 2, in which ** is in the S-configuration.

11. The method according to claim 2, in which *1, *2and *3located in the R-configuration, the atom On between the glucosamine residue and the aglycone is in the Equatorial position, and ** is in the S-configuration.

12. The method according to claim 1, in which an infectious disease caused by a bacterium, virus, parasite or fungus.

13. The method according to item 12, in which the bacterium presents the gram-negative bacterium or a gram-positive bacterium.

14. The method according to item 12, in which an infectious disease caused by a bacterium selected from the group consisting of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus and Staphylococcus.

15. The method according to 14, in which an infectious disease is a pneumonia.

16. The method according to item 15, in which pneumonia is a nosocomial pneumonia.

17. The method according to clause 16, in which pneumonia in HIV-positive patients.

18. The method according to claim 1, in which an infectious disease is a chronic infection.

19. The method according to p in which chronic infection include chronic hepatitis, human papillomavirus, oral or vaginal candidiasis, periodontal disease or chronic rhinosinusitis caused by the colonization of fungi.

20. The method according to claim 1, wherein the allergic condition is selected from the group consisting of asthma, the WPPT is known of neurodermatitis, seasonal allergies and chronic rhinosinusitis.

21. The method according to claim 1, in which the autoimmune disease is selected from the group consisting of chronic inflammation of the intestine, rheumatoid arthritis, chronic arthritis, multiple sclerosis and psoriasis.

22. The method according to claim 1, wherein the compound is transferred to the animal by a method selected from the group consisting of parenteral, oral, intravenous, infusion, intranasal, inhalation, trandermal or transmucosal methods.

23. The method according to claim 2, in which the compound of formula V is a N-[(R)-3-dodecadodecahedron]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-dodecadodecahedron]-3-O-[(R)-3-dodecadodecahedron]-β-D-glucopyranosid or its pharmaceutically acceptable salt.

24. The method according to claim 2, in which the compound of formula V is a N-[(R)-3-technologietransfer]-(S)-2-pyrrolidinyl-2-deoxy-4-O-phosphono-2-[(R)-3-technologytechnology]-3-O-[(R)-3-technologietransfer]-β-D-glucopyranosid or its pharmaceutically acceptable salt.

25. A method of prophylactic treatment of bacterial or viral infection in a patient, comprising contacting the patient with an effective amount of one or more compounds of the following formula:

or their pharmaceutically acceptable salts, where X is selected from the group consisting of-O - and-NH-;

R1, R2and R3independently from each other selected from the group consisting of (C2-C20)acyl groups,

if this *1, *2, *3and ** represents a chiral centers.

26. The method according A.25, where X represented by-O-.

27. The method according A.25, in which each of R1, R2and R3presents (C6-C14)acyl group.

28. The method according A.25, in which each of R1, R2and R3presents (C6-C12)acyl group.

29. The method according to p, in which each of R1, R2and R3presents decanolide balance.

30. The method according to p, in which each of R1, R2and R3presents dodecanolide balance.

31. The method according to p, in which each of R1, R2and R3presents tetradecanoyl balance.

32. The method according to p where *1, *2and *3located in the R-configuration.

33. The method according to p, in which the atom On between the glucosamine residue and the aglycone is in the Equatorial position.

34. The method according to p, where ** is in the S-configuration.

35. The method according to p where *1, *2and *3located in the R-configuration, the atom On between the glucosamine residue and the aglycone is in Equatoriale position, a ** is in the S-configuration.

36. The method according A.25, in which the bacterium presents the gram-negative bacterium or a gram-positive bacterium.

37. The method according A.25, in which an infectious disease caused by a bacterium selected from the group consisting of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus and Staphylococcus.

38. The method according to clause 37, in which an infectious disease is a pneumonia.

39. The method according to § 38, in which pneumonia is a nosocomial pneumonia.

40. Pharmaceutical composition for alleviating or substantially prevent infectious diseases, autoimmune diseases or allergic condition, which is drawn up and entered in the absence of exogenous antigen, comprising one or more compounds of the following formula:

or their pharmaceutically acceptable salts, where X is selected from the group consisting of-O - and-NH-;

R1, R2and R3independently from each other selected from the group consisting of (C2-C20)acyl groups,

if this *1, *2, *3and ** represents a chiral centers.

41. The pharmaceutical composition according p, in which one or more compounds of the formula V X represented by-O-.

42. The pharmaceutical composition according p where one is or several compounds of formula V of each of R 1, R2and R3presents (C6-C14)acyl group.

43. The pharmaceutical composition according p, in which one or more compounds of the formula V of each of R1, R2and R3presents (C6-C12)acyl group.

44. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V of each of R1, R2and R3presents decanolide balance.

45. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V of each of R1, R2and R3presents dodecanolide balance.

46. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V of each of R1, R2and R3presents tetradecanoyl balance.

47. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V *1, *2and *3located in the R-configuration.

48. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V atom On between the glucosamine residue and the aglycone is in the Equatorial position.

49. The pharmaceutical composition according to paragraph 41, in which one or more compounds of the formula V ** is in the S-configuration.

50. The pharmaceutical composition according to paragraph 41, in which one or not is how many compounds of the formula V * 1, *2and *3located in the R-configuration, the atom On between the glucosamine residue and the aglycone is in the Equatorial position, and ** is in the S-configuration.

51. The pharmaceutical composition according p, optionally including one or more surface-active substances.

52. The pharmaceutical composition according to § 51, in which one or more surfactants selected from the group consisting of dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPG), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine acid (DMPA), dipalmitoylphosphatidyl acid (DPPA), distearoylphosphatidylcholine acid (DSPA), dimyristoylphosphatidylcholine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE) and distearoylphosphatidylcholine (cells of the dspe).



 

Same patents:

FIELD: medicine, immunology, pharmacy.

SUBSTANCE: invention relates to methods for treatment of autoimmune, rheumatic diseases, immune disorders associated with rejection of transplant and involves administration to patient mutant molecules of a soluble CTLA4. These molecules can be administrated in common or successively with the second agent that is chosen from the group consisting of corticosteroid, nonsteroid anti-inflammatory agent, azathioprine, methotrexate, blocker or antagonist of TNFα, hydroxychlorokin, sulfasalazin, gold salt, anakinra, cyclophosphamide and leflunomide. CTLA4 molecule represented in Fig. 23 given in the invention description comprises mutation in position +104 CTLA4 wherein leucine is substituted with glutamic acid, and mutation in position +29 CTLA4 wherein alanine is substituted with tyrosine. CTLA4 molecule can comprise an extracellular domain and involves a sequence shown in Fig. 19 given in the invention description beginning from methionine in position +1 or from alanine in position -1 and terminating by aspartic acid in position +124. CTLA4 molecule can represent L104EA29YIg beginning from methionine in position +1 or from alanine in position -1 and terminating by lysine in position +357 as shown in Fig. 19. Invention provides blocking the immune interaction between T- and B-cells and prevention of activation of B-cells based on binding B7 molecule by using indicated CTLA4 molecule wherein mutations in its molecule result to positive changes in avidity binding with B7.

EFFECT: improved method of treatment.

31 cl, 3 tbl, 33 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to tablet containing cetirizine and pseudoephedrine used in treatment of allergic disorders. Invention relates to a tablet comprising two separate layers. Invention relates to combinations of two pharmaceutical substances representing cetirizine and pseudoephedrine prepared in the weight ratio pseudoephedrine to cetirizine = 12-30. Pseudoephedrine-containing segment comprises inert pharmaceutical excipients and an alkalinizing agent. Pharmacokinetics patterns of cetirizine and pseudoephedrine are similar practically with pharmacokinetic pattern of medicinal preparations containing each of these components taken separately in the same doses. Invention provides the development of combination of pharmaceutical substances useful in treatment being without adverse effects.

EFFECT: improved and valuable medicinal properties of tablet.

44 cl, 5 tbl, 3 ex

FIELD: chemical and pharmaceutical industry.

SUBSTANCE: invention relates to natural immunocorrective preparation Tactivine in spray form. Claimed agent contains Tactivina, vitamin C and 0.14 M sodium chloride solution as solvent in specific component ratio.

EFFECT: agent of improved effectiveness and storage stability.

2 cl, 5 tbl, 4 dwg, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted pyrazoles of general formula I , wherein X, Y, Z are nitrogen or R12C; R1 is, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano nitro, R9R10N, R9OC=O, R10R11NC=O or R10R11NSO2; R2 is hydrogen, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano or R48R49N; R3, R4, R5, R6 are hydrogen or alkyl. Pharmaceutical composition and method for inhibiting of S. cathepsin also are disclosed.

EFFECT: agents useful in treatment of autoimmune diseases mediated by S. cathepsin.

43 cl, 312 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing anti-staphylococcus-proteus-blu-pus-bacillus vaccine twice: once before and once after an operation with 7-10 days long interval. Antibiotic and vaccination therapy is administered in combination with immunomodulator introduced. The immunomodulator is selected from a group composed of immunomodulator of microbial origin, synthetic chemical substance immunomodulator, immunomodulator obtained from marrow and nucleic acid-based immunomodulator. The treatment is continued by administering probiotics combined with biologically active nutrient additive selected from a group composed of blackberry syrup with Echinacea, Echinacea with vitamin C added and Immunostat E, given beginning from 5th-10th day.

EFFECT: enhanced effectiveness in restoring soft tissue structure in postoperative wound region.

6 cl

FIELD: medicine.

SUBSTANCE: method involves introducing anti-staphylococcus-proteus-blu-pus-bacillus vaccine twice: once before and once after an operation with 7-10 days long interval. Antibiotic and vaccination therapy is administered in combination with immunomodulator introduced. The immunomodulator is selected from a group composed of immunomodulator of microbial origin, synthetic chemical substance immunomodulator, immunomodulator obtained from marrow and nucleic acid-based immunomodulator. The treatment is continued by administering probiotics combined with biologically active nutrient additive selected from a group composed of blackberry syrup with Echinacea, Echinacea with vitamin C added and Immunostat E, given beginning from 5th-10th day.

EFFECT: enhanced effectiveness in restoring soft tissue structure in postoperative wound region.

6 cl

FIELD: medicine, immunology.

SUBSTANCE: claimed method includes administration of composition comprising immunoregulatory anti-CD80 antibody or immunoregulatory binding fragment thereof and anti-CD80 antibody having activity directed to attenuation of B-cells in claimed dosages and regimes. Method of present invention makes it possible to effectively treat of autoimmune diseases due to attenuation of B-cell population caused by selective directivity of claimed combination against both activated and non-activated B-cells.

EFFECT: effective method for treatment of autoimmune diseases.

3 ex, 1 tbl, 36 cl

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to stone oil, extracted from stones of date (Phoenix pubeccens), yellow wood, or walnut containing specific amounts of triglycerides, diglycerides, monoglycerides, sitosterols, and cycloalanosterol. In one embodiment method for extraction of stone oil includes pressing of stones or powered stones, extraction with organic solvent or selectively by using of liquid in above-critical state to produce crude oil; discoloration thereof with adsorbing discoloration agent; dissolution of discolored oil in light ligroin; addition of stoichiometric amount of NaOH under stirring; settlement and aliquation; washing of organic phase with warm water to produce emulsion; addition of acetone to emulsion under stirring; layer separation and producing of oily phase in upper layer; treatment of oily phase to absorb thereof subsequently with neutral aluminum oxide and kaolin; removing after filtration of organic solvent from filtrate in nitrogen atmosphere; oily phase washing with warm water; heating of oily phase in nitrogen atmosphere to dehydrate thereof; and adsorption with neutral aluminum oxide. In another embodiment method for extraction of stone oil includes pressing of stones or powered stones, extraction with organic solvent or selectively by using of liquid in above-critical state to produce crude oil; stirring and heating of crude oil; adding of phosphorus acid to provide full degumming; addition of NaOH or Na2CO3 solution to degummed oil at the same temperature to provide full caustic purification; mixture settlement and aliquation to produce purified oil; washing of purified oil with pure water; addition of adsorbent to washed oil or heating thereof in vacuum to remove water and produce transparent dehydrated oil; discoloration thereof with adsorbing discoloration agent under heating in vacuum and under stirring in nitrogen atmosphere and oil heating up to certain temperature; passing of pure water steam at certain temperature and holding for certain time followed by stopping of purified water steam passing and nitrogen passing under stirring to remove moisture from oil. Pharmaceutical compositions improving of immunological function, increasing serum protein content and tumor growth inhibiting, which contains therapeutically effective amount of stone oil and one or more pharmaceutically acceptable adjuvants also are disclosed.

EFFECT: stone oil effectively improving of immunological function, increasing serum protein content and tumor growth inhibiting.

14 cl, 5 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-thio-substituted derivatives of imidazole of the formula (I) , their optical isomers and physiologically acceptable salts wherein R1, R2, R3 and R4 have values given in claim 1 of the invention. Compounds possess immunomodulating and/or inhibitory effect on cytokine release and can be useful in treatment of diseases associated with the immune system disorder. Also, invention relates to a pharmaceutical agent inhibiting release of cytokines based on compounds of the formula (I) and using these compounds for preparing a pharmaceutical agent inhibiting release of cytokines for treatment of diseases associated with the immune system disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 1 tbl, 88 ex

FIELD: medicine.

SUBSTANCE: invention relates to two-layered solid composition including a) the first layer of direct action containing effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable carrier and b) the second layer of prolonged action containing effective amount of nasal anti-oedema agent and pharmaceutically acceptable carrier, wherein composition contains less than 2 % of desloratadine deterioration products. Composition is stable in administration of one or two times per day.

EFFECT: new composition for treatment and/or amelioration of prodromes or symptoms associated with common cold and allergic and/or phlogistic skin or pipe conditions.

28 cl, 1 dwg, 6 ex

FIELD: virology, biotechnology, medicine, pharmacy.

SUBSTANCE: invention proposes the envelope HCV protein (hepatitis C virus). Protein comprises 80% of glycosylated sites. Such protein is more preferable for diagnostic, prophylactic and therapeutic using. Also, invention proposes a method for preparing such protein, and a drug, vaccine and different pharmaceutical compositions also comprising such protein. Proposed group of inventions can be used in medicine for diagnosis, treatment and prophylaxis of HCV infection and to prediction of clinical effectiveness of treatment.

EFFECT: improved preparing method, valuable medicinal properties of protein.

37 cl, 77 dwg, 16 tbl, 29 ex

FIELD: genetic engineering, virology, pharmacy.

SUBSTANCE: invention proposes the recombinant modified virus OF VACCINE Ankara able to express structural antigens of hepatitis C virus. Virus comprises DNA sequences encoding structural antigens of hepatitis C virus or their functional regions or epitopes of hepatitis C virus structural antigens. Also, invention proposes a pharmaceutical composition comprising such virus, eucaryotic cell infected with such virus, a method for preparing such virus and a method for preparing hepatitis C virus structural polypeptides. Invention can be used in virology and medicine for preparing hepatitis C virus antigen.

EFFECT: valuable properties of virus.

20 cl, 14 dwg, 1 tbl

FIELD: medicine, obstetrics, gynecology.

SUBSTANCE: uterine cavity should be drained in the course of operation, moreover, irrigator's distal end should be withdrawn through operation wound at anterior abdominal wall, and 2 h after the end of operation uterine cavity should be washed through irrigator with 400 ml of cooled 0.06%-sodium hypochlorite solution at perfusion rate being 200 ml/h, 6 times every 12 h up to 3-4 d; after each perfusion one should introduce 1 g kanamycin directly into uterine cavity, moreover, in case of availability of bacterioid and/or anaerobic flora in uterine cavity according to the results obtained due to pre-operational antibioticogram one should add 100 ml 3%-hydrogen peroxide solution into perfusion solution. The present innovation enables to efficiently sanitize uterine cavity due to intrauterine injection of antibiotics by taking into account antibioticogram performed at all stages of operative treatment.

EFFECT: higher efficiency of prophylaxis.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves administering 1-methyl-2-phenylthiomethyl-3-carbetoxi-4-dimethyl-aminomethyl-5-oxibromoindol or its salts selected from a group containing hydrochloride monohydrate (arbidol) earlier known as immunomodulator, besilate, fumarate, maleate, citrate or their hydrates.

EFFECT: enhanced effectiveness in healing organism from rotavirus.

4 cl, 8 tbl

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:

wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.

EFFECT: valuable properties of compounds.

4 tbl, 2 dwg, 18 ex

FIELD: medicine, virology, pharmacy.

SUBSTANCE: invention proposes an agent for treatment and prophylaxis of infection caused by coronaviruses, in particular, for treatment of atypical pneumonia (SARS), and pharmaceutical composition of indicated designation based on thereof. Agent represents 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxybromoindole or 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxybromoindole monohydrate hydrochloride (arbidol) known early as an immunomodulator and preparation used against influenza viruses. Invention provides reducing accumulation of coronaviruses (on example with TOPS virus) in lung.

EFFECT: valuable medicinal properties of agent.

2 cl, 7 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

The invention relates to medicine, specifically to pharmacology

The invention relates to medicine, namely to the treatment of HIV-infected patients

The invention relates to the field of medicine and pharmaceutical industries and can be used in the creation, production and application of therapeutic and preventive drugs

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to anhydrous, antifungal, lubricating gel compositions comprising polyhydric alcohol, gelatinizing agent and an antifungal azole compound, and to a method for treatment of a patient with fungal infections comprising administration of indicated composition in a patient. Compositions shows the excellent warming and lubricating effect after its applying on skin and mucosal tissues and provides the effective treatment of fungal infections.

EFFECT: improved and valuable properties of compositions.

21 cl, 2 tbl, 11 dwg, 9 ex

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