Method for preparing 4''-substituted derivatives of 9-deoxo-9a-aza-9a-homoerythromycin a

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: derivative of 9-deoxo-9a-aza-9a-homoerythromycin A of the formula (3) wherein R4 represents hydroxyl protecting group is prepared by protection of 2'-hydroxy-group of compound of the formula (5) to form compound of the formula (4)

and by oxidation of C-4''-hydroxy-group of compound of the formula (4) that is carried out by addition of dimethylsulfoxide to solution containing compound of the formula (4) and a solvent followed by cooling the mixture up to about -70°C, activation of dimethylsulfoxide in situ and defoaming the reaction mixture. Compound of the formula (4) is converted to the oxidation stage directly without its isolation. Also, invention proposes additive salt of trifluoroacetic acid of compound of the formula (3) and a method for its preparing by treatment of compound of the formula (3) with trifluoroacetic acid. Invention provides increasing yield and improving purity of the end product.

EFFECT: improved preparing method.

11 cl, 6 ex

 

BACKGROUND of INVENTION

The invention relates to methods for C-4"-substituted derivatives of 9-deoxo-9a-Aza-9a-homoerythromycin And (hereinafter "the azalides(s)"), which are useful as antibacterial and Antiprotozoal agents in mammals, including man, as well as fish and birds. This invention relates also to methods for stable intermediates considered azalides, and the crystalline salt of the intermediate product in the process for consideration of azalides. This invention relates also to pharmaceutical compositions containing the new compounds obtained by the considered methods, and to methods for treating bacterial infections and protozoal infections in mammals, fish and birds by the introduction of new compounds obtained by the considered methods, mammals, fish and birds in need of such treatment.

It is known that macrolide antibiotics are useful for treating a wide spectrum of bacterial infections and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A, such as azithromycin, which is commercially available and is referred to in U.S. patent 4474768 and 4517359, both of which are included in the description by reference in their entirety. Podobnestrony and other macrolide antibiotics, macrolide compounds of the present invention possess strong activity against various bacterial infections and protozoal infections, as described below.

Getting considered azalides on a commercial scale has some difficulties, including, but not limited to, low outputs and the instability of some synthetic intermediates, as well as the presence of undesirable impurities.

SUMMARY of INVENTION

The present invention relates to a method for obtaining compounds of formula 1

or its pharmaceutically acceptable salt, which includes:

the interaction of the compounds of formula 2

with an amine of the formula HNR8R15in an organic solvent containing isopropanol; where the interaction is carried out at a temperature of at least about 40°C;

where:

R3is CH2NR8R15;

R8is1-C10-alkyl and

R15represents N or C1-C10-alkyl.

In a preferred embodiment of the method, R8is propyl and R15represents N. In a particularly preferred embodiment, R8represents n-propyl and R15represents N. In especially predpochtitel the om embodiment, the organic solvent is isopropanol.

Another preferred variant implementation of the invention relates to a method for obtaining compounds of formula 1A or its pharmaceutically acceptable salt

the interaction of the compounds of formula 2 with n-Propylamine in an organic solvent containing isopropanol; where the interaction is carried out at a temperature of at least about 40°C. In a particularly preferred variant implementation of the organic solvent is isopropanol.

It should be noted that when used herein, the terms "solution" and "mixture"unless otherwise stated, are used interchangeably without regard to the state of dispersion of their components. The phrase "organic solvent containing the isopropanol used in the description, unless otherwise stated, means a non-aqueous solvent or mixture of non-aqueous solvents, where at least one solvent is isopropanol. In this application, the term "compound of formula 1" includes the compound of formula 1 and the compound of formula 1A. The compound of formula 1A is particularly preferred compounds of formula 1, for which use all of the embodiments and preferred embodiments described here.

In the embodiment described here the rate the temperature is lower than approximately 95° With, and in the preferred embodiment, the temperature is lower than about 80°C. In a more preferred embodiment, temperature is from about 50°With up to approximately 76°C. In a particularly preferred embodiment, temperature is from about 50°C to about 55°C.

In the preferred embodiment described here the interaction is carried out at approximately atmospheric pressure. In this application, the term "atmospheric pressure" means the pressure within the normal range of meteorological atmospheric pressure to a certain height, while the term "high pressure" means a pressure above atmospheric pressure. In another embodiment described here the interaction is carried out at elevated pressures. In another embodiment of the invention in addition to isopropanol may be triethylamine.

In addition to the preferred options of the implementation of the interaction of the compounds of formula 2 with an amine to obtain the compounds of formula 1 has been successfully carried out in solvents, non-solvents, containing isopropanol. Accordingly, the invention relates also to a method for obtaining compounds of formula 1 by the interaction of the compound f is rmula 2 with an amine of the formula with other 8R15in an organic solvent, where the solvent is selected from the group consisting of benzyl alcohol, acetone, isobutyl ketone, dimethyl sulfoxide (DMSO), tert-butanol, n-butanol, isopropyl ether, a mixture of methyl tertiary butyl ether (MTBE) and dimethylformamide (DMF) and their combinations, where the interaction is carried out at a temperature of at least about 40°C. the Interaction can be performed at elevated pressures, but preferably it is carried out at approximately atmospheric pressure. In the following embodiment, the interaction accelerate the addition of catalytic amounts of Lewis acid. In the embodiment, the Lewis acid is a reagent, such as magnesium bromide, potassium iodide, lithium perchlorate, magnesium perchlorate, tetrafluoroborate lithium hydrochloride, pyridinium or tetrabutylammonium iodide. The preferred Lewis acid is magnesium bromide.

In the embodiment described here the molar quantity of the amine is at least approximately five times the molar amount of the compounds of formula 2. In another embodiment described here, the concentration of amine in isopropanol is at least about 5 Mosley. In a particularly preferred embodiment, the concentration of the-Propylamine is approximately 6-7 Mosley in isopropanol.

In the embodiment, the above methods, the compound of formula 2 is subjected to interaction with the amine for at least about 24 hours. In a preferred embodiment, the molar quantity of the amine is at least five times the molar amount of the compounds of formula 2 and the compound of formula 2 is subjected to interaction with the amine for at least 24 hours. In a more preferred embodiment, temperature is from about 50°With up to about 80°C. In a more preferred embodiment, the molar amount of amine is about twelve the number of the molar amount of the compounds of formula 2, the concentration of amine in isopropanol is approximately 6 Mosley, and the compound of formula 2 interacts with the amine for at least about 24 hours at a temperature of from about 50°C to about 55°C.

Another option is the implementation described here, the methods further includes the crystallization of the free base form of the compounds of formula 1. In the embodiment, the form of the free base of the compounds of formula 1 is crystallized from the aqueous solvent mixture. In a preferred embodiment, the aqueous solvent mixture contains water ineptly solvent, selected from the group consisting of methanol, ethanol, isopropanol and acetone. In another embodiment, the form of the free base of the compounds of formula 1 is crystallized from organic (C6-C10)alkangovolo solvent or a mixture of such organic alkanovykh solvents. In a preferred embodiment, the compound of formula 1 is crystallized by heating the compounds together with alkanoyl solvent and then cooled to implement crystallization. In a preferred embodiment, organic (C6-C10)alkanoyl solvent selected from heptane or octane, more preferably heptane. In another embodiment described below, the free base is obtained from the acid additive salts of the compounds of formula 1. It should be understood that "alkane", as used here, unless otherwise noted, includes saturated monovalent hydrocarbon having unbranched, cyclic or branched fragments or mixtures thereof.

In the following the embodiment described here the acid additive salt of the compounds of formula 1 is obtained by treatment of compounds of formula 1 with a solution containing the acid to mix with the water solvent. In a preferred embodiment, the acid solution are added to a solution containing compounds is their formula 1 and water. In a more preferred embodiment, the acid is phosphoric acid, L-tartaric acid or Dibenzoyl-D-tartaric acid. In a particularly preferred embodiment, the acid is phosphoric acid. In another preferred embodiment, the solvent includes ethanol. In another preferred embodiment, the above methods further include the selection of the acid additive salts of the compounds of formula 1.

In the embodiment described here, the methods give the compound of formula 1, which has a purity of at least 90%, more preferably a purity of at least 95% and most preferably a purity of at least 98%. In particular, the methods of the invention provide a compound of formula 1, having the profile of purity, suitable for use with the compounds of formula 1 when receiving preparative forms for parenteral administration. Requirements for parenteral preparative forms well known in this field, for example exceptional purity and small particle size in solution and sterility in the manufacture of preparative forms and elimination of pyrogens (see Remington,'s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18th Edition, Gennaro, ed. (1990), pages 1545-1580.

In another preferred embodiment, the above methods further include the processing of acid additive salts of the compounds of formula 1 in a mixture of water and non-polar solvent with the formation of the forms of the free base of the compounds of formula 1. In a more preferred embodiment, the base is a carbonate dibasic salt and in a particularly preferred embodiment, dibasic carbonate salt is potassium carbonate. In another preferred embodiment, the nonpolar solvent is dichloromethane. In another preferred embodiment, the method further includes the crystallization of the free base form of the compounds of formula 1, as described above, and additional embodiments of relating to him, which are described above.

The invention relates also to a method for obtaining compounds of formula 2, which includes:

(a) interactions of the form of the free base of the compounds of formula

with the ion matilida sulfone;

(b) quenching the reaction mixture of stage (a) aqueous weak acid and distribution of the product in non-aqueous solution and

(C) removing the protection of the product of stage (b) with the formation of compounds of formula 2 where R4is hydroxyamino group.

In the embodiment, the above method further includes the selection of the compounds of formula 2. In a preferred embodiment, the compound of formula 2 is isolated in the form of a hydrate, more preferably monohydrate. In the embodiment, the content is of water is determined by the method of Karl Fischer. In the embodiment, the hydrate is prepared from a mixture containing the compound of formula 2 and the solvent or mixture of solvents selected from acetone, mixtures of acetone/water, acetone/heptane and MTBE/heptane. In other embodiments, implementation of the compound of formula 2 is isolated in the form of its acetate salt, L-tartrate salt or Dibenzoyl-D-tartrate salt.

The invention relates to a monohydrate of the compound of formula 2. In a preferred embodiment, the above method R4is benzyloxycarbonyl.

In another preferred embodiment, the above method stage (a) is conducted at a temperature of from about -80°With up to approximately -45°C.

In another embodiment, the above method the form of the free base of the compounds of formula 3 is obtained from the acid additive salts of the compounds of formula 3. In a preferred embodiment, the acid-salt additive is additive salt triperoxonane acid. In other embodiments, the implementation of the above method, an acid additive salt of the compounds of formula 3 are selected from Dibenzoyl-D-tartrate salt, L-tartrate salt or phosphate salt. Acid additive salts of compounds described herein can easily get accepted methods.

In the embodiment, the above method matilida Sul is one is metered dimethylsulfone. In a preferred embodiment, metered dimethylsulfone produced by interaction of the halide or sulfonate trimethylsilane with a strong base. In a more preferred embodiment, use halide trimethylsilane, which, preferably, is a bromide trimethylsilane. In another more preferred embodiment, the halide trimethylsulfonium subjected to interaction with a strong base in an inert organic solvent or mixtures thereof. In a particularly preferred embodiment, the inert organic solvent is an ether solvent, most preferably represents tetrahydrofuran, or a mixture of tetrahydrofuran and dichloromethane.

In the embodiment, stage (C) comprises catalytic hydrogenation, where R4is benzyloxycarbonyl. In a preferred embodiment, a catalyst for the hydrogenation catalyst is palladium/carbon. In a particularly preferred embodiment, the catalyst is palladium/carbon is 10% Pd/C (type A-10 Johnson-Matthey). In another embodiment, stage (C) of the product of stage (b) remove the protection by catalytic transfer hydrogenation, preferably, ammonium formate, Pd/C in methanol. In the next version assests the of the product of stage (b) prior to hydrogenation the process fallerovo the ground. Suitable solvents for the method of hydrogenation are acetone, ethyl acetate, THF, MTBE, isopropanol, ethanol and methanol. The preferred solvent is acetone.

The invention relates to 2'-benzyloxycarbonylamino connection II:

get with the exception of stage (C) of the above methods.

This invention relates to a method for obtaining compounds of formula 3

oxidation of the C-4"-hydroxy-group of compounds of formula 4

where R4is hydroxyamino group.

In the embodiment, the oxidation is conducted by adding dimethyl sulfoxide ("DMSO") to the solution containing the compound of formula 4 and the solvent, cooling the mixture to approximately -70°and then adding triperoxonane anhydride followed by the addition of triethylamine. In another embodiment, DMSO activate using oxalicacid (trimethylsilylacetamide or without it), polyphosphoric acid, pyridine-SO3or acetic anhydride. In the following embodiment, the temperature of the support between -70°and -60°while adding triperoxonane anhydride. In another embodiment, the solvent is dichloromethane. Special pre which gives the above method is the activation of DMSO in situ in the presence of interacting alcohol, which eliminates the formation of impurities, in the typical case encountered in ocalenia activated DMSO, which usually includes the introduction of alcohol in the solution containing the activated DMSO.

In the embodiment, the above method further includes the selection of the acid additive salts of the compounds of formula 3. In a preferred embodiment, the acid additive salt is Dibenzoyl-D-tartrate salt or phosphate salt. In a particularly preferred embodiment, this invention relates to a method for producing a salt additive triperoxonane acid compounds of formula 3, which includes the processing of the compounds of formula 3 triperoxonane acid and crystallization of the resulting acid salt additive; where R4is hydroxyamino group.

In a preferred embodiment, the above method R4is benzyloxycarbonyl.

In another preferred embodiment, the above method of acid additive salt is crystallized from isopropanol.

In another preferred embodiment, the above method of acid additive salt is crystallized from a mixture of methylene chloride and methyl tert-butyl ether.

Additive salt triperoxonane acids obtained by methods Nast is asego of the invention, are not pharmaceutically acceptable, but provide excellent cleaning and stability that allows for the storage and transport of suitable starting materials for commercial obtain compounds of formula 1.

In the embodiment, the above method, the compound of formula 4 is obtained by protection of the 2'-hydroxy-group of compounds of formula 5

In a preferred embodiment, the 2'-hydroxy-group protect benzyloxycarbonyl. In another preferred embodiment, the compound of formula 5 is subjected to interaction with at least two molar equivalents of benzylchloride. In a more preferred embodiment, the interaction is carried out in dichloromethane. In an even more preferred embodiment, dichloromethane is present in at least 15-fold excess volume relative to the volume of the source material. This invention relates to additive salt triperoxonane acid compounds of formula 3, where R4is benzyloxycarbonyl:

In a preferred embodiment, the salt has the structure shown in formula 3A,

where R4is benzyloxycarbonyl.

The invention from OSISA also to Dibenzoyl-D-tartrate salts of the compounds of formula 3, where R4is benzyloxycarbonyl.

The term "hidroxizina group", as used here, unless otherwise noted, includes acetyl, benzyloxycarbonyl, and various hydroxyamine groups, such groups known to the person skilled in the art, include the groups specified in T.W.Greene, P.G.M.Wuts, "Protective Groups in Organic Synthesis", (J.Wiley & Sons, 1991).

Hydroxyamino group, R4preferably is benzyloxycarbonyl ("CBZ").

The term "halogen", as used here, unless otherwise noted, includes fluorine, chlorine or bromine, and the term "halide" refers to the respective monoanions, F-, Cl-or Br-respectively.

The term "alkyl", as used here, unless otherwise noted, includes saturated monovalent hydrocarbon radicals having unbranched, cyclic or branched fragments or mixtures thereof.

The phrase "pharmaceutically acceptable salt(s)"used here, unless otherwise noted, includes salts of acidic or basic groups that may be present in the compounds of the present invention. Compounds obtained by the methods of the present invention that are basic in nature, especially, for example, the form of the free base compounds of formula 1, can form a large number of salts with various inorganic and organizes the mi acids. Acids that can be used to obtain pharmaceutically acceptable acid additive salts of such basic compounds of the present invention are acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)]. Compounds obtained by the methods of the present invention, which include an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the above-mentioned acids.

The term "treatment", as used herein, unless otherwise stated, includes the treatment or prevention of a bacterial infection or protozoal infection, as suggested in the method of the present invention.

The present invention includes compounds of the present invention and their pharmaceutically acceptable salts, in which one or more atoms of hydrogen, carbon, nitrogen or other the volume replaced by their isotopes. Such compounds can be useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in the analyses of the binding.

DETAILED description of the INVENTION

The method of the present invention can be carried out according to the following schemes 1-4 and the description that follows it. In the following schemes, unless otherwise noted, the substituents R3, R4, R8and R15have the above values.

The compound of formula 4, which is used as a starting material for the methods of the present invention is easily produced from compound 5, i.e. compounds in which R4represents hydrogen, see WO 98/56802 and U.S. patent 4328334, 4474768 and 4517359, all of which are included in the description by reference in their entirety.

The above are only illustrative and are described in more detail below and in the examples noted below. Scheme 1 epoxide of formula 2 is converted into the amine of formula 1, where R3represents-CH2NR15R8where R15and R8have the values specified above. In the most preferred embodiment of the invention the amine is n-Propylamine, i.e. R8represents n-propyl and R15 is N.

To obtain the compounds of formula 1, the compound of formula 2 is preferably treated with a compound of the formula HNR15R8where R15and R8have the meanings specified above, in the presence of a suitable solvent, such as isopropanol, or a mixture of organic solvents containing isopropanol, preferably at a temperature of from about 40°to 95°C. the Most preferred temperature for carrying out the interaction range is from about 50°C to 55°but you can also use a higher temperature, for example 76°C. the preferred pressure for interaction is approximately atmospheric pressure; however, the interaction can also be carried out at elevated pressures.

In one method of the disclosure ring epoxide of formula 2 (see WO 98/56802, examples 48, 50, 51 and 70) 2'-hydroxy-group protect and obtaining the compounds of formula 1 or formula 1A, respectively) requires the simultaneous hydrolysis of the protective group and amination of epoxide. This method was not preferred, since the hydrolysis during the stage of disclosure of the epoxide ring was ineffective, and the allocation of the compounds of formula 1 has become more difficult due to the presence of non-hydrolyzed protective group, etc the other impurities. In another previous method, the compound of formula 2 (2'-hydroxy-group is unprotected) were subjected to interaction with pure alkylamino, i.e. without organic solvent. In this case, the interaction proceeded slowly at normal boiling point of n-Propylamine (approximately 48°). Therefore, in order to create a higher temperature interaction was carried out at elevated pressure, less preferable characteristics at commercial scale. (See WO 98/56802, example 8 (getting 2)with a yield of 11%.) In addition, in the reaction used catalyst. The applicants had made the discovery that a mixture of n-Propylamine and isopropanol has a boiling point at atmospheric ambient pressure of approximately 76°, which allows the reaction to proceed with high yield (above 85%) at a temperature of about 50-55°without using the reaction operating at high pressure vessel or catalyst(s). The way applicants provides high yield (85%) and the best profile of purity than earlier methods, and allows you to use different procedures crystallization for both forms of the free base and acid salts of the compounds of formula 1 to obtain the compound of formula 1 in the form connections with such high purity that is required for use in p is renderlng formulation.

In scheme 2, the compound of formula 2 can be obtained by treating compound of formula 3 matilida sulfur at a temperature of from about -80°With up to approximately -45°With subsequent removal of the 2'-protective group in a common manner with the formation of compounds of formula 2. The starting material for the method of scheme 2 is preferably additive salt triperoxonane acid compounds of formula 3, which was at the first turn in the form of a free base, is cooled to a low temperature of approximately -70°C, and then subjected to interaction with cooled to a low temperature solution matilida sulfur. Matilida sulfur is preferably metered dimethylsulfone, for example (CH3)2S+CH2-received conventional ways, for example by processing trimethylsulfonium salts, for example (CH3)3SX, where X represents halogen, preferably bromine, or a sulfonate, more preferably bromide trimethylsilane, an activating agent, such as potassium hydroxide, tert-piperonyl potassium tert-piperonyl sodium, atoxic potassium, ethoxide sodium, hexamethyldisilazide potassium (KHMDS) or sodium methoxide, preferably tert-piperonyl potassium, in the ether solvent such as THF or CH2Cl2, DMF or DMSO, or a mixture of two or more of the above solvent is. The protective group is removed in a common manner, for example by catalytic hydrogenation, when R4is CBZ.

Figure 3 4"-ketone obtained from the compounds of formula 5 a continuous process carried out in a single vessel. In the first phase of method 2'-hydroxy-group selectively protect conventional methods, preferably by treatment of 2'-hydroxy of formula 5, where R4represents hydrogen, benzylchloride in dichloromethane to obtain the compounds of formula 4 where R4is benzyloxycarbonyl ("CBZ"). Use preferably at least 2 molar equivalents of benzylchloride to ensure complete conversion of 2'-hydroxy-group in its protected form. As the preferred solvent is dichloromethane, when the interaction is performed using at least 15 volumes of dichloromethane relative to the volume of the source material, which thus minimizes the formation of impurities bis-CBZ. The compound of formula 4 where R4is CBZ, can be identified in the form of his Dibenzoyl-D-tartrate salt, which allows you to clear the connection from possible impurities bis-CBZ. However, water extraction processing of the compounds of formula 4 is not preferred because the selected product is unstable because of the presence of benzylamine formed Amin is haunted by alkylation of compounds of formula 4 benzylchloride (formed by the decomposition of benzylchloride). In accordance with this after protection phase reaction mixture is preferably transferred directly to the second stage without isolating the compounds of formula 4. The second stage, which can be performed in the same vessel as the first stage involves the oxidation of the 4"-hydroxyl groups with the formation of 4"-ketone of formula 3. Oxidation, preferably, oxidation is activated-DMSO, as described above, i.e. carried out at low temperature, for example at a temperature of from -60 to -70°s, and it includes the activation of DMSO in situ by adding triperoxonane anhydride to a cooled solution of the compound in DMSO followed by the addition of triethylamine. The reaction mixture was then added to water and gradually heated to ambient temperature. The mixture is preferably washed in water, thus obtaining a solution of the compounds of formula 3.

Salt triperoxonane acid compounds of formula 3 can be obtained by washing the reaction mixture under oxidizing water and then adding triperoxonane acid and then the solvent suitable for the crystallization of salts, for example isopropanol or a mixture of methylene chloride and methyl tert-butyl ether ("MTBE""). An accepted way you can also get other acid additive salts such as Dibenzoyl-D-tartrate salt and phosphate salt. Dibenzoyl-D-tartrate is Aya and phosphate salts are useful in the methods of the invention, but less preferred compared to triperoxonane acid.

As shown in figure 4, in General the invention relates to a method for obtaining compounds of formula 1 in two stages: in the first stage, the compound of formula 3 get carried out in a single vessel, the method including protection benzyloxycarbonyl 2'-hydroxy-group of compounds of formula 5 with the formation of compounds of formula 4, followed by direct oxidation of the 4"-hydroxy-group of compounds 4 with the formation of the ketone of formula 3, which is preferably isolated in the form of its salt additive with triperoxonane acid. In the second stage, the form of the free base of the compounds of formula 3 (preferably obtained from its salts triperoxonane acid) turn 4"-epoxide of formula 2, 2'-protective group is removed to return the 2'-hydroxy-group and epoxy ring unlock the amine by heating in a mixture containing isopropanol, thus obtaining the compound of formula 1.

Compounds obtained by the methods of the present invention that are basic in nature are capable of forming a large number of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the connection is out, obtained by the methods of the present invention, from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter back to the compound in the form of free base by treatment with an alkaline reagent for use in subsequent reactions or to obtain a pharmaceutically acceptable acid salt additive. Acid additive salts of the basic compounds obtained by the methods of this invention are easily obtained by processing the primary connection essentially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent. The desired solid salt is easily obtained after careful evaporation of the solvent. The desired salt can also precipitate from a solution of the free base in an organic solvent by adding to the solution a suitable mineral or organic acid. The compounds of formula 1 obtained by the methods of this invention, and their pharmaceutically acceptable salts (hereinafter "the active compounds") can be entered via oral, parenteral, local or rectal route in the treatment of bacterial and protozoal infections.

In General, the active compounds are most preferably administered in a dose comprising from about 0.2 mg per kg of body weight per day (mg/kg/day) up to approx is approximately 200 mg/kg/day as a single dose or divided doses (i.e. from 1 to 4 doses per day), although, of course, there may be variations depending on the species, weight and condition being treated subject and the specific route of administration. However, the level of dose that ranges from approximately 4 mg/kg/day to about 50 mg/kg/day, is most preferably used. However, there may be options depending on the species being treated mammal, fish or poultry, and their personal reactions to the specified medication, as well as the type of the selected pharmaceutical composition and time period and interval at which carry out this introduction. In some cases, the dose levels below the lower limit of the above range may be more than adequate, while in other cases it can be used even higher doses do not cause any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compounds can be entered separately or in combination with pharmaceutically acceptable carriers or diluents previously specified paths, and such introduction can be carried out in the form of a single dose or multiple doses. More specifically, the active compounds can be introduced in the form of a large number of different the dosage forms, i.e. they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, pellets, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, liniments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. in Addition, the oral pharmaceutical compositions can be suitably sweetened and/or flavored. In General, the active compounds are present in such dosage forms at concentration levels that comprise from about 5.0 to about 70 wt.%.

For oral administration can be used tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various disintegrants such as starch (preferably corn, potato or tapioca), alginic acid and certain complex silicates, together with binding granulation such as polyvinylpyrrolidone, sucrose, gelatin and Arabian gum. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very is ery useful for tabletting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar and high molecular weight glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active compound can be combined with various sweetening agents or flavoring agents, coloring matter or dyes and, if desired, emulsifying and/or suspendresume agents, in addition, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations.

For parenteral administration, you can use the solutions of active compounds in either sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions, if necessary, should be appropriately buffered and the liquid diluent first should be given isotonicity. These aqueous solutions are suitable for the purposes of intravenous injection. Oil solutions are appropriate for the purposes of intra-articular, intramuscular and subcutaneous injection. Obtaining all these solutions under sterile conditions easily perform standard pharmaceutical methods, well known to specialists in this field.

In addition, the compounds of the present invention can also enter the local way and this can be done by means of creams, jellies, gels, pastes, plasters, ointments and the like in accordance with standard pharmaceutical practice.

For administration to animals other than humans, such as cats or Pets, the active compounds can be introduced in animal feed or administered orally in the form of a composition for injection of the animal.

The active compounds can also be introduced in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposome can be obtained from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. The active compounds can also be coupled with soluble polymers as carriers to deliver the drug to the target. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted palmitoleate remains. In addition, the active compounds can be combined with a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polietilentireftalat, polyhydroxyalkanoic acid, polychaete the AMI, polyacetylene, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

The following additional examples illustrate the method and intermediate products of the present invention. It should be clear that the present invention is not limited to the specific details of the examples below.

Example 1

Obtain (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-abovecaptionskip)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-[(phenylmethoxy)carbonyl]-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she

To a solution of 25 kg (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-abovecaptionskip)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she 425 liters of methylene chloride, cooled to 0-5°C, add a solution of 13.7 kg benzylchloride in 25 l of methylene chloride at a speed that allows you to maintain the temperature at 5°C. the Resulting mixture is stirred at this temperature for three hours and then concentrated to 148 l, thus obtaining a dry solution containing approximately 26,6 kg (90%) of the product (defined HPLC Waters Symmetry C8 column 15 cm x 3.9 mm I.D. mobile phase 25 mm phosphate ka is in Oia as a buffer (pH 7.5):acetonitrile:methanol (35:50:15), the flow rate 2.0 ml/min, electrochemical detection, retention time=8.2 minutes). This mixture is directly used in example 2.

Example 2

Obtaining bis-triptoreline salt of (2R,3S,4R,5R,8R,10R, 11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-abovecaptionskip)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-[(phenylmethoxy)carbonyl]-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she

To the solution obtained in example 1 add to 58.6 kg of dimethyl sulfoxide ("DMSO") and then cooled to -70°C. maintaining the temperature between -70 and -60°add 16 kg triperoxonane anhydride and the mixture is stirred for 30 minutes, then add 17,2 kg of triethylamine and the resulting mixture is stirred for an additional 30 minutes. The reaction mixture was added to 175 liters of water and after gradual warming to ambient temperature, the layers separated. The organic layer is washed twice with 170 litres of water and concentrated to approximately 100 HP Then add 7.8 kg triperoxonane acid followed by the addition of 236 l of isopropanol and the mixture is concentrated for crystallization, while receiving 29,5 kg (87,9%) of product, which has a purity according to HPLC 98%. Analytical data: TPL=187-192°C. Elemental analysis. (Calculated for C49H76F 6N2O18: C, 53,74; N 6,99; F 10,41; N 2,56; found: C, 53,87; N 6,99; F 10,12; N 2,59. The HPLC system: the same as in example 1; retention time=9,5 min Powder x-ray diffraction (d distance): 6,3, 8,3, 8,8, 9,4, 10,8, 11,8, 12,6, 13,0, 14,3, 15,4, 15,9, 16,4, 17,1, 17,4, 17,8, 18,1 19,1, 19,8, 20,4, 21,1, 21,5, 21,7, 22,8, 23,4, 24,0.

Example 3

Obtain (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,

10-trihydroxy-13-[[3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2,5]Oct-6-yl]oxy]-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-[(phenylmethoxy)carbonyl]-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she

(a) a Solution of 109 kg of the product of example 2 in 327 l of methylene chloride is treated with a solution of 27.5 kg of potassium carbonate in 327 liters of water. The layers separated, the aqueous layer was washed 327 l of methylene chloride and the combined organic layers dried and evaporated to approximately 327 l and cooled to -70°C.

(b) In a separate vessel, the suspension 29,7 kg bromide trimethylsilane in 436 l of tetrahydrofuran ("THF") evaporated to approximately 170 l, cooled to -12°and process 36.8 kg of tert-butoxide potassium for 75 minutes at a temperature of -10 to -15°C. This mixture was then added to a solution in methylene chloride phase (a) during a period of approximately 30 minutes while maintaining the temperature at from -70 to -80°and the resulting mixture is allowed the opportunity to warm up to -65°C and stirred during the s, at least 1 hour. The mixture was then added to a solution of 55.4 kg of ammonium chloride in 469 liters of water. After stirring the mixture at 15-25°C for 15 minutes, the layers separated and the aqueous layer was washed with 360 liters of methylene chloride and the combined organic layers evaporated to approximately 227 HP To the resulting mixture add 750 l of acetone. Finally, the mixture is evaporated to 227 l of a solution containing approximately 70.1 kg (80%) specified in the header of the product (HPLC system HPLC: column C18 MetaSil AQ (MetaChem, lot number 0520-h), the mobile phase of 50 mm potassium phosphate as a buffer (pH 8.0):acetonitrile:methanol (30:60:10), flow rate 1.0 ml/min, electrochemical detection, retention time=31,1 minutes). This mixture is directly used in example 4.

Example 4

Obtain (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[[3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2,5]Oct-6-yl]oxy]-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she

The solution containing the product of example 3 is mixed with 11 kg of activated carbon, 17.5 kg of 10% palladium on carbon (Johnson Matthey type A402028-10) and 637 l of acetone. The resulting mixture is treated with hydrogen at 50 psi at 20-25°until completion of the reaction, and the mixture is then filtered. The filtrate is concentrated to approximately 350 l and then for 90 minutes on billaut 1055 l of water. The crystallized product is collected by filtration, washed with a mixture of 132 liters of water and 45 l of acetone and dried, thus obtaining 57.5 kg (94,4%) specified in the header of the epoxide in the form of a monohydrate (water content by way of Karl-Fischer).

Analytical data: HPLC system: the same as in example 3; retention time=13.3 minutes. Powder x-ray diffraction (d distance): 6,0, 8,5, 9,4, 11,9, 12,7, 13,4, 15,2, 16,9, 17,5, 18,0, 18,9, 19,4, 19,9, 20,7, 21,2, 21,6, 22,8.

Example 5

Obtaining bis-phosphate salt of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-[(propylamino)methyl]-α-L-abovecaptionskip)oxy-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she

The monohydrate of the epoxide of example 4 in the amount of 56 kg mixed with 280 l of isopropanol and to 108.2 kg n-Propylamine. The mixture is heated at 50-55°for thirty hours and then concentrated in vacuo to approximately 112 HP To concentrate add 560 l of ethanol and 44.8 l of water. To the resulting mixture for about two hours 16.8 kg of phosphoric acid in 252 liters of ethanol for crystallization of the product. After stirring the resulting suspension for 18 hours the mixture is filtered, the solid washed with 28 l of ethanol and the product is dried, thus obtaining a 64.6 kg (88%) specified in the header connect the FL (HPLC system HPLC: YMC-PacK Pro C18 (YMC Inc. Part #AS-12S03-1546WT), the mobile phase 50 mm dibasic potassium phosphate as a buffer (pH 8.0):acetonitrile:methanol (61:21:18), flow rate 1.0 ml/min, electrochemical detection, retention time = 26,4 minutes).

Example 6

Obtain (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-[(propylamino)methyl]-α-L-abovecaptionskip)oxy-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,

14-HEXAMETHYL-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-ksilopiranozil]oxy]-1-oxa-6-azacyclopentadecan-15-she, free base

The product of example 5 in number 64,6 kg mixed with 433 l of methylene chloride, 433 liters of water and 27.6 kg of potassium carbonate. After stirring the mixture for thirty minutes, the layers separated and the aqueous layer was washed with 32 l of methylene chloride. The combined organic layers are cleaned by filtration and evaporated to approximately 155 HP To concentrate add 386 l heptanol and the solution evaporated to approximately 155 l and cooled to 20-25°for the implementation of crystallization. After stirring the mixture for six hours, the solid is collected by filtration, washed with 110 l of heptanol and dried, thus obtaining of 40.3 kg (77%) specified in the connection header (HPLC: the same system as in example 5; retention time of 26.4 minutes).

1. The method of deriving 9 deoxo-9a-Aza-9a-homoerythromycin And formula 3

where R4represents a hydroxyl protective group, including the stage of protection of the 2' - hydroxy-group of compounds of formula 5

with the formation of compounds of formula 4

where R represents hydroxyamino group, oxidation of the C-4"-hydroxy-group of compounds of formula 4, which is carried out by adding dimethyl sulfoxide to a solution containing the compound of formula 4 and the solvent, cooling the mixture to approximately -70°and then activation of dimethyl sulfoxide in situ, and finally quenching the reaction mixture, characterized in that the compound of formula 4 is directly transferred to the stage of oxidation without highlighting.

2. The method according to claim 1, where the temperature of the support between -70 and -60°until then, until the reaction mixture will not be repaid.

3. The method according to claim 2, where the sulfoxide activate using triperoxonane anhydride, oxalicacid, oxalicacid with trimethylsilylacetamide, polyphosphoric acid, pyridine-SO3or acetic anhydride.

4. The method of obtaining salt additive triperoxonane acid derived Azalea formula 3

where R4is hydroxyamino group includes treatment of compounds of formula 3 trifero ssnoi acid and crystallization of the resulting acid additive salt.

5. The method according to claim 4, where R4is benzyloxycarbonyl.

6. The method according to claim 4, where the acid additive salt is crystallized from isopropanol.

7. The method according to claim 4, where the acid additive salt is crystallized from a mixture of methylene chloride and methyl tert-butyl ether.

8. The method according to claim 1, where 2'-hydroxy-group protect benzyloxycarbonyl.

9. The method of claim 8, where benzyloxycarbonyl protective group introducing interaction derived Azalea formula 5, at least two molar equivalents of benzylchloride.

10. Additive salt triperoxonane acid compounds of formula 3

where R4is benzyloxycarbonyl.

11. Salt of claim 10 having the structure shown by the formula

where R4is benzyloxycarbonyl.



 

Same patents:

FIELD: antibiotics, chemical technology.

SUBSTANCE: crystallization of azithromycin dihydrate is carried out by alkalization of an aqueous-organic azithromycin salt with the ratio water/solvent = from 1:1 to 3;1 and up to pH value 8-10. Methanol, ethanol, isopropanol, acetonitrile or dioxane can be used as a solvent. Method provides enhancing stability and homogeneity of the end crystalline product.

EFFECT: improved crystallizing method.

1 dwg, 3 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: azithromycin is prepared by the methylation reaction of 11-aza-10-deoxo-10-dihydroerythromycin in boiling in chlorinated hydrocarbon medium, in the presence of formic acid taken in the amount from 0.1 to 0.2 weight part per one weight part of 11-aza-10-deoxo-10-dihydroerythromycin. Paraform is used as a methylating agent taken in the amount from 0.05 to 0.2 weight part per one part of 11-aza-10-deoxo-10-dihydroerythromycin. Invention provides increasing yield and improved quality of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds - pluraflavines of the formula (I): wherein R1 represents sugar group of the formula: ; R2 represents -COOH or -CH2-O-(R7)m wherein R7 represents sugar group of the formula: ; R3 is taken among the groups: and , and to all its stereochemical forms and mixtures of indicated forms in any ratio, and to their physiologically acceptable salts; R5 means hydrogen atom; R4 and R6 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O); R8 and R10 represent in common group -X2 with a double bond wherein X2 means oxygen atom (O), and m = n = 1, and to all its stereochemical forms and mixtures of indicated forms in any ratio and to its physiologically acceptable salts. Invention relates to a method for preparing these compounds from culture of microorganism actinomycetes HAG 003959, DSM 12931 by fermentation, to the strain Actinomycetales HAG 003959, DSM 12931 used for preparing compounds of the formula (I) and to pharmaceutical composition inhibiting transcriptase activity and eliciting cytotoxic effect based on above said compounds. Compounds of the formula (I) are used as medicinal agents, for example, as antitumor agents.

EFFECT: improved method for preparing, valuable medicinal properties of compounds and composition.

19 cl, 3 tbl, 12 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, pharmaceutical industry.

SUBSTANCE: invention relates to clathrate of azithromycin hydrate with 1,2-propyleneglycol of formula I , wherein m =1-2 and n = 0.20-0.40. Method for production of target compound includes azithromycin dissolution in acetone followed by addition of 1,2-propyleneglycol and water in solution, formed crystal filtering, washing with water and drying. Also disclosed is pharmaceutical composition for microbial infection treatment based on clathrate of formula I.

EFFECT: azithromycin with reduced hygroscopicity and increased storage stability.

7 cl, 7 dwg, 2 tbl, 4 ex

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.

EFFECT: improved preparing and purifying method.

28 cl, 11 ex

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-descimated the

The invention relates to enriched troxerutin containing at least 92 wt.% 7,3',4'-trihydroxyethylrutoside, from 2 to 4 wt.% 5,7,3',4'-tetrahydrochloride and from 1 to 3 wt.% 7,4'-dihydroxytoluene and method thereof

FIELD: medicine.

SUBSTANCE: the present innovation deals with infecting macrophages and cells of macrophagous cell lines with pathogenic microorganisms, their treatment with medicinal remedies followed by gamma-irradiation, immunization of disease-resistant and disease-sensitive animal lines and infecting vaccinated animals with alive pathogenic microorganisms that leads to improved immunity to pathogenic microorganisms.

EFFECT: higher efficiency.

4 cl, 1 dwg, 3 ex

FIELD: medicine, gynecology.

SUBSTANCE: one should perform laparoscopy, drain purulent foci, remove destructive tissues and wash abdominal cavity with great amount of "Baliz-2" introduced into abdominal cavity by fractional portions per 1-1.5 l at exposure up to 3 min either once or up to three times. The method provides complex impact as antibacterial, antioxidant and immunocorrecting actions of the preparation in area of lesion and, thus, quick interruption of acute stage by preventing the development of adhesions and saving reproductive function in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: biotechnology, microbiology, medicine, veterinary science.

SUBSTANCE: for preparing vaccine toxigenic strains of S. dysenteriae R-forms are grown, cells are subjected for lysis by treatment with chloroform, mixture is centrifuged and prepared supernatant is treated with saturated monobasic carboxylic acid or their derivatives and pH value is brought about to 3.0-5.0. Mixture if centrifuged and precipitate containing corpuscular antigens and shigellosis exotoxin are obtained. Precipitate is dissolved in buffer and pH value is brought about to 7.5-9.0. Then formalin is added in the amount 0.4-0.8% of the solution volume, or benzoic acid or benzoic acid salts are added in the amount 0.07-4.0% of the solution volume, or a mixture consisting of formalin and benzoic acid or benzoic acid salt solutions in the amount 0.10.3% and 0.03-2.5% of the solution volume, respectively. The solution is kept at temperature 30-60°C for 2 h - 60 days to provide the conversion of exotoxin to anatoxin and vaccine is prepared. Another variant of the claimed invention involves additional treatment with formalin or benzoic acid or benzoic acid salts to provide conversion of exotoxin to anatoxin, vaccine is prepared followed by its bagging and corking. For preparing immunoglobulin preparation animals are immunized with vaccine prepared by abovementioned methods followed by taking off blood, milk and/or colostrums, and/or blood, immunoglobulin fraction is prepared, sterilized, bagged and corked. This preparation is a component of the immunobiological preparation. The immunobiological preparation comprises the immunoglobulin preparation and at least one component taken among the following row: human and/or animal immunoglobulin preparations, lactoferrin, enzymes, inhibitors of proteolytic enzymes, human and/or animal normoflora preparations, yeast, vitamins, vitamin-like substances, human and/or animal proteins of acute phase, human and/or animal cytokines, higher plants components, lower plants components, components of natural origin products, apiculture products, enterosorbents, antibiotics, antibacterial chemopreparations, sulfanilamide drugs, antibacterial, anti-tuberculosis, antiviral preparations, antifungal antibiotics, synthetic antifungal preparations, stimulators of metabolic processes, antioxidants, mineral supplements, carbohydrates, lipids, replaceable and/or essential amino acids, organic acids, alkaloids, glycosides, taste supplements, aromatic supplements, base for suppositories, base for ointment formulations, technological additives for tableting, or their mixture. Invention provides preparing preparations eliciting antigenic activity with respect to broad species of pathogenic and opportunistic gram-negative microorganisms of intestine group and their exotoxins and therefore eliciting with prophylactic and curative effect with respect to diseases causing with these microorganisms.

EFFECT: improved preparing method, valuable properties of vaccine.

13 cl, 112 ex

Antibacterial agent // 2262346

FIELD: biotechnology, microbiology.

SUBSTANCE: invention proposes applying Flavobacterium odoratum culture as an antibacterial agent isolated from drinking mineral water "Ust-Kachkinskaya" from the hole 1/99. Microorganism Flavobacterium odoratum inhibits growth of Staphylococcus aureus, colon bacillus and yeast-like fungi Candida albicans that allows using microorganism Flavobacterium odoratum as an antibacterial agent. Invention can be used as an antibacterial agent.

EFFECT: valuable medicinal properties of agent.

2 ex

FIELD: biotechnology, medicine, antibiotics.

SUBSTANCE: invention proposes to the new compound amycomycin of the molecular formula C65H115NO18 (structural formula is given on the invention claim) that shows an antibacterial activity. Amycomycin, its pharmaceutically acceptable salts and derivatives in all their stereoisomeris and tautomeric forms can be obtained by culturing microorganism Amycolatopsis sp. ST 101170 (DSM 12216) under aerobic conditions on the nutrient medium containing the necessary nutrient components. The end product is isolated and purified and converted if necessary to its pharmacologically acceptable salt, ester, ether and other chemical derivatives and eliciting the same spectrum of antibacterial activity. Amycomycin is a component of the pharmaceutical composition eliciting an antibacterial activity. Amycomycin acts as an antibiotic. Invention provides inhibition of microorganisms with resistance to vancomycin and teicoplanin used in treatment of infections caused by Staphylococcus aureus.

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

7 cl, 2 tbl, 4 ex

FIELD: biochemistry, medicine.

SUBSTANCE: invention relates to two forms of peptide isolated from annelid worm (Arenicola marina) eliciting the broad spectrum of antibacterial effect. Indicated forms differ by a single amino acid residue at position 10 wherein at position 10 arenicin-1 has Val and arenicin-2 has Ile. Invention provides expanding assortment of antibacterial agents.

EFFECT: valuable medicinal properties of peptides.

1 tbl, 3 dwg, 4 ex

FIELD: medicine, gynecology, pharmacy.

SUBSTANCE: invention proposes using pimafucin (natamycin) as agent for treatment of bacterial vaginitis. Method for treatment of bacterial vaginitis involves intravaginal administration of pimafucin as 2% cream, 2 times per a day in morning and evening for 7-10 days and for first 3 days pimafucin-containing vaginal suppository in the dose 100 mg is administrated additionally in evening after administration of cream into vagina. Invention provides high effectiveness of treatment and clinical-etiological recovery in 92.3% of cases being without prescription of medicinal preparations. Method has no contraindications and can be used in all period of pregnancy and without adverse effects.

EFFECT: improved treatment method, enhanced effectiveness of agent and treatment.

2 cl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new substituted 7-sulfonyl-benzo[b][1,4]diazepines of the general formula (1) , their pharmaceutically acceptable salts, N-oxides or hydrates that elicit properties of a protein kinase inhibitor that can be used in pharmaceutical industry. In compounds of the general formula (1) R1 and R2 represent independently of one another hydrogen atom, inert substitute, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group; R3 and R4 represent independently of one another hydrogen atom or inert substituted, or R3 and R4 in common with carbon atom to which they are bound form optionally substituted (C3-C7)-cycloalkyl, optionally substituted (C4-C7)-heterocyclyl or optionally substituted ethylene group; R5 represents optionally substituted amino-group or optionally substituted azaheterocyclyl. Also, invention relates to sulfochlorides of the general formula (2) that are used for preparing compound of the formula (1), and to methods for preparing compounds of general formulae (1) and (2). Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injection formulations placed into pharmaceutically acceptable package, and to the focused library for the search of biologically active compound-leaders.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.

7 cl, 2 sch, 1 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to an aqueous composition consisting of moxifloxacin hydrochloride and sodium chloride and comprising from 0.04% to 0.4% (mas/vol) (as measured for the amount of moxifloxacin) of moxifloxacin hydrochloride and from 0.4% to 0.9% (mas/vol) of sodium chloride. Also, invention relates to applying this composition with the aim for preparing a medicinal agent used for prophylaxis or treatment of bacterial infections in humans or animals. Invention provides stability of the prepared moxifloxacin solution as moxifloxacin hydrochloride in the presence of iron ions.

EFFECT: improved properties of compositions.

6 cl.

FIELD: antibiotics, chemical technology.

SUBSTANCE: crystallization of azithromycin dihydrate is carried out by alkalization of an aqueous-organic azithromycin salt with the ratio water/solvent = from 1:1 to 3;1 and up to pH value 8-10. Methanol, ethanol, isopropanol, acetonitrile or dioxane can be used as a solvent. Method provides enhancing stability and homogeneity of the end crystalline product.

EFFECT: improved crystallizing method.

1 dwg, 3 ex

FIELD: biotechnology, medicine, infectious diseases, medicinal microbiology.

SUBSTANCE: invention relates to a composition designated for treatment and prophylaxis of infections caused by Neisseria microorganism that comprises the following components: (a) protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of a single species (the first group of amino acid sequences is given in the text) and/or its fragment consisting of 10 and more amino acids and eliciting antigen properties; (b) the second protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of another species (the second group of amino acid sequences with even numbers is given in the text), and/or its fragment consisting of 10 or more amino acids and eliciting antigen properties; in particular, the second protein represents NspA. The composition comprises additionally adjuvant. The composition is used both a medicinal agent and for manufacturing the medicinal agent. Applying the invention provides enhancing the effectiveness of prophylaxis or treatment due to the universal effect of the composition (vaccine). Invention can be used in medicine for treatment of infections.

EFFECT: valuable medicinal properties of composition.

8 cl, 137 dwg, 5 tbl, 12 ex

Up!