Oxazolidine-containing dimer compounds, compositions and methods of their obtaining and application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and describes pharmaceutical composition, including therapeutically effective quantity of compound, which has the following structure: , where compound in pharmaceutical composition is present in quantity, efficient for treatment or prevention of antibacterial infection in mammalian subject. Methods of obtaining and application of said dosed forms or pharmaceutical compositions are also claimed.

EFFECT: obtaining composition for treatment or prevention of antibacterial infection in mammalian subject.

15 cl, 8 tbl, 5 ex, 4 dwg

 

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application takes priority under Provisional patent application U.S. No. 61/181,955, which is reproduced here for reference in its entirety.

The SCOPE of the INVENTION

The technical field to which the invention relates

[0002] the Present description relates to pharmaceutically useful oxazolidinones dimeric compounds, compositions and methods for their preparation and use for the treatment and prevention of diseases in mammals.

Description of the prior art

[0003] Various oxazolidinedione compounds are used as antibiotics. For example, oxazolidinedione compounds have been described in application for U.S. patent No. 10/596,412 (filed December 17, 2004) and WO 04/048350, WO 03/022824 and WO 01/94342, reproduced here for reference.

[0004] the patent Application U.S. No. 12/577,089 (filed October 9, 2009) and the application for U.S. patent No. 12/699,864 (filed February 3, 2010) belong to the same owner as that of the present application, and open the impurity dimer phosphate obtained in the process of producing compounds of the present invention. Unexpectedly, it was found that compounds containing at least two of the phosphate linking the two oxazolidinones fragment, such as dimers oxazolidinones compounds possess antibacterial activity, p�daubney their divodorod monophosphate analogue, but primarily have a different release curve, as discussed in detail below.

[0005] Bacterial infections are unresolved medical problem because antibiotic drugs usually cause resistance in bacteria against which they are used. Consequently, there is a need for new drugs effective against pathogenic bacteria for use in the treatment and prevention of bacterial infections.

[0006] In particular, a need exists in antibacterial drugs with different pharmacokinetic properties, such as drugs with a slow release, giving the opportunity to prescribe various schedules of admission to therapeutic and prophylactic purposes in different clinical conditions, and also with different physicochemical properties to facilitate the obtaining of various forms with similar mechanisms of action.

BRIEF DESCRIPTION of the INVENTION

[0007] Metered shapes and compositions presented here are consistent with these objectives.

[0008] In some aspects of dosage form or pharmaceutical composition comprises a therapeutically effective amount of compounds having structural formula IV:

where n repre�ulation of a nonnegative integer;

where each Z is an oxazolidinone-containing fragment with antibiotic activity in vivo upon cleavage,

where M independently represents an OR1or NR1R2;

where R1and R2are independently selected from the group consisting of H, an optionally substituted hydrocarbon residue that may contain one or more heteroatoms, or a pharmaceutically acceptable cation.

[0009] In some embodiments, each Z dosed forms or pharmaceutical compositions described herein represents:

where * represents the point of attachment to Z P;

where R1a and R2b each independently selected from H and F, provided that at least one of R1a and R2b represents F, and

Het represents an optionally substituted five - or six-membered heterocycle containing at least one N, O or S atom.

[0010] In some embodiments, the compound in dosage form or composition described herein has the structure:

where M represents a OR1and R1represents a pharmaceutically acceptable cation, such as nitrogen-containing cation, e.g., imidazolium cation. In some AC�the projects of these embodiments of the invention each Z represents:

or

[0011] a dosage form or pharmaceutical composition may also contain pharmaceutically acceptable carrier, diluent or excipient.

[0012] In some embodiments, each Z in the compound in dosage form or pharmaceutical composition has R stereochemistry, for example, each Z represents:

.

[0013] In some embodiments, the compound in dosage form or pharmaceutical composition is:

In some aspects Het represents tetrazolyl.

[0014] Some embodiments of the also include the methods for obtaining compounds in dosage form or pharmaceutical composition described herein, comprising the step of processing the compound of formula Z-H fosforiliruyusciye agent such as POCl3.

[0015] Some embodiments of the invention include methods for obtaining compounds described herein, in dosage form or pharmaceutical composition, comprising the step of processing dehydrating agent connection Z-P', where P' represents a mono - or divodorod phosphate group.

[0016] embodiments of the invention also include methods and application d�I the treatment of bacterial infection comprising administering a metered form or pharmaceutical composition described herein to a subject in need of treatment.

[0017] These and other embodiments of the invention described in detail below.

BRIEF DESCRIPTION of FIGURES

[0018] Figure 1 shows a graph of the pharmacokinetics of a compound of Formula IV (as illustrated in Example 2), when injected or administered orally or intravenously, showing how the concentration of the prodrug of Formula IV and the active antibacterial agent Formula 1A.

[0019] Figure 2 is a graph of the pharmacokinetics of a compound of Formula III (as illustrated in Example 1) when injected or administered orally or intravenously, showing how the concentration of the prodrug of Formula III and the active antibacterial agent Formula Ia.

[0020] Figure 3 shows a graph of the in vivo effectiveness of the compounds of TR-701 and dimer of Formula IV with 24 - and 48-hour intervals at different dose levels in accordance with Example 5.

[0021] Figure 4 is a graph showing the effectiveness of the compounds of TR-701 and dimer of Formula IV against Staphylococcus aureus (Staphylococcus aureus) in vivo at 24 - and 48-hour intervals at different dose levels in accordance with Example 5.

DETAILED DESCRIPTION of PREFERRED embodiments of the INVENTION

[0022] In some embodiments of the invention presented�hree new connections prodrug, possess antibiotic activity, and pharmaceutical compositions containing the compounds, and methods for their preparation and use. In some embodiments, compounds are prodrugs that are cleaved after the introduction with the release of the active oxazolidinones metabolite in vivo. In some embodiments, the compound has the structure of Formula IV:

where n is a nonnegative integer;

where each Z is oxazolidinedione fragment having antibiotic activity in vivo upon cleavage,

where M independently represents an OR1or NR1R2;

where R1and R2are independently selected from the group consisting of H, an optionally substituted hydrocarbon residue that may contain one or more heteroatoms, or a pharmaceutically acceptable cation.

[0023] In some embodiments, the compound is in a pharmaceutical composition or dosage form, where the pharmaceutical composition or dosage form contains a number of compounds for antibiotic treatment or prophylaxis.

[0024] In some embodiments, oxazolidinedione FR�gment Z has the structure:

where * represents the point of attachment to Z P;

where R1a and R2b each independently selected from H and F, provided that at least one of R1a and R2b represents F, and

[0025] Het represents an optionally substituted five - or six-membered heterocycle containing at least one N, O or S atom, such as tetrazolyl or oxadiazolyl.

[0026] In some aspects, R1a represents F and R1b represents h, and Het represents a 2-methyl-tetrazol-5-yl. For example, in some embodiments, Z is:

or

[0027] In some aspects, the active metabolite obtained after cleavage in vivo Z of a fragment of the compounds described herein. For example, an active metabolite may have the following formula:

.

[0028] In some embodiments, an active drug of Formula I is (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(gidroximetil)-2-oxazolidinone, i.e.:

,

[0029] These active compounds are described in WO 05/058886 and patent publication US No. 20070155798, methods of obtaining these and related compounds is described in application for U.S. patent 1/577,089 (filed October 9, 2009), and crystalline form of the phosphate ester and the corresponding salts of the above compounds in the patent application U.S. 12/699,864 (filed February 3, 2010). The last two requests belong to the same owner as that of the present application. Each sipoc cited here is listed here for reference in its entirety.

[0030] Compounds of Formula IV may appear in the form of impurities, together with other impurities in the process of phosphorylation of the active metabolite oxazolidinones antibiotic (e.g., Formula I). Thus, these "impurities" may not be considered for use as medicines. As an illustration phosphorylation of Formula I forms a phosphate divodorod of monoether a prodrug of the Formula II:

,

where M is represented here, for example, the compound with the following formula:

[0031] Similarly, in this illustration, the phosphorylation of compound Ia (TR-700) gives the phosphate divodorod of monoether Formula IIa, [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-5-oxazolidinyl]methyl]phosphate:

.

[0032] Optionally, salts of the Formula II, such as the disodium salt of the Formula IIA, can also be obtained, for example Formula IIb below:

.

[0033] Examples of impurities that may happen during the phosphorylation of the active metabolite oxazolidinones antibiotic includes a compound of Formula III (bis - compounds):

such as phosphate monosodium diester (where M=HE), where Z represents:

and

where * represents the point of attachment of Z to R.

By-products can also include a compound of Formula IV:

where n is a nonnegative integer such as 0, 1 or 2. In some embodiments, n is 0 and has the following formula:

where Z is as defined above, for example, diphosphate divodorod the diester of Formula I (where M=IT).

[0034] In some embodiments of Formula IV is an acid or acid derivative, such as salt, ester or amide. In some embodiments, M represents, independently OR1or NR1R2; where R1and R2independently selected from the group consisting of H, an optionally substituted hydrocarbon residue that may contain one or more heteroatoms, pharmaceutically acceptable cations and positively charged nitrogen-containing ion. In some embodiments, the presence of M may not significantly disturb the antibiotic activity of the active �of metabolite of a compound of Formula IV. However, in some embodiments, the presence of M can alter the degree of antibiotic activity.

[0035] In some embodiments, an optional Deputy hydrocarbon residue of the above may not significantly disturb the antibiotic activity of the metabolite of a compound of Formula IV. In some embodiments, the Deputy can alter the degree of antibiotic activity. Antibiotic activity can be measured in various ways known in the prior art, in a murine model of septicemia described in Example 5.

[0036] As used here, the term "hydrocarbon residue" refers to a residue that contains only carbon and hydrogen. The residue may be aliphatic or aromatic, linear, cyclic, branched, saturated or unsaturated. Hydrocarbon residue, where specified, may contain heteroatoms, in addition to carbon and hydrogen in the substituent. In this case, when separately stated that the residue contains heteroatoms such, a hydrocarbon residue may also contain carbonyl groups, amino groups, hydroxyl groups and the like, or contain heteroatoms in the main chain of the hydrocarbon radical. In some embodiments, a hydrocarbon residue, with�holding With 1-20, has 0-5 heteroatoms selected from O, S and N.

[0037] As used here, the term "alkyl", "alkenyl" and "alkynyl" includes linear or branched chain and cyclic monovalent substituents. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylmethyl, 2-propenyl, 3-butenyl and the like. Typically, the alkyl, alkenyl and alkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl), such as 1-6C (alkyl), 2-6C (alkenyl or alkynyl) or 3-6C cycloalkyl. Heteroalkyl, heteroalkyl and heteroalkyl determine also, they can only contain 1-2 O, S or N heteroatom, or combinations thereof in the main chain of the residue.

[0038] As used here, the term "acyl" encompasses the definitions of alkyl, alkenyl, alkynyl and related hetero-forms which are attached to an additional residue through a carbonyl group.

[0039] the "Aromatic" fragment refers to monocyclic or condensed bicyclic fragment, such as phenyl or naphthyl; "heteroaromatic" fragment also refers to monocyclic or condensed bicyclic ring system, containing one or more heteroatoms selected from O, S and N. the Introduction of a heteroatom covers both 5-membered rings and 6-membered rings. Thus, typical aromatic systems include pyridyl, pyrimidyl, indole, Ben�imidazolyl, benzotriazolyl, ethenolysis, chinoline, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, oxadiazolyl and the like. Any monocyclic or condensed ring system, which has the characteristics of aromaticity in terms of electron distribution in the ring system is included in this definition. Typically, the ring system contains 5 to 12 atoms in the ring.

[0040] similarly, "aralkyl" and "heteroaromatic" refers to aromatic or heteroaromatic systems, which is attached to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, typically from 1-6 C. the carbon chain may also contain a carbonyl group, which makes them able to provide substituents acyl fragment.

[0041] Optional substituents may be selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, halo, OR, NR2, SR, -OOCR, -NROCR, RCO, -COOR, -CONR2, SO2NR2, CN, CF3and NO2where each R independently represents H or alkyl (1-4C).

[0042] In some embodiments, M=OR1, R1can be H or a metal cation such as an alkali metal cation or alkaline earth cation�about metal. In some embodiments, the metal cation is a sodium, calcium, potassium, magnesium, aluminum, zinc or lithium cation.

[0043] In some embodiments, where M=OR1, R1may be a positively charged nitrogen-containing group which forms a salt with the negatively charged oxygen of the Formula IV, such as ammonium or Quaternary or positively charged salt of imidazole, N-methylglucamine, choline, piperazine, tromethamine, diethylamine, 4-phenylcyclohexylamine or benzatin. In this context, "Quaternary" refers to the nitrogen atom having four bonds and thus has a net positive charge, such as nitrogen with four groups or connections, for example with one double bond. In some embodiments, the group may represent one or more of hydrogen. In some embodiments, M is an O-imidazolium salt, i.e., O-.

[0044) Pharmaceutically acceptable cations, distinctive features of which are well known in the art, provided in R. Heinrich Stahl and Camille G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002, and L. D. Bighley, S. M. Berge, D. C. Monkhouse, in "Encyclopedia of Pharmaceutical Technology'. Eds. J. Swarbrick and J. C. Boylan, Vol.13, Marcel Dekker, Inc., New ork, Basel, Hong Kong 1995, pp.453-499.

[0045] In some aspects the compound is not a dimer, described in application for U.S. patent No. 12/577,089 (filed October 9, 2009), which has the following structure, or is a pharmaceutically acceptable salt of dimer:

where R1a and R1b each independently can be selected from H and F, provided that at least one of R1a and R1b is not F.

[0046] Het represents an optionally substituted five - or six-membered heterocycle containing at least one atom of N, O or S, for example tetrazolyl or oxadiazolyl.

[0047] In some aspects the compound is not a dimer, described in application for U.S. patent No. 12/699,864 (filed February 3, 2010), i.e.:

[0049] Compounds of Formula IV can be obtained in a variety of ways, including phosphorylation of the active metabolite oxazolidinone-containing antibiotic, for example, the compound of Formula I. When the phosphorylation reaction is carried out with two or more equivalents of the active metabolite, such as a compound of Formula I, the formation of bis-esters, such as compound of the Formula III, is favorable. However, in some embodiments, bis-esters are ineffective antibiotic agents, demonstrating that not all the phosphorus�containing compounds are effective. Thus, in some embodiments, at least two equivalents of the active metabolite, such as a compound of Formula I, is used. Methods of phosphorylation typically cover the use of electrophilic phosphorus (V) containing compounds, such as phosphorus oxychloride POCl3or phosphate in the presence of dehydrating agents, such as carbodiimide, but other methods can be used. For example, compounds of Formula IV can be obtained by transesterification reactions of phosphate ester, such as a diphosphate-ether with an active metabolite, such as a compound of formula I. Such reactions transesterification reactions are well known. Similarly, the compound of Formula IV can be obtained in high yield from oxazolidinones phosphates, such as the monophosphate of the Formula II by treatment with a dehydrating agent such as carbonyldiimidazole (CDI).

[0050] In some embodiments, compounds of Formula IV are valuable in the form of a water-soluble prodrug antibacterial agents oxazolidinones antibiotics such as the compounds of Formula I. In some embodiments, the phosphate dimers of Formula IV have a longer half-life in vivo than oxazolidinedione phosphates, such as the monophosphate of the Formula II. Therefore, in �short embodiments of a compound of Formula IV release of the active metabolites (e.g., Formula (I) for a longer period that extends the in vivo half-life of an antibacterial agent. The longer the half-life increases the period during which an active connection remains above the minimum inhibitory concentration (MIC), and thus improves the effectiveness of the lower dose of medication. A longer half-life also reduces the maximum concentration, Cmaxsome variants of implementation antibacterial agents, reducing, thus, side effects, where Cmaxis a pharmacodynamic factor.

[0051] the person skilled in the art will understand that many of the prodrug, salts, hydrates, solvates and polymorphs can be obtained from the compounds presented herein, and that various substituted with isotopes options (for example, through the substitution of hydrogen for deuterium, carbon13C, nitrogen15N or phosphorus to32P) can also be easily derived. It is implied that all such derivatives are included in the scope of claims in the application.

[0052] In another aspect, the present description relates to pharmaceutical compositions containing one or more physiologically acceptable surface active agents, additional media, diluents, excipients, smoothing agents, suspension agents, film-forming AG�on components and auxiliary agents for the formation of the coating, or combinations thereof and compositions described here. Acceptable additional media or diluent for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), reproduced here for reference in its entirety. Preservatives, stabilizers, colorants, sweeteners, fragrances, flavors and the like can be provided in pharmaceutical compositions. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Additionally the antioxidants and suspendresume agents can be used. In various embodiments, alcohols, esters, sulfate aliphatic alcohols and the like can be used as surface-active agents; sucrose, glucose, lactose, starch, microcrystalline cellulose, crystalline cellulose, mannitol, light anhydrous silicate, sodium aluminate, and metasilicate of magnesium aluminate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose and the like can be used as excipients; magnesium stearate, talc, hydrogenated oil and the like can be used as a smoothing Angora�RH; coconut oil, olive oil; sesame oil, peanut oil, soybean oil can be used as suspension agents or lubricants; phthalate cellulose acetate as a derivative of a carbohydrate such as cellulose or sugar, or methyl acetate - methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents, and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0053] the Term "pharmaceutical composition" refers to a mixture of compounds described herein with other chemical components, such as diluent or additional media. Pharmaceutical composition facilitates the introduction of compounds into the body. Numerous techniques the introduction of pharmaceutical compositions exist in the prior art, without limitation these include oral, injection, aerosol, parenteral and local injection methods. Pharmaceutical compositions can be obtained by the interaction divodorod phosphate free acid with an inorganic or organic base, such as sodium hydroxide or magnesium hydroxide. In some embodiments, pharmaceutically acceptable salts of the compounds described herein (e.g., obtained in situ during sex�termination form for intravenous injection) are presented.

[0054] the Term "carrier" refers to a chemical compound that facilitates the introduction of compounds into cells or tissues.

[0055] the Term "diluent" refers to chemical compounds diluted in water that will dissolve the composition, as well as stabilize the biologically active form of the compound. Salt dissolved in buffer solutions are used as diluents in the prior art. One commonly used buffered solution is phosphate buffer saline because it mimics the salt content of human blood. Since buffer salts can control the pH of the solution at low concentrations, buffer diluent rarely modifies the biological activity of the compounds. As used here, "excipient" refers to an inert substance that is added to the composition to give it the following properties, without limitation, volume, consistency, stability, binding capacity, grease, destroys ability and so on. "Diluent" is a type of excipient.

[0056] the Term "physiologically acceptable" refers to a carrier or diluent, which does not affect the biological activity and properties of the connection.

[0057] the Pharmaceutical composition described herein can be administered to a patient by itself, or in pharmaceutical compositions where they are mixed with other active ingredients in the form of combination therapy, or suitable carriers or excipients. In some embodiments, a dosage form includes forms in which the compound is introduced by itself. Additionally, a dosage form can include a pharmaceutical composition. In any case, a dosage form can contain a sufficient amount of dimer compounds for the treatment of bacterial infection as part of a specific Protocol for the introduction of medications that clear to the person skilled in the art. Technology the establishment and administration of the compounds of the present invention may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0058] Suitable routes of administration may include, for example, oral, rectal, introduction through the mucous membrane, local or intestinal method; parenteral delivery, including intramuscular, intravenous, intramedullary injections, well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compound can be administered in a metered dose forms with prolonged or controlled release, including the injection of substances slow suction, osmotic pumps, pills, transdermal (including electrotransport) plots and the like, for prolonged and/or temporal pulse with a predetermined with�orotu.

[0059] Pharmaceutical compositions of the present invention may be manufactured in known manner, for example using conventional mixing, dissolving, granulating, production drops, grinding into powder, emulsification, encapsulation or tableting.

[0060] Pharmaceutical compositions can be obtained in the usual way using one or more physiologically acceptable carriers comprising eccipienti and auxiliaries, which facilitate the preparation of active compounds for inclusion in a form that can be used pharmaceutically. The composition depends on the selected method of administration. Any of well known techniques, diluents, media and excipients can be used as suitable and understandable, for example, are listed in Remington's Pharmaceutical Sciences, see above.

[0061] the Injectable substances may be produced in conventional form or in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to injection or as emulsions. Suitable excipient represent, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. Additionally, if desired, the injectable pharmaceutical compositions can sod�neigh of a small amount of nontoxic auxiliary substances, such as wetting agents, pH buffering agents and the like. Physiologically compatible buffers include, without limitation, Hanks ' solution (Hanks), a solution of Ringer (Ringer) or physiological salt solution. If desired, absorption enhancing production, can be used.

[0062] For introduction through the mucous membrane, penetrating agents, is required for penetration through the barrier, can be used in forms.

[0063] the Pharmaceutical forms for parenteral administration, for example, bolus injection or continuous infusion, include aqueous solutions of active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds, allowing to obtain highly concentrated solutions. Formulations for injection may be presented in unit dosage form, eg in ampoules or containers containing multiple doses, with added preservative. Compositions may contain such f�PMS in the form of suspensions, solutions or emulsions in oily or aqueous filler, and may contain agents to obtain a composition, for example suspendida, stabilizing and/or dispersing agents. Alternative before applying the active ingredient may be in powder form to obtain a dosage form with a suitable filler, for example a sterile apyrogenic water.

[0064] For oral administration the composition may be composed of a combination of interest compositions and pharmaceutically acceptable carriers well known in the art. Such carriers may be used in addition to the cationic polymeric carrier that gives the opportunity to prepare the compositions according to the invention in the form of tablets, pills, dragees, liquids, gels, syrups, suspensions and the like for oral administration to patients in need for treatment. Pharmaceutical forms for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or nucleoli pills. Suitable excipient represent, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; �ellulose form such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP), for example Povidone. If desirable, dezintegriruetsja agents can be added, such as cross-linked polyvinylpyrrolidone (e.g., Crospovidone), agar or alginic acid or its salt, such as sodium alginate. The nucleolus jelly beans are covered with a suitable membrane. For this purpose, concentrated solutions of sugars can be used, which optionally contain gum Arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the shell of the tablets or dragee for identification or to characterize different combinations of doses of active compounds.

[0065] the Pharmaceutical forms which can be used orally include push-fit capsules (hard capsule two parts) made of gelatin and also soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredients in admixture with filler such as lactose, binders substances�PTO, such as starches and/or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additional stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0066] For buccal administration the compositions may be in the form of tablets or lozenges in the usual way.

[0067] For administration by inhalation, the composition may be delivered in the usual way in the form of an aerosol spray under pressure or a nebulizer, with the use of a suitable propellant, e.g., DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure dosage unit may be determined by the presence of the valve to deliver a fixed number. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may contain a powder mix of the compound and a suitable base, such as lactose or starch.

[0068] Also described herein, various pharmaceutical compositions comprise well known in the pharmaceutical field intraoc�polar, intranasal and intraocular delivery. Suitable penetrating agents for this application are well known in the art. Such suitable pharmaceutical forms and often be preferable that they be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to simulate nasal secretions to ensure maintenance of normal ciliary action. As described in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), reproduced here for reference in its entirety and is well known to specialists in this field, suitable pharmaceutical formulations are most often and preferably isotonic, buffered to maintain a pH of 5.5-6.5, and most often and preferably do contain antimicrobial preservatives and appropriate stabilizers medicines. Pharmaceutical forms for intraarticular delivery include suspensions and ointments for topical application in the ear. The most common solvents for these ear forms are glycerin and water.

[0069] the Composition can also be a rectal compositions such as suppositories or retention enemas, e.g., containing a regular t� basis for suppositories, such as cocoa butter or other glycerides.

[0070] in addition to the forms described previously, the compositions can also be prepared in the form of forms with substances slow suction. Such long acting forms can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be mixed with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ionoobmennymi resins, or sparingly soluble derivatives, for example in the form of a sparingly soluble salt.

[0071] For hydrophobic compounds suitable pharmaceutical carrier may be a system of co-solvents, benzyl alcohol, a nonpolar surfactant (surfactant), water-soluble organic polymer and aqueous phase. A common system is the VPD co-solvents, which contains a solution of 3% W/V benzyl alcohol, 8% weight/volume of the nonpolar surfactant POLYSORBATE 80™, and 65% weight/volume of polyethylene glycol 300, brought to volume with absolute ethanol. Naturally, the proportions of the cosolvent system may change significantly without violating their characteristics of solubility and toxicity. Moreover, the identity component of cosolvent can vary: for example, d�pie low-toxicity surfactants may be used instead of POLYSORBATE 80™; the amount of polyethylene glycol may be changed; other biocompatible polymers can replace polyethylene glycol, e.g. polyvinylpyrrolidone and other sugars or polysaccharides may substitute for dextrose.

[0072] Methods of treating bacterial infections may include the introduction of therapeutically effective amounts of compounds described herein. Treatment bacterial infections may also include prophylactic administration of therapeutic compounds to prevent infection or spread of infection in the patient at imminent risk, for example a patient who just underwent a surgery, or the patient is immunocompromised or the patient at risk if the connection has not been entered. Compounds show inhibitory activity against a broad spectrum of bacteria, against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE) and have relative antibiotic activity with a relatively low concentration or in vivo. Also compounds of the present invention can be potentially antibacterial activity versus various human and animal pathogens, including gram-positive bacteria, such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms, such as bacterium and Clostridia, and acid-resistant organisms�s, such as Mycobacterium tuberculosis and Mycobacterium avium. In one embodiment, a bacterial infection that can be treated or the condition of the patient with this infection can be improved, is a MRSA.

[0073] the Compositions or pharmaceutical compositions described herein can be administered to a patient without the appropriate tools. Examples, not limiting the scope of the claims include, among other things, (a) the introduction of through oral means, when you enter a capsule, tablet, granule, spray, syrup, or other such forms; (b) the introduction of non-oral routes, such as rectal, vaginal, intraurethral, intraocular, intranasal or intraarticularly where you enter the aqueous suspension or oil form or the like, or drops, spray, suppository, lotion, ointment or the like; (C) introducing through an injection, subcutaneously, intraperitoneally (intraperitoneal), intravenously, intramuscularly, intradermally, intraorbitally, intra-articular, intraspinal, intrasternal or the like, including infusion delivery pump; (d) local injection; as is clear to a person skilled in the art for bringing the active compound into contact with living tissue.

[0074] Pharmaceutical compositions suitable for administration include compositions where the active ingredients will not damage�options are present in amounts effective to achieve the stated purpose. In some embodiments, a therapeutically effective amount of compound is an amount effective to treat a bacterial infection, for example, a mammal (human). A therapeutically effective amount of the compounds described herein and required as a dose will depend on the method of administration, the animal species, including humans, which must be subjected to treatment, and specific physical characteristics of the considered animal. The dosage may be selected to achieve the desired effect, but it will also depend on such factors as weight, diet, concurrent medical course and other factors that a person skilled in the art will easily identify. In particular, a therapeutically effective amount means an amount of compound effective to prevent or alleviate the symptoms of the disease or improve the condition or prolong the patient's life. Determination of a therapeutically effective amount is within the capabilities of a person skilled in the art, particularly in light of the detailed description presented herein.

[0075] As is evident to the person skilled in the art, the useful in vivo dosage for administration and the particular mode of administration will vary depending on the age, weight and mammalian species, used with specific�unity and purpose, for which these compounds are used. Determining the level of the effective dose necessary to achieve the desired result, can be carried out by a person skilled in the art using conventional pharmacological methods. Usually clinical trials in humans begin with a low dose, with gradual increase to achieve the desired effect. Alternative acceptable in vivo studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

[0076] In animals (not human) trials of potential products is carried out with doses higher level, with a gradual reduction of the dose to a level that until, until the desired effect is no longer achieved, and the opposite effect will not disappear. The dosage may vary widely, depending on the desired effects and therapeutic purposes. Usually the dosage can be equal to about 10 micrograms/kg to about 100 mg/kg body weight, preferably 100 micrograms/kg to about 10 mg/kg of body weight. The dosage can be based and calculated from the surface area of the patient that is clear to the expert in this field.

[0077] the Exact form, method of administration and dosage pharmaceutical grade�algebraic compositions of the present invention can be selected individually by a medical professional from the point of view of the patient's condition. (See, for example, Fingl and others, 1975, in "The Pharmacological Basis of Therapeutics", which is reproduced here for reference in its entirety, with specific reference to Chapter 1, page 1). Typically, the dose range of the composition administered to a patient may range from 0.5 to 1000 mg/kg of body weight of the patient. The dosage may be single or consist of a series of two or more techniques within one or more days, as needed by the patient. In the case where the dosage for humans has been established, at least for some state, the present invention will use those same dosages, or dosages that ranged from 0.1% to about 500%, more preferably from 25% to 250% of the established human dosage. Where dose for humans has not been established, as is the cases of new pharmaceutical compositions, a suitable human dosage can be chosen from the ED50or ID50values or other appropriate values derived from in vitro or in vivo studies, as determined by toxicity studies and efficacy in animals.

[0078] it Should be noted that the practitioner knows how and when to terminate, interrupt or change treatment because of toxicity or organ dysfunction. On the contrary the practitioner will also know how to change the treatment to higher doses if clinical�ski response is not expected (except toxicity). The magnitude of the input dose will vary depending on the severity of the patient's condition and the method of administration. The severity of the condition may, for example, be partially evaluated, standard prognostic evaluation techniques. Dose and frequency of dose will also vary according to age, body weight and individual response of the patient. A program comparable to that discussed above, can be used in veterinary medicine.

[0079] Although the exact dosage will be determined only depending on the specific drug, in most cases, some General rules regarding the dosage can be formulated. The daily administration to an adult patient may present, for example, an oral dose of from about 0.1 mg to 2000 mg of each active ingredient, preferably from 1 mg to 500 mg, e.g. 5 to 200 mg. In other embodiments, an intravenous, subcutaneous or intramuscular dose of each active ingredient is from about 0.01 mg to 100 mg, preferably from 0.1 mg to 60 mg, e.g. 1 to 40 mg. In the cases of introducing a pharmaceutically acceptable salt dosage can be calculated for free base. In some embodiments, the composition is injected from 1 to 4 times daily. Alternative compositions of the invention can be� introduced continuous intravenous infusion, preferably the dose of each active ingredient up to 1000 mg per day. As is clear to a person skilled in the art, in some situations it is necessary to enter the compounds described herein in amounts that exceed, or even far exceed, the above, preferred dosage range to effectively and rapidly cure a specific disease or infection. In some embodiments, compounds will be administered within a period of continuous therapy, for example in the course of a week or more or months or years.

[0080] the Amount and interval may be adjusted individually to provide plasma levels of the active segment, which are sufficient to maintain the modulating effects, or minimal effective concentration (MONTHS). MONTH will vary for each compound but can be estimated from in vitro data. The dose required to achieve MONTHS, will depend on individual characteristics and route of administration. However, HPLC studies or bosslaguna can be used to determine plasma concentrations.

[0081] the dosage Range may also be defined using the value of the MONTH. Compositions should be administered using a regimen, which maintains the levels in plasma above MONTHS within 10-90% of the time, preferably �between 30-90% and most preferably 50-90%.

[0082] In cases of local administration or selective consumption of an effective local concentration of the drug may not be related to plasma concentration.

[0083] the Amount of the composition administered may depend on the patient, from the patient's weight, severity of infection, the mode of administration and appointment prescribed by doctors.

[0084] the Compositions described herein may be assessed for efficacy and toxicity using known methods. For example, toxicology connections can be established by determining in vitro toxicity towards a cell line, e.g., mammalian, or preferably human. The results of these studies often predict toxicity in animals, such as mammals or, in particular, in humans. Alternative toxicity of specific compounds on animal models such as mice, rats, rabbits, or monkeys, can be determined using known methods. The effectiveness of a particular connection can be established using a variety of recognized methods such as in vitro methods, animal models or clinical studies in humans. Recognized in vitro models exist for nearly every class of States. In a similar manner acceptable animal models can be used to ascertain the effectiveness of chemical compounds for l�treatment of such conditions. When choosing a model to determine the effectiveness of the specialist will be able to follow the state of the prior art to select the appropriate model, dose, and route of administration, regime. Of course, clinical trials on humans can be used to determine the effectiveness of compounds in humans.

[0085] the Compositions, if desired, can be presented in a pack or dispenser, which may contain one or more dosage form with the active ingredient. A package may contain, for example, metal or plastic foil, such as blister packaging. The pack or dispenser may contain instructions for administration. The pack or dispenser may also include a notice associated with the container in form prescribed by a governmental Agency regulating the manufacture, use or sale of drugs, this notice reflects approval of the form of the medicinal product for administration to humans or its use in veterinary medicine. Such notice, for example, may be the labeling approved by the U.S. Administration on supervision in the sphere of medicines and food products, or the approved product insert. The compositions containing the compound according to the invention, with a compatible pharmaceutical carrier may also be obtained, placed in a suitable container and m�Kirovka for the treatment of this condition should be applied.

[0086] In some embodiments, the pharmaceutical industry is considered standard practice to use mostly clean material in obtaining pharmaceutical compositions. Thus, in some embodiments, the "mostly clean" refers to the degree of purity required for the production of dosage forms, which may include, for example, a small amount of amorphous material or another material, where the material can still achieve a significant degree of fluidity, lack of hygroscopicity and purity suitable for pharmaceutical applications. In some embodiments, preferably pure compound contains at least about 96% of the compound by weight, for example at least, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100% connection.

[0087] the Terms "approximately, "about" and "substantially" when used here to specify the number, closest to the claimed, which is still running the desired function or achieves a desired result. For example, the terms "approximately, "about" and "substantially" may refer to a quantity that is different from the claimed value� within less than 10%, less than 5%, less than 1%, less than 0.1% and less than 0.01%.

Examples

Example 1. Obtaining phosphate monosodium diester of the Formula III

[0088] In this and the following examples, "Formula III" refers to a compound wherein Z represents:and M=IT.

[0089] a 1-liter, three-neck round bottom flask equipped with a magnetic stirrer, inlet/outlet for nitrogen and a thermocouple was loaded compound of Formula Ia, is presented below (16.0 g, 0.0499 mol), THF (320 ml, 20 volumes) and Et3N (21.9 g, 0.216 mol, 5.0 equivalents):

[0090] POCl3(3.31 g, 0.0216 mol, 0.5 equivalents) was added dropwise via syringe over 5 minutes. Reaction temperature was maintained below 25°C. the Mixture was left for 16 hours at room temperature, then HPLC analysis (XBridge, C18) showed that the reaction was completed. The reaction vessel was then immersed in an ice bath, 500-ml dropping funnels with 320 ml of N2Oh was attached to the reaction vessel. When the reaction temperature reached 2.7°C, H2O was added dropwise over 30 minutes. Reaction temperature was maintained below 10°C. Upon completion of addition of H2O ice bath was removed and the mixture is left for 3 hours. The solution was transferred to a 2-liter round bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of ballinstadt from solution aqueous mixture was extracted 5 1-liter portions of CH 2C2:MeOH (9:1). Layers of CH2Cl2were combined and concentrated to a dark oil. This material was purified on 200 g of silica gel, eluent 10% MeOH/CH2Cl2up to 20% 2 n NH] in MeOH/CH2Cl2. The fractions containing most of bis-ether (assessed by TLC Rf=0.3 eluent 20% 2 n NH] in MeOH/CH2Cl2), were combined and concentrated under reduced pressure on a rotary evaporator, the resulting white precipitate was formed. The flask containing the suspension was removed with a rotary evaporator equipped with a magnetic stirrer and then left to stir with cooling to room temperature for 3 hours, during this time, the suspension has thickened. The precipitate was filtered and dried in a vacuum oven at 45°C for 16 hours to obtain 3.55 g of bis-ether in the form of a grayish-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. the reaction was repeated and the United party of a compound of Formula III (6.7 g) were suspended in 100 ml MeOH (15 volumes). The suspension was heated to 40°C for 30 minutes and then allowed to cool to room temperature for 1 hour. Grayish-white solid residue was filtered and dried in a vacuum oven at 40°C for 16 hours to obtain 6.15 g of a compound of Formula III (92% yield).1H NMR analysis of the product complies with the stated structure. HPLC analysis (Method A): 99.0% (AUC), tR=1.3 min.

Example 2. Obtaining a diester divodorod phosphate, Formula IV

[0091] In Examples 2-5 "Formula IV" refers to a compound wherein Z represents:, n=0 and M=O-imidazolium salt.

[0092] In a 250-ml three-neck round bottom flask equipped with a magnetic stirrer, inlet/outlet for nitrogen and a thermocouple was loaded compound of the Formula IIA, is presented below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equivalents) and DMF (100 ml, 20 volumes):

[0093] the Suspension was heated at 50°C and maintained at this temperature for 4 hours, at this point HPLC analysis (XBridge, 18) showed that the reaction was completed. The reaction mixture was filtered at 50°C and dried in a vacuum oven at 50°C for 24 hours to obtain 5.15 g of imidazolium salt (i.e. compound of Formula (IV) in the form of a grayish-white solid precipitate (98% yield).1H NMR analysis of the product corresponds to the claimed structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min (see tab. 1):

Table 1
Method A (Waters XBridge C18 Column)
Time (min)Speed (ml/min)%%
0.01.098.02.0
15.01.05.095.0
25.01.05.095.0
27.01.098.02.0
30.01.098.02.0
A = 87% 25 mm solution of ammonium bicarbonate in water/13% acetonitrile
B = Acetonitrile
Wavelength = 300 nm

Example 3. Pharmacokinetic studies

[0094] Female Balb/c (white laboratory mice, 6-7 weeks of age (~20 g) were randomly divided into groups of three animals. The pharmacokinetics of each of the tested compounds was evaluated. Test compounds (10 mg/kg) were injected via the tail vein or oral study in mice. Blood was sampled via puncture of the heart 5 (only for intravenously administered compounds), 15, 30 minutes and 1, 4, 6, 8, 12 and 24 hours (n=3 at each time point). Plasma concentration of each of SOEDINENIYa Ia, III (as defined in Example 1), and IV (as defined in Example 2) was analyzed by using approved HPLC/UV method. Data are presented on the Figure 1 and Figure 2 (see tab. 1-4):

Table 2
Pharmacokinetic data for both the prodrug and active components, when the prodrug of Formula IV (as defined in Example 2) and Formula III (as defined in Example 1) was injected into mice
Entered connectionMeasured connectionRsqτ1/2(h)Tmax(h)Cmax(ág/ml)AUC0-24h(µg h/ml)Vzobs(L/kg)CLobs(L/h/kg)
intravenous Formula IV 10 mg/kgFormula IV1.000.770.084.307.00 1.531.39
intravenous Formula IV 10 mg/kgFormula Ia0.973.744.004.0636.401.460.27
Oral Formula IV 10 mg/kgFormula Ia0.993.896.001.7018.33.010.54
intravenous Formula III 10 u mg/kgFormula III0.933.050.085.791.1433.437.61
intravenous Formula III 10 10 mg/kgFormula Ia 0.5812.044.000.171.1648.652.80
Table 3
Pharmacokinetic data for related prodrug of Formula IV (as defined in Example 2). and for the active antibacterial agent Formula Ia, when the compound of the Formula IV or administered orally or intravenously in an amount of 10 mg/kg (all concentrations in ng/ml).
Time (hour)Oral method Formula Ia conc.Oral method Formula IV conc.Intravenous method Formula Ia conc.Intravenous method Formula IV conc.
0.08NDND984.414300
0.25381.22ND 1439.021515
0.5821.29ND1588.673450
11053.56ND2692.212661
41520.58ND4059.94157
61697.18ND2341.86ND
81029.09ND896.47ND
12667.74ND1385.48ND
2465.26ND84.06ND
ND: Not detected, because the number of compounds below detection limits.
Table 4
Pharmacokinetic data for related prodrug of Formula III (as defined in Example 1). and for the active antibacterial agent Formula Ia when prodrug Formula III (as defined in Example 1) administered intravenously in an amount of 10 mg/kg (all concentrations in ng/ml)
Time (h)Intravenous Formula III conc.Intravenous Formula la conc.
0.085794.47Is at 124.18
0.25749.0278.46
0.5210.06 90.85
181.05123.76
253.78167.77
4Is at 39.49174.61
6ND131.45
8ND138.71
ND: Not detected, because the number of compounds below detection limits.

Example 4. The determination of the minimum inhibitory concentration

[0095] the Minimum inhibitory concentrations were determined by microdolly nutritional micro-environment in accordance with the methods (M7-A7), approved by the Institute for Clinical and Laboratory Standards (CLSI), and interpreted using the Alamar Blue to visualize cell viability of the cell. Diluzio each of the compounds were tested against S. aureus (Staphylococcus aureus) strain Smith or S. aureus plus 20% of the murine savor�TKA (see tab.5):

Table 5
MIC results (in µg/ml)
S. aureus SmithS. aureus Smith + 20% mouse serum
Formula IIb (TR-701)>644
Formula III (as defined in Example 1)>64>64
Formula IV (as defined in Example 2)>6432

Example 5

Test efficiency: a murine model of septicemia

[0096] Female Balb/c (white laboratory mice, 6-7 weeks of age (~20 g) were randomly divided into groups of 10 animals. Staphylococcus ayreus strain Smith of ATS# 13709 was cultured overnight in BHI medium (cardio-cerebral extract) at 37°C. Cells were again diluted 1:10 and left to grow for 5 hours. Inoculum used to infect mice, was obtained by dilution of culture in 5% porcine gastric mucus/phosphate buffer solution to a concentration of 1×106CFU/ml 100 ál of culture/mucus was� saved to calculate an initial CFU/ml by serial dilution and cultivation of culture. Mice were infected with 500 μl of inoculum before drug administration. Drugs were injected 15 minutes after infection.

[0097] Mice received an intravenous dose of each of the test compounds at the concentrations presented in Tables 6 and 7, based on calculated average weight of all mice (~20 g). 48 hours after infection, the number of surviving mice was determined.

Table 6
The survival of female white mice Balb/c, intravenous. 200 μl dose of a compound of Formula III (as defined in Example 1), 10 mice were treated in each group.
GroupTreatmentConcentration, mg/kgConcentration, mg/m248 h survival
1Formula III100.21/10
2Formula III50.11/10
3FD�mule III 2.50.050/10
4Formula III1.250.0251/10
5infection control-1/10

[0098] the Data in Table 6 indicate that the compound of Formula III is ineffective as an antibiotic, because the surviving mice were similar to control infections, thus, it was demonstrated that not all phosphate-containing compounds are effective.

Table 7
The survival of female white mice Balh/c, intravenous injection, 200 μl dose of a compound of Formula IV (as defined in Example 2), 10 mice were treated in each group
GroupTreatmentConcentration mg/kgConcentration mg/m248 h survivalGroup
1Formula IV100.210/1010/10
2Formula IV50.110/1010/10
3Formula IV2.50.058/107/10
4Formula IV1.250.0255/102/10
5infection control-2/101/10

[0099] the Data presented in Table 7, show 100% (10/10), the degree of survival after 24 - and 48-hour interval at doses of 10 and 5 mg/kg. without pretending to any theory, it can be noted that, apparently, the presence of additional phosphate in the Formula (IV increases the space between Z fragments in comparison with the Formula III, allowing the phosphatase to phosphate release more easily. So�way, it is expected that the presence of additional phosphate groups between Z fragments would act as the diphosphate.

Table 8
Comparison of survival of female white mice Balb/c, intravenous administration of a compound of Formula IV (as defined in Example 2) and salts disodium phosphate Formula Ia (TR-701), a dose of 200 µl, 10 mice were treated in each group
Concentration, mg/kg% Survival - 10 mice per group
201052.51.25infection control
24 h TR701100100906060
24 h dimer1001008050
0 treatment20
48 h TR701100100904050
48 h dimer1001007020
0 treatment 4810

[0100] the same procedures were used as in the description of the Verification of the Effectiveness of Example 5. The data in table 8 demonstrate that the level of unexpectedly increased survival when administered intravenously, the compound of formula IV (as defined in Example 2) in comparison with TR-701 (salt disodium phosphate Formula Ia) in quantities of 5 and 2.5 mg/kg, as shown in Table 8.

1. Pharmaceutical composition comprising a therapeutically effective amount of the compounds having the following structure:

where each Z n�ecstasy:

where * is the connection point Z with P;
where M represents a ORl;
where Rla and Rlb independently from each other are selected from H and F, provided that
at least one of Rla and Rlb represents F; and
where Rlrepresents H or a pharmaceutically acceptable cation.

2. The pharmaceutical composition according p.. 1, in which Rlis a pharmaceutically acceptable cation.

3. Pharmaceutical composition according to claim 2, in which Rlis a cation of sodium.

4. Pharmaceutical composition according to claim 1, in which each Z represents:

5. Pharmaceutical composition according to claim 4, in which each Z represents:

6. Pharmaceutical composition according to claim 1, further comprising pharmaceutically acceptable carrier, diluent or filler.

7. Pharmaceutical composition according to claim 5, in which Rlis a cation of sodium.

8. Pharmaceutical composition according to claim 5, in which Rlrepresents N.

9. Pharmaceutical composition according to claim 1, in which the specified connection is:

or its pharmaceutically acceptable salt.

10. Pharmaceutical composition according to claim 9, in which the decree�TES the connection is:

or its pharmaceutically acceptable salt.

11. A method of producing compound in the pharmaceutical composition according to claim 1, comprising the step of processing compounds having the structural formula Z-H, fosforiliruyusciye agent
where Z is H is:

where Rla and Rlb independently from each other are selected from H and F, provided that at least one of Rla and Rlb is an F.

12. A method of producing compound in the pharmaceutical composition according to claim 1, comprising the step of processing compounds having the structural formula Z-P', a dehydrating agent, where Z Is P' is:

where R' represents a mono - or divodorod phosphate group; and
where Rla and Rlb independently from each other are selected from H and F, provided that
at least one of Rla and Rlb is an F.

13. A method according to claim 11, in which fosforiliruyusciye agent represents ROS3.

14. A method of treating a bacterial infection, including the appointment of a pharmaceutical composition according to claim 1 to the needy in this patient.

15. A method of treating a bacterial infection, including the appointment of a pharmaceutical composition according to claim 9 to the needy in this patient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula

,

or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.

EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).

32 cl, 86 tbl, 387 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine, represented by the general formula : where X=O or S, Ar=3-nitrophenyl or 2-thienyl. The described method consists in the fact that at the first stage 5-brom-4-(2-thienyl)-2-(thio)morpholylpyrimidine is obtained by interaction with the excess of 2-thienyllithium in the absolute ether at first at a temperature from -20 to -25°C for not less than 1 hour, and then at room temperature for not less than 18 hours, a solution of a mixture of potassium hexacyonoferrate (III) and potassium hydroxide in water are added with further mixing for 4 hours at room temperature, the ether phase is separated and distilled and the obtained remaining part is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate-hexane, 1:3, with (het)arylboric acid and tetrakis(triphenyphosphine)palladium(0) in tetrahydrofurane, a water solution of potassium carbonate is added and the obtained mixture is irradiated by microwave radiation at 155°C for 20 minutes, the solvent is distilled under a reduced pressure, the obtained residual is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate - hexane, 1:2 with obtaining the target product.

EFFECT: claimed is the highly-efficient two-stage method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidines, which can have a wide spectrum of biological activity.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to veterinary science and is applicable for treating bovine mastitis. What is declared is a nosode for producing a preparation for treating bovine mastitis. That involves taking mastitis milk 1 ml with clinical signs of purulent-catarrhal mastitis, filling it 70° alcohol 9 ml to produce a homogenous solution; the produced solution is diluted to "Д6" with 70° alcohol. What is also declared is a preparation for treating bovine mastitis containing an aqueous-alcoholic solution of components. The components are Belladonna, Sulphur, Apis mellifica, Conium, Phytolacca, Silicea and above nosode in the following proportions, wt %: Belladonna - 5, Sulphur - 20, Apis mellifica - 20, Conium - 10, Phytolacca - 10, Silicea - 5, nosode - 15, aqueous-alcoholic solution up to 100%. What is also declared is a method of treating bovine mastitis involving the intracisternal administration of the preparation. The preparation is administered in a dose of 5-10 ml per 1 animal once a day.

EFFECT: declared group of inventions is highly effective in treating bovine mastitis.

3 cl, 5 tbl, 1 ex

Antimicrobial agent // 2556509

FIELD: medicine.

SUBSTANCE: compound 2-(1'-hydroxy-4'-isopropenyl-1'-methylcyclohexyl-2'-thio)-methylethanoate having structural formula I: is applicable as an antimicrobial agent.

EFFECT: using the compound of formula I possessing antimicrobial activity provides treating infectious processes caused by susceptible organisms.

5 tbl

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to field of veterinary. Claimed are: vaccine, aimed against actinobacillous pleuropneumonia, including lipopolysaccharide in complex with one or more repeats of ApxI, ApxII and ApxIII toxins, separated from bacterial culture and polymyxin to reduce symptoms of endotoxic shock, caused by lipopolysaccharide, method of obtaining such vaccine, application of polymyxin to reduce endotoxic shock symptoms when vaccine is introduced, in which polymixyn is added into vaccine in dose from 2.6 to 60 mcg/ml.

EFFECT: claimed group of inventions provides effective means and methods to reduce endotoxic shock symptoms, caused by lipopolysaccharide, when vaccine against actinobacillous pleuropneumonia is introduced to animal.

14 cl, 4 tbl, 4 ex

FIELD: veterinary medicine.

SUBSTANCE: complex antibacterial agent for animals, containing a compound from the group of fluoroquinolones and auxiliary substances, characterised in that it additionally comprises a compound from the group of pleuromutilins in an effective amount.

EFFECT: invention is effective against vegetative and spore forms of bacteria, it is harmless, has no allergenic properties, has a stimulating effect on the indices of humoral immune response, and is stable during storage.

6 cl, 9 ex

FIELD: veterinary medicine.

SUBSTANCE: agent comprises enrofloxacin and excipients. The agent additionally comprises humates of peat or sapropel, with the following ratio of the components, wt %: enrofloxacin substance - 0.5; alkaline solution of humates (pH=12-13) - 80; succinic acid - to pH 10-11; propylene glycol - the rest. The agent is administered with the liquid feed once a day for three to five days at a dose of from 0.5 to 1.0 ml per 1 kg of body weight.

EFFECT: manifestation of pronounced therapeutic effect.

5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 7-hydroxyroyleanon, possessing antimicrobial action. said method includes extraction of crushed roots of salvia officinalis with 96% ethyl alcohol with further extract evaporation, processing with water, alcohol distillation and processing with hydrophobic solvent or extraction of said raw material with chloroform with further extract processing with water and evaporation; after which target product is extracted from organic phase by transfer into water-soluble phenolates, with processing with sodium hydroxide water solution; alkali solution is washed with chloroform; acidified with hydrochloric or sulphuric acid; obtained sediment is filtered; dried and crushed.

EFFECT: invention is characterised by improved process manufacturability and provides obtaining individual substance with higher antimicrobial activity than previously extracted royleanon derivatives from salvia officinalis.

2 tbl, 6 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to a strain of the pathogen of pseudomonosis of pigs of the collection of Federal state budgetary institution "VGNKI", deposited under the name "Pseudomonas aeruginosa No.9" and the registration number "No.9-DEP", intended for production of a vaccine against pseudomonosis of pigs.

EFFECT: invention provides high immunogenic activity and the ability of production of the vaccine against pseudomonosis of pigs.

4 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to clinical microbiology and antimicrobial chemotherapy, and concerns developing and creating new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection caused by methicillin-resistant S. aureus by using two classes of compounds possessing the essentially different mechanism of antimicrobial action.

EFFECT: developing and creating the new combinations providing potentiating bactericidal action and effectively inhibiting the purulent infection.

2 dwg, 6 tbl

FIELD: medicine.

SUBSTANCE: drops possessing antiviral and immunomodulatory effects characterised by the fact that they represent a 95% ethanol infusion of wild strawberry leaves and fruit specified in: red raspberry fruit, mountain ash fruit, bilberry fruit, blood-red hawthorn fruit, cinnamon rose fruit; 15-25 mg of the substance in 1 ml of the infusion.

EFFECT: drops possess pronounced antiviral and immunomodulatory effects.

15 tbl, 5 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to polymer ketimine derivatives of doxycycline, which are obtained by condensation of doxycycline hydrochloride with cationic copolymers of acrylamide with 2-ammine-ethyl methacrylate (MW=16-20 kDa) with a molar ratio of copolymer/antibiotic equal to 1.1-2.0/1 in aqueous solution with pH 8.0 at 23°C. where: m=(78.0-80.0) mol %; n=(10.0-14.0) mol.%; k=(6.0-12.0) mol %.

EFFECT: polymer ketimine derivatives of doxycycline, which are non-toxic and combine the antimicrobial and immunosuppressive properties.

2 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: early postoperative period involves administering low-molecular heparins and anti-inflammatory agents. Anti-inflammatory therapy requires administering cycloferon according to the schedule: 2 tablets of cycloferon 0.15 mg on the first preoperative day, 2 tablets on the first postoperative day, 2 tablets in the morning on the 2nd, 4th, 6th postoperative day, and further, every third day throughout 1 postoperative month (on the 9th, 12th, 15th, 18th, 21st, 24th, 27th, 30th day).

EFFECT: method provides the effective prevention of postpericardiotomy syndrome with a lower risk of side effects by administering cycloferon according to the developed schedule requiring non-steroidal anti-inflammatory agents and glucocorticosteroids.

2 ex, 3 tbl

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