Derivatives carbapenem and their pharmaceutically acceptable salts

 

(57) Abstract:

The essence of the invention. Derivatives carbapenem General formula (I) in which R1- a lower alkyl which may be substituted by hydroxyl or protected hydroxyl; R2is lower alkyl, R3- carboxyl, which may be esterified; R4- H or aminoamides group; R5and R6identical or different, denote H, hydroxyl, halogen, R7- H, lower alkyl or carboxyl; R8- H, lower alkyl or hydroxylase alkyl; or R7and R8taken together form a (C2-C6) alkylene; R9and R10identical or different, mean aminoamides group, H or lower alkyl; Z is a simple bond, O, S or a group CR11R12or the group NR13- CO - where R11and R12identical or different, denote H, hydroxyl or lower alkyl, and R13- H, m and n are integers from 0 to 6; and their pharmaceutical acceptable salts. Otherwise leave the compounds exhibit antibacterial activity. 5 C.p. f-crystals.

in

The invention relates to new antibiotics that have carbapenemases skeleton.

Thienamycin with carbapenemases skeleton, was considered a promising new anti-Christ. which are resistant to known antibiotics, and can exhibit excellent antibacterial activity.

However, thienamycin and various other derivatives carbapenem described after this, could used as a mixed preparation with inhibitor digidropeptidazy /BPH/, because they not only are physico-chemically unstable, but can also decompose BPH and similar enzyme in the kidneys, causing the side effects such as renal toxicity.

In addition, published without examination Japanese patent application N JP-A-60-233076 described 1- -methylcarbamate compounds that are stable against b-lactamase producing strains are stable physico-chemical nature and exhibit a strong antibacterial activity. However, these compounds are still unsatisfactory in terms of their stability against BPH and antibacterial activity.

The inventors of the present invention conducted intensive studies with the aim of detecting derived carbapenem having the best properties, and as a result undertook the present invention, after detecting the connection, which is effective against various bacterial strains, including Psptx2">

The present invention relates to the production of carbapenem having the following formula (I) and salts thereof:

< / BR>
where R1is lower alkyl or hydroxy-lower alkyl which may have a protecting group;

R2is a hydrogen atom or lower alkyl;

R3is carboxyla, which may be esterified;

R4is protecting the amino group, a hydrogen atom or lower alkyl;

R5and R6that may be the same or different, each is hydrogen atom, hydroxyl, lower alkyl, ossenisse by alkyl or halogen atom, and R5and R6together can form alkylenes group having 2 to 6 carbon atoms;

R7is a hydrogen atom, a lower alkyl, carboxyla, carbamoyl, carboxyla, which may have a protecting group, or a partial structure represented by-CONR71R72where R71and R72that may be the same or different, each is hydrogen atom or lower alkyl;

R8is a hydrogen atom, lower alkyl or hydroxy-lower alkyl, and R7and R8together can form alkylenes group having 2 to 6 alwaysa amino group, a hydrogen atom or lower alkyl;

Z is a simple bond, an oxygen atom, a sulfur atom or a partial structure represented-CR11R12-, -NR13-CO-, -CONR14or-NR15- where R11and R12that may be the same or different, each is hydrogen atom, hydroxyl, lower alkyl, hydroxy-lower alkyl or a halogen atom, and R11and R12together can form alkylenes group having 2 to 6 carbon atoms, R13and R14that may be the same or different, each is hydrogen atom or lower alkyl, and R15is protecting the amino group, a hydrogen atom or lower alkyl; and each of m and n is an integer from 0 to 6.

The term carbapenem, as it is used here, means a compound having the following structural core, and the present invention relates to a derivative of carbapenem, in which different types of replacement groups attached to the kernel.

< / BR>
The following describes the replacement group in the General formula (I). In this case, the term lower alkyl, as used herein, means alkyl having 1 to 6 carbon atoms (these are denoted respectively as C1-C6, then one.

R1is lower alkyl or product substitution by hydroxyl, namely oxyalkyl, which also may have a protecting group. Among them, preferred is 1-oxyethyl, especially when 1-oxyethyl linked to the carbon atom at the 6 position carbapenemase skeleton in the form of S-configuration, and its hydroxyl group attached to the 1-position of the ethyl group (usually called 8-progeniem carbapenem) in the R-configuration.

R2is a hydrogen atom or lower alkyl, preferably C1-C4-alkyl straight or branched chain such as methyl, ethyl or propyl, more preferably, stands. In this case, such groups are preferably may have the R-configuration in relation to the carbon at the 1-position carbapenemase skeleton.

R3is carboxyla, which can be esterified. Examples of the ester residue include C1-C6-alkali straight or branched chain such as methyl, ethyl, isobutyl or tert.-butyl; C1-C6-alkoxy-C1-C6-alkyl groups, such as methoxymethyl or methoxyethyl; C2-C7-aliphatic acyloxymethyl groups, such as pivaloyloxymethyl; italicising group and the like. Also useful are Sloopy, they include, for example, kalkilya groups such as p-nitrobenzyl, o-nitrobenzyl, benzhydryl or 2-naphthylmethyl, 2,2,2-trichlorethylene group, allyl group /CH2= CH-CH2-/ C1-C6-alkyl substituted silyl group such as trimethylsilyl and the like. Examples of ester groups which are useful as protecting carboxyl groups during the synthesis reaction are n-nitrobenzyl, allyl and the like. Can also be used metabolisme ester residues, the preferred examples are pivaloyloxymethyl group, felicilda group, ecotoxicologically group and the like. The carboxyl group may be in the form of carboxylate anion in relation to other substituting groups, salt and the like.

R4is a hydrogen atom, C1-C6-alkyl straight or branched chain such as methyl, ethyl or propyl, protecting the amino group, the group that is typically used in 3-lactam antibiotics, such as p-nitrobenzenesulfonyl, tert.-butoxycarbonyl or allyloxycarbonyl and the like

R5and R6that may be the same or different, each is hydrogen atom, hydroxyl or the polyalkylene chain with 2 to 6 carbon atoms, and to form a cyclic structure together with the carbon atom that is attached to R5and R6.

R7are a hydrogen atom, a lower alkyl, carboxyla, carbamoyl, which may have a protecting group, or a substituted carbamaepine groups represented by the following partial structural formula.

< / BR>
In the above formula, each of R71and R72is a hydrogen atom or lower alkyl. Together they can form a polyalkylene chain with 2 to 6 carbon atoms, to form a cyclic structure with the nitrogen atom that is attached to R71and R72.

R8is a hydrogen atom, lower alkyl or hydroxy-lower alkyl. In addition, R7and R8together may form a polyalkylene chain with 2 to 6 carbon atoms, to form a cyclic structure together with the carbon atom that is attached to R7and R8.

Each of R9and R10are protecting the amino group, a hydrogen atom or lower alkyl. Preferred examples of protecting the amino groups include those typically used in the-lactam antibiotics, for example, p-nitrobenzisoxazole oxygen /-O-/ or sulfur atom /-S-/, or a partial structure represented-CR11R12, -NR13CO-, -CONR14- or-NR15-. In these formulas, R11R12that may be the same or different, each represents a hydrogen atom, hydroxyl, lower alkyl, hydroxy-lower alkyl, such as oxymethyl or oxyethyl, or halogen atom. In addition, R11and R12together may form a polyalkylene chain with 2 to 6 carbon atoms to form a cyclic structure together with carbon atoms to which are attached R11and R12.

Each of R13and R14is a hydrogen atom or lower alkyl.

In addition, R15is protecting the amino group, a hydrogen atom or lower alkyl. Preferred examples of protecting the amino group are those that are commonly used in b-lactam antibiotics, such as p-nitrobenzenesulfonyl, tert.-butoxycarbonyl, allyloxycarbonyl and the like.

Each of m and n is an integer from 0 to 6.

With respect to the configuration of the substituted pyrrolidinium the Deputy located in position 2 carbapenemase skeleton is preferable that the area associated with carbonfibre.

The compound of the present invention and some of their intermediates may have tautomeric structures. Although these structures shows a single structural formula in this description, it should be clear that it does not limit it.

The compound of the present invention can be used in the form of pharmaceutically acceptable salts. Examples of such salts include non-toxic salts of carboxylic acids, such as sodium, potassium, aluminum, magnesium and the like, metal salts; ammonium salt; triethylamine salt, prokeinova salt and benzylamine salt, and salts with other amines, which are typically used for salt formation of the penicillin and cephalosporin. Among them, particularly preferred are the sodium and potassium salts. As derived carbapenems of the present invention contains the main Deputy, it can also be converted into a pharmacologically acceptable salt accession acid, for example, inorganic acid, such as hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or organic acid, such as acetic acid, citric acid, succinic acid, ascorbic acid or Metasploit to be used in different solvate, such as hydrate.

Because the connection of the present invention can exhibit excellent antibacterial properties against Escherichia coli, Proteus, Klebsiella, Enterobacter, Salmonella, Serratia, Streptococcus, Staphylococcus, and the like, but also against Pseudomonas aeruginosa, it can be effectively used for the treatment of various infectious diseases, secondary infection, caused by injury, burns or surgical wounds, purulent diseases.

The compound of the present invention may be formulated into pharmaceutical preparations in the usual way with commonly used pharmaceutical excipients, such as a carrier, stabilizer, solubilizers agent and a filler. It can be entered in various ways, such as oral introduction of the dosage form in the form of tablets, pills, capsules, granules or the like, or parenteral introduction of the dosage form in the form of nutrivene injections, intramuscular injections, suppositories and the like, of which is preferable to intravenous injection.

Usually it can be entered in the appropriate dosage from 100 mg to 3 g per adult once a day or dividing each day of the patient's symptoms, subject to treatment.

The compound of the present invention can be obtained in accordance with the method represented by the following reaction scheme:

< / BR>
Reactive intermediate product (III) can be obtained by reaction of compound (II) (R1, R2and R3in the formula have the previously indicated values) diphenylphosphinylchloride by a known method (D. H. Shin et al. Heterocycles, 21, 29 (1984)), or its modified version.

This reaction can be conducted preferably in the presence of an alkylamine, such as triethylamine, diisopropylethylamine or the like, alicyclic amine such as 1,8-diazabicyclo/5.4.O/-7-undecene (DWI), N-methylmorpholine or the like, organic bases such as Hinkley, 3-hinokitiol or the like, inorganic compounds such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and the like, metal alcoholate, such as tert.butoxy potassium, sodium methoxide or the like, or sodium amide; among them, particularly preferred are diisopropylethylamine or DWI. Also preferably, this reaction can be carried out in a solvent which has no adverse effect on telethon and the like, acetonitrile, dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane and chloroform, and optionally mixtures thereof.

The reaction temperature may be in the range from -50oC to room temperature, preferably -40 to 0oC. the Reaction can be carried out in a period of time from 15 min to 1 days, preferably from 30 minutes to 8 o'clock

Reactive intermediate product (III) when it is highlighted or as such then subjected to substitution reaction with tilenum compound (IV) to obtain the compound (I).

< / BR>
Tilne compound (IV) can be obtained according to the method described in the reference examples below. Reaction with tilenum compound (IV) having a high reactivity, it takes place in the presence of a base, although this reaction takes place also without Foundation. The reasons given above in respect of the previous stages of the reaction, they can also be used in this reaction, of which particularly preferred are diisopropylethylamine and DWI. Such a base may preferably be used in an amount equivalent to toolname connection, but when tilne the connection is in the form of a salt of joining the constituent to neutralize the salt accession acid.

This reaction can be carried out in a solvent which has no adverse effect on the original products and the product of the reaction, the solvents described for the earlier stages of the reaction, can be used as a solvent. When the intermediate product (III) are not allocated, it is preferable to continue the reaction in the same solvent.

The compound of formula (IV) can be used in an amount of from 1 to 3 equivalents, preferably 1 to 2 equivalents, to the compound of formula (III). The reaction temperature may be in the range from -50oC to room temperature, preferably between -10 and 0oC. the Reaction can be conducted over a period of time from 30 minutes to 1 days, preferably for 1 to 6 hours the substitute Product may be isolated by conventional means and, if necessary, purified by chromatography on a column of silica gel, using chloroform, ethyl acetate, dichloromethane, methanol or mixtures thereof.

When the reaction product substitution has a protecting group, it may optionally be removed. Its removal can be carried out rehabilitation hydrogenolysis, chemical recovery, or by hydrolysis using acid, base or enzyme.

Goldenzelle group, benzhydryl group or 2-nightimeyou group, this compound can be converted into a derivative carbapenem, in which R3in the General formula (I) is a carboxyl group or a carboxylate anion, with the help of the reaction remove the protection by catalytic reduction in the presence of known metal catalyst such as palladium on charcoal, platinum oxide and the like. More specifically, this reaction can be carried out in a reaction solvent such as dioxane, THF, water, buffer solution, or a mixture thereof, preferably in water or in a mixed solvent consisting of phosphate buffer and THF, at a hydrogen pressure from 1 to 5 atmospheres, at a temperature from 0 to 50oC, preferably from 10 to 30oC, during the period of time from 30 min to 16 h, usually from 10 min to 1 h

When R3in compound (I) is p-nitrobenzisoxazole group, it can react with aqueous solution of aluminum chloride and iron powder in water-soluble organic solvent such as THF or dioxane, to obtain the desired compound, which R3is carboxyla or carboxylate anion, or when R3is allyloxy the eat (O), the triphenylphosphine and 2-ethylhexanoic acid in an aprotic solvent such as THF or dichloromethane.

When using protecting groups commonly used in the synthesis of-lactam antibiotics, such as p-nitrobenzisoxazole group, for the replacement of the groups R4, R9, R10or R15in the General formula (I), such a connection can be turned into a derived carbapenem, in which R4, R9, R10or R15in the General formula (I) is a hydrogen atom, if the reaction unprotect by catalytic reduction to known metal catalyst such as palladium on coal or platinum oxide. The catalytic reduction reaction can be carried out in a solvent such as dioxane, THF, water, buffer solution or their mixture, preferably in aqueous dioxane or a mixed solvent consisting of phosphate buffer and THF, at a hydrogen pressure of 1 to 5 atmospheres, at a temperature from 0 to 50oC, preferably from 10 to 30oC, during the period of time from 30 min to 16 h, usually from 10 min to 1 h, the result is derived carbapenem (I).

The use of other protecting groups commonly used in the synthesis of b >5this connection can be turned into a derived carbapenem, in which R4, R9, R10or R15in the General formula (I) is a hydrogen atom, if the reaction to unprotect tetrahetarenoporphyrazines (O), triphenylphosphine and 2-ethylhexanoic acid in an aprotic solvent such as THF or dichloromethane.

When many of the above-mentioned protecting groups simultaneously exists in R3, R4, R9, R10and R15in the compound of formula (I), this compound can be converted into a derivative of carbapenem in which such protecting groups are simultaneously removed during processing in accordance with the above-mentioned reaction conditions.

The target compound can be purified commonly used methods, for example, by extraction and subsequent concentration, then, if necessary, by recrystallization, presidenial, by chromatography on a column and the like. In addition, compound (I) can be obtained in highly purified form in its crystallization, and this goal can be achieved with high efficiency when the connection is in the form of a salt. In this case, the salt does not need to be non-toxic the AI it in the form of toxic salts, salt is purified and then remove the acid or turn salt in a pharmacologically acceptable salt.

Esters, which are metabolized in vivo, can be obtained by translation of R3in the compound of General formula (I) in esterified form in accordance with methods commonly used in the synthesis of penicillins to cephalosporins (for example, J. Med. Chem. 13, 607 (1970)), or by subjecting a carboxyl group or a carboxylate anion compounds of esterification.

The best option of carrying out the invention

The following inventive and reference examples are intended to further illustrate the method of obtaining the compounds of the present invention. Used here abbreviations indicate the following:

PNZ: p-nitrobenzisoxazole group

Business continuity plan: p-nitroaniline group

DMC: p-methoxybenzylideneamino group

MBP: p-methoxybenzylidene group

Side: tert.-butoxycarbonyl group

TK: p-toluensulfonyl group

Fn: phenyl group

Unless otherwise noted, the configuration of the replaced parts in the following formula (IVa) is a mixture of R and S forms.

< / BR>
Referential example 1.

/2S, 4S/4-mercapto-1-/-p-nitrobenzyl 3.75 g glycine dissolved in 25 Il 2H aqueous solution of sodium hydroxide and the resulting solution, chilled in an ice bath, and simultaneously added dropwise 10,77 g p-nitrobenzotrifluoride dissolved in ether and 12.5 ml 4H aqueous solution of sodium hydroxide. After 2 h stirring at the same temperature the reaction solution is washed with ether, acidifying the resulting aqueous layer was concentrated hydrochloric acid and filtered precipitated precipitated solid product is washed with water, then dried, get 11,98 g N-/p-nitrobenzenesulfonyl/glycine in the form of a solid product.

NMR/DMSO-d6/ 3,69 /2H, d/, 5,20 /2H,/, 7,60 /2H, d/, 8,23 /2H, d/.

2. A portion of 2.67 g of N-p-/nitrobenzisoxazole/glycine suspended in 30 ml of dichloromethane and add one drop of dimethylformamide to the suspension, and then for 1 h conduct the reaction at room temperature.

After evaporation of the solvent under reduced pressure the residue is dissolved in 25 ml of dichloromethane and cooled to -30oC is added to the solution 2,63 g 1/p-methoxybenzenesulfonyl/- piperizine and 2.13 g of triethylamine, then spend 2 hours reaction at room temperature. The reaction solution is mixed with chloroform, washed with water and then dried over sodium sulfate, the solvent is then removed myprivatekey way get 4,13 g 1/p-methoxybenzenesulfonyl/-4-/2-/p - nitrobenzenesulfonyl/aminoacetyl/piperazine.

NMR/CDCl3/ d 3,2 3,7 /8H, m/ 3,80 /3H/, 4,00 /2H, d/, 5,06 /2H,, 5,18 /2H,/, 6,90 /2H, d/, 7,30 /2H, d/, of 7.48 /2H, d/, 8,20 /2H, d/.

3. To 3,74 g 1/p-methoxybenzenesulfonyl/-4- /2-/p-nitrobenzenesulfonyl/aminoacetyl/piperazine are added to 4.17 ml of anisole and cooled in an ice bath, 20 ml triperoxonane acid, then carry out the reaction for 1 h at room temperature. After removal triperoxonane acid by evaporation under reduced pressure alkalinized the remainder of the aqueous solution of sodium hydroxide and extracted with chloroform, the organic layer washed with water and dried over sodium sulfate, the solvent is then removed under reduced pressure and then added n-hexane to the residue, filtered off the solid material, thereby obtaining of 2.45 g of 1-/2-/p-nitrobenzenesulfonyl/aminoacetyl/piperazine.

NMR/CDCl3/ d 2,7 3,0 /4H, m/, 3,3 3,5 /2H, m, 3,5 3,7 /2H, m, was 4.02 /2H, d/, 5,20 /2H,/, 7,50 /2H, d/, by 8.22 /2H, d/.

4. A dose of 1.25 g /2S, 4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/Proline suspended in 10 ml of dichloramine and add 0,76 g oxalicacid and one drop of dimethylformamide to the resulting suspension is then stirred for 1 h the solvent is Evaporated under reduced pressure and the resulting residue was dissolved jocstarbunny/aminoacetyl/piperazine and 0.61 g of triethylamine, then carry out the reaction for two nights at room temperature. The resulting reaction mixture was mixed with chloroform, washed with aqueous citric acid solution, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, in that order then the solvent is evaporated under reduced pressure and purify the resulting residue by chromatography on a column of silica gel, get quantitative output /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/aminoacetyl/piperazine-4 - yl/carbonyl/pyrrolidine as a white syrup.

NMR /CDCl3/ d 1,8 2,2 /1H, m, 2,5 3,0 /1H, m, 3,1 4,4 /13H, m/, 4,6 4,9 /1H, m, 5,20 /4H/, 7,3 7,7 /7H, m/, of 7.90 /2H, d/, by 8.22 /4H, m/.

5. A portion of 1.47 g /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2//1-(2-/p-nitrobenzenesulfonyl/aminoacetyl/-piperazine-4-yl/carbonyl/pyrrolidine dissolved in 9 ml of methanol, 6 ml of tetrahydrofuran, the resulting solution was added to 0.22 g of sodium methoxide under cooling in an ice bath and a stream of argon, and then conduct the reaction for one hour. After neutralization with an aqueous solution of citric acid and concentration of the solvent, the resulting reaction solution was extracted with chloroform, chloroform embedded in the residue purified by chromatography on a column of silica gel, obtain 1.10 g of the target compound as a white foam.

NMR /CDCl3/ d 1,8 2,1 /1H, m, 2,5 3,0 /1H, m, 3,0 4,3 /13H, m/, 4,5 4,8 /1H, m, 5,20 /4H/, 7,50 /4H, m/, by 8.22 /4H, m/.

Referential example 2.

/2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-/ 2-N,N-dimethylaminoacetyl/piperazine-4-yl/carbonyl/pyrrolidine

1. A portion of 14.9 g /2S,4R/-1-/p-nitrobenzenesulfonyl/4-hydroxyproline, 12.4 g of dicyclohexylcarbodiimide and 6.75 g of N-oxybisethanol added to 100 ml of tetrahydrofuran, then carry out the reaction for 1 h at room temperature, get active ester of Proline. The reaction product is mixed with 16.5 g of 1-/p-methoxybenzenesulfonyl/piperazine and carry out the reaction for 2 h at room temperature with stirring. After completion of the reaction, filtered dicyclohexylphosphino, the remaining filtrate is evaporated under reduced pressure, the residue is dissolved in chloroform and washed with 10% aqueous citric acid solution and water, dried over sodium sulfate, then the solvent is evaporated under reduced pressure to obtain an oily residue. It is applied to the chromatographic column with silica gel and are chloroform and a mixture of chloroform and methanol, to obtain 16.5 g /2S,4R/-1-/p-nitrobenzyloxy.

NMR /CDCl3/ d 0,90 1,40 /2H, m, 3,00 3,90 /11H, m/ 3,80 /3H/, 4,40 4,70 /1H, m, 4,90 5,44 /4H, m/ 6,75 7,02 /2H, m, 7,20 - 7,60 /4H, m/ 8,08 8,30 /2H, m/.

2. Dissolve a portion of 11.8 g of triphenylphosphine in 200 ml of tetrahydrofuran, to which sequentially added dropwise 7,06 ml of diethylazodicarboxylate when cooled to -20oC. After 40 min to the solution are added dropwise 15.9 g /2S,4R/-1-/p-nitrobenzenesulfonyl/piperazine-4-yl/carbonyl/- 4-oxopyrrolidin and 5.2 ml thiobenzoic acid dissolved in tetrahydrofuran consistently. After stirring at room temperature overnight distilled tetrahydrofuran under reduced pressure, the thus obtained residue is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution, the organic layer washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure. Thus obtained /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//1-/p - methoxybenzenesulfonyl/piperazine-4-yl/carbonyl/pyrrolidine used in subsequent reactions without further purification.

3. The result of the above crude product was added to ice mixture consisting of 200 ml triperoxonane acid and 50 ml of anisole, and then spend Rea, the STATCOM is dissolved in ethyl acetate, neutralized and washed with aqueous sodium bicarbonate solution, washed with water and then dried over sodium sulfate, then the solvent is evaporated under reduced pressure. The remainder is applied to the chromatographic column with silica gel and elute with a mixture of chloroform and methanol receive 12 g /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//piperazine-1 - Il/carbonyl/pyrrolidine.

NMR/CDCl3/ d 1,8 2,3 /1H, m, 2,6 3,3 /5H, m/, 3,3 4,0 /5H, m/ 4,0 4,4 /2H, m, 4,6 5,0 /1H, m, 5,23 /2H, 7,3 7,7 /5H, m/, 7,8 8,0 /2H, m, 8,23 /2H, d/.

4. Suspended portion of 0.29 g of N,N-dimethylglycine in 10 ml of chloroform and added to a mixture of 0.53 g of oxalicacid and 1 drop of dimethylformamide, then carry out the reaction for 1 h at room temperature. To the mixture was added under cooling in an ice bath and 1.0 g /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//piperazin-1-yl/carbonyl/pyrrolidine and 0.63 g of triethylamine, then carry out the reaction for 2 hours, the Reaction solution is mixed with chloroform, washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure and purified by chromatography on a column of silica gel, get 0,49 g /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/- 2-//1-/2-N,N-dimethylamino,10 /2H, with/, 3,3 3,9 /8H, m/ 3,9 4,4 /3H, m/, 4,6 5,0 /1H, m, 5,22 /2H, m, 7,3 7,7 /5H, m/ 7,9 /2H, d/, 8,20 /2H, d/.

5. Dissolve a portion of 0.49 g /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//1-/2-N,N-dimethylaminoacetyl /piperazine-4-yl/carbonitriding in a mixture of 10 ml of methanol and 5 ml of tetrahydrofuran and added to the solution while cooling in an ice bath and a stream of argon 0,069 g of sodium methoxide, and then conduct the reaction for 60 minutes the Reaction solution is neutralized under cooling in an ice bath 0,076 g of acetic acid and concentrating the solvent, the residue is mixed with chloroform, washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure and purified by chromatography on a column of silica gel, to obtain 0.31 g of the target compound as a white foam.

NMR /CDCl3/ d 1,8 2,1 /1H, m, 2,20 /6H, m/, 2,5 3,0 /1H, m, 3,12 /2H,/, 3,2 3,9 /10H, m/ 3,9 4,2 /1H, m, 4,5 4,9 /1H, m, 5,20 /2H,/, 7,50 /2H, d/, 8,20 /2H, d/.

Reference example 3.

/2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-/4-/p-nitrobenzenesulfonyl/aminobutyryl/piperazine-4 - yl/carbonyl/pyrrolidine

1. Dissolve a portion of 3.10 g of 4-aminobutyric acid in 15 ml 2H sodium hydroxide, to the solution are simultaneously added dropwise 6,48 g-p-nitrobenzotrifluoride the same temperature, the solution was washed with ether, acidifying the resulting aqueous layer was concentrated hydrochloric acid and filtered phase precipitate the solid product washed with water and then dried, get to 7.64 g of 4-/p-nitrobenzenesulfonyl/aminobutyric acid.

NMR /DMCO-d6/ d 1,5 1,9 /2H, m, 2,28 /2H, t/, 3.04 from /2H,/, 5,18 /2H,, 7,62 /2H, d/, 8,25 /2H, d/.

2. To 1.13 g of 4-p-/nitrobenzisoxazole/aminobutyric acid, dissolved in tetrahydrofuran, was added under cooling in an ice bath to 0.48 g of N-oxysuccinimide and 0.87 g dicyclohexylcarbodiimide, then carry out the reaction under stirring overnight. To the solution was added 1.0 g 1-/p-methoxybenzenesulfonyl/-piperazine and 0.41 g of triethylamine, conduct the reaction for 2 hours After removal of insoluble material from the reaction mixture by filtration and subsequent concentration of the filtrate thus obtained residue is mixed with ethyl acetate, washed with aqueous sodium bicarbonate solution, aqueous solution of citric acid and an aqueous solution of sodium chloride in this order, then dried over sodium sulfate and the solvent is evaporated under reduced pressure. Thereafter, the resulting residue is subjected to chromatography on a column of silica gel, floor NMR /CDCl3/ d 1,5 2,1 /2H, m/ 2,40 /2H, t/, 3,1 3,7 /10H, m/ 3,80 /3H/, 5,08 /2H,/, 5,20/2H,/, 6,90 /2H, d/, 7,30 /2H, d/, 7,50 /2H, d/, 8,20 /2H, d/.

3. Suspended portion 0,86 g /2S,4S/4 benzylthio - 1-/p-nitrobenzenesulfonyl/Proline in 10 ml of dichloromethane and added to a suspension of 0.51 g of oxalicacid and 1 drop of dimethylformamide, then carry out the reaction for one hour at room temperature. To the solution was added under cooling in an ice bath 0.74 g of 1-/4-/p - nitrobenzenesulfonyl/aminobutyryl/piperazine and 0.42 g of triethylamine, then conduct the reaction for 3 h at room temperature. The resulting reaction mixture was mixed with chloroform, washed with aqueous sodium bicarbonate solution, aqueous solution of citric acid and an aqueous solution of sodium chloride in that order and then dried over sodium sulfate, then the solvent is evaporated under reduced pressure. After that, the residue is subjected to chromatography on a column of silica gel, to obtain 1.64 g of foam /2S,4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//1-/4-/p-nitrobenzenesulfonyl/ aminobutyryl/piperazine-4-yl-carbonyl/pyrrolidine.

NMR /CDCl3/ d 1,5 2,1 /3H, m/, 2,2 2,5 /2N, m/, 2,5 4,4 /14N, m/, 4,5 4,9 /1H, m, 5,20 /2N,/, 5,25 /2N,/, 7,3 7,7 /7H, m/, of 7.90 /2N, m/, 8,20 /4H, m/.

4. Dissolve a portion of 1.53 g /nil/pyrrolidine in a mixture of 20 ml methanol and 10 ml of tetrahydrofuran, added 0.16 g of sodium methoxide to the solution while cooling in an ice bath, then carry out the reaction for 1 h, the Mixture is neutralized under cooling in an ice bath with an aqueous solution of citric acid and concentrated, the residue is dissolved in chloroform, washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure and subject the residue chromatography on a column of silica gel, get a quantitative yield of the target compound.

NMR /CDCl3/ d 1,5 2,1 /3H, m/, 2,2 2,5 /2N, m/, 2,5 3,0 /1H, m, 3,0 4,2 /13H, m/, 4,5 4,8 /1H, m, 5,20 /2N,, 5,22 /2N,/, 7,50 /4H, m/, 8,20 /4H, m/.

Reference example 4.

/2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-//2S/-/4-/p-nitrobenzenesulfonyl/amino-2-oxobutyric/piperazine-4-yl/pyrrolidin

1. Dissolve a portion 2,82 g /2S/-4-amino-2-hydroxybutyric acid in 15 ml 2H sodium hydroxide to chilled on ice to the solution are added simultaneously dropwise 0.15 g of p-nitrobenzotrifluoride, dissolved in ether, and 7.5 ml 4H sodium hydroxide. After 2 h stirring at the same temperature the aqueous layer was acidified with concentrated hydrochloric acid and filtered precipitated in the sediment solid material washed with water and then dried, get 4,48 GN, m/ 3,99 /1H, DD/, 5,16 /2H,/, to 7.59 /2H,/, to 7.59 /2H, d/, 8,23 /2H, d/.

2. K 0.9 g /2S/-4-/p - nitrobenzenesulfonyl/amino-2-hydroxybutyric acid, dissolved in tetrahydrofuran, was added under cooling in an ice bath 0.36 g of N-oxysuccinimide and 0.65 g of dicyclohexylcarbodiimide, then carry out the reaction under stirring overnight. To the solution was added 0.75 g 1-/p-methoxybenzenesulfonyl/piperazine and 0.31 g of triethylamine, conduct the reaction for 2 hours After removal of insoluble material from the reaction mixture by filtration and subsequent concentration of the filter residue is mixed with ethyl acetate, washed with aqueous sodium bicarbonate solution, aqueous solution of citric acid and an aqueous solution of sodium chloride in this order, then dried over sodium sulfate, the solvent is evaporated under reduced pressure. After this, the resulting residue chromatographic on a column of silica gel, get 1,33 g 1/p-methoxybenzenesulfonyl/-4-//2S/- /4-p-nitrobenzenesulfonyl/amino-2-oxobutyric/piperazine.

NMR /CDCl3/ d of 1.5-2.1 /2H, m, 3,2-3,8 /4H, m/ 3,80 /3H/, 4,3-4,5 /1H, m, of 5.05 /2H,, 5,18 /2H,/6,90 /2H, d/, 7,30 /2H, d/, of 7.48 /2H, d/, 8,20 /2H, d/.

3. Add 2,32 g 1/p-methoxybenzenesulfonyl/-4-//2S/-4-/-p - microbe the t reaction for 1 h at room temperature. After removal triperoxonane acid by evaporation under reduced pressure alkalinized the residue with sodium hydroxide and extracted with chloroform, the organic layer washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure. The resulting residue is subjected to chromatography gain of 0.91 g of 1-//2S/-4-/p-nitrobenzenesulfonyl/amino-2-oxobutyric/piperazine in the form of syrup.

NMR /CDCl3/ d 1.5-2,3 /2H, m, 2,4-3,1 /4H, m/, 3,2-3,8 /6H, m/, 4,42 /1H, DD/, 5,20 /2H,/, 7,50 /2H, d/, by 8.22 /2H, d/

4. Dissolve a portion of 1.04 g /2S, 4S/4 benzothia-1-/p-nitrobenzenesulfonyl/Proline in 20 ml of tetrahydrofuran and cooled in an ice bath was added to a solution of 0.55 g of N-oxibendazole and 1,49 g dicyclohexylcarbodiimide, then carry out the reaction for 1 h under stirring at room temperature. Added to a solution of 0.88 g of 1-//2S/-4-/p-nitrobenzenesulfonyl/-amino-2-oxobutyric/piperazine and 0.49 g of triethylamine, then carry out the reaction for 1 h at room temperature. After concentration of the solvent the residue is mixed with ethyl acetate to remove insoluble material, washed with aqueous sodium bicarbonate solution, aqueous solution of citric acid and water rastey balance chromatographic on a column of silica gel, get 1,80 g /2S, 4S/4 benzylthio-1-/p-nitrobenzenesulfonyl/-2-//1-//2S/-4-/p-nitrobenzenesulfonyl/amino-2-oxobutyric/piperazine-4-yl/carbonyl/pyrrolidine.

NMR /CDCl3/ d 1,5-2,2 /3H, m/, 2,5-4,6 /15H, m/, 4,7-5,0 /1H, m, 5,18 /2H,/, 5,24 /2H,/, of 7.48 /7H, m/, 7,92 /2H, d/, 8,20 /4H, m/.

5. Dissolve a portion of 1.56 g /2S,4S/4 benzothia-1-/p-nitrobenzenesulfonyl/-2-//1-/2S/-4-/p-nitrobenzenesulfonyl/amino-2-oxobutyric/piperazin-4-yl/carbonyl/pyrrolidine in a mixture of 10 ml methanol and 10 ml of tetrahydrofuran, the resulting solution was added 0.32 g of sodium methoxide under cooling in an ice bath and a stream of argon, then carry out the reaction for 1 hour While cooling in an ice bath, the reaction mixture was neutralized with an aqueous solution of citric acid and concentrating the solvent, the residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate and the solvent is evaporated under reduced pressure. After this, the resulting residue chromatographic on a column of silica gel, earn 1.25 g of target compound in a light yellow color.

NMR /CDCl3/ d of 1.5-2.1 /2H, m, 2,2-2,9 /2H, m, 3,01-4,3 /13H m/, 4,3-4,6 /1H, m, 4,6-4,9 /1H, m, 5,20 /4H,, 7,52 /4H, m/, 8,24 /4H, m/.

Below is shown the replacement group structural part represented (IVa) the other compounds (IV), obtained in the same manner, and the results of NMR analysis. If there are no other indications, R4is p-nitrobenzisoxazole group.

Compound IV-I: Z is a simple bond, m n 0, R7R8H, R9PNZ, R10H,

Compound IV-2: Z is a simple bond, m n 0, R7R8H, R9R10CH3,

Compound IV 3: Z is a simple bond, m is 0, n is 2, R7R8H, R9PNZ, R10H,

Compound IV 4: Z is a simple bond, R5H, R6OH, m n 1, R7R8H, R9PNZ, R10H, 2S,

Compound IV 5: Z is a simple bond, m n 0, R7CH3, R8H, R9PNZ, R10H, 2R,

of 1.36 (3H, d), 2,4 2,9 (1H, m), 3,1 4,2 (11H, m), 4,5 4,9 (2H, m), 5,20 (4H, s) to 7.50 (4H, d), by 8.22 (4H, d)

Compound IV-6: Z is a simple bond, m n 0, R7CH3, R8H, R9PNZ, R10H, 2S,

of 1.36 (3H, d), 2,4 3,0 (1H, m), 3,0 4,3 (11H, m), 4,5 4,9 (2H, m), 5,20 (4H, s) to 7.50 (4H, d), by 8.22 (4H, d)

Compound IV-7: Z is a simple bond, m n 0, R7R8H, R9CH3, R10PNZ,

1,8 2,1 (1H, m), 2,5 3,0 (1H, m), 3,05 (3H, s), 3,2 3,9 (11H, m) 4,06 (2H, s), 4,70 (1H, t), 5,20 (2H, s), of 5.24 (2H, s) to 7.50 (4H, d), to 8.20 (4H, d)

Compound IV-8: Z is a simple bond, m n 0, R7R8CH3R9PNZ, R10H,

of 1.59 (6H, s), 1,80 2,00 (1H, m), 2,4 2,9 (1H, m), 3.00 and a 3.9 (10H, m), 4,0 4,2 (1H, m) 4,5 4,8 (1H, m), is 5.18 (2H, s), with 5.22 (2H, s), 7,51 (4H, d), by 8.22 (4H, d)
40 (4H, m) 1,75 to 2.13 (1H, m), 2,50 3,00 (1H, m), 3,10 - are 3.90 (9H, m), 4,00 4,20 (2H, m), 4,50 4,90 (2H, m), 5,00 5,30 (4H, m) to 7.50 (4H, d), to 8.20 (4H, d).

Compound IV-10: Z is a simple bond, m is 0, n is 1, R7R8H, R9PNZ, R10H,

1,7 2,1 (1H, m), 2,4 3,0 (3H, m), 3,0 4,2 (13H, m) and 4.65 (1H, t), 5,20 (2H, in), 5.25 (2H, s) to 7.50 (4H, d), to 8.20 (4H, d)

Compound IV-11: Z is a simple bond, m n 0, R7H, R8CH2OH, R9PNZ, R10H, 2R,

2,4 2,9 (1H, m), 3,0 4,2 (13H, m), 4,5 4,9 (2H, m), a total of 5.21 (4H, s) to 7.50 (4H, d), by 8.22 (4H, d).

Compound IV-12: Z is a simple bond, m n 0, R7H, R8CH2OH, R9PNZ, R10H, 2S,

2,65 2,80 (1H, m), 3,0 4,2 (13H, m), 4,6 and 4.75 (2H, m), 5,15 of 5.25 (4H, m) to 7.50 (2H, d), 7,51 (2H, d), by 8.22 (2H, d), 8,23 (2H, d)

Compound IV-13: Z is a simple bond, R5H, R6OH, m 1, n 0, R7R8H, R9PNZ, R10H, 2S, 1,6 3,0 (2H, m), 3,0 4,3 (13H, m), 4,3 4,9 (2H, m), 5,20 (4H, s) to 7.50 (4H, d), to 8.20 (4H, d)

Compound IV-14: Z is a simple bond, R5H, R6F, m 1, n 0, R7R8H, R9PNZ, R10H, 2R, 1,90 2,30 (1H, m), 2,50 was 3.05 (1H, m), 3,05 4,00 (11H, m), 4,00 4,45 (2H, m), 4,60 5,70 (6H, m) to 7.50 (4H, d), by 8.22 (4H, d).

Compound IV-15: Z is a simple bond, m is 0, n is 2, R7H, R8CH2OH, R9PNZ, R10H, 4S, 1,40 2,20 (3H, m), 2,20 2,60 (2H, m), 2,60 3,10 (1H, m), 3,10 3,90 (13H, m), 3,90 5,30 (7H, m) to 7.50 (4H, m), 8,10 8,33 (4H, m)

Compound IV-16: Z CR11R12, R5R6H, m 2, n 0, R7R8H, R930 7,80 (4H, m), 8,05 8,24 (4H, m)

Compound IV-17: Z CR11R12, R5R6H, m 1, n 0, R7R8H, R9PNZ, R10H, R11H, R12OH.

2,3 2,5 (2H, m), 2,5 2,9 (1H, m), 3,0 3,9 (12H, m), 3.9 to 4.25 in (2H, m), 4,5 4,8 (1H, m), a total of 5.21 (4H, s), 7,51 (4H, d), by 8.22 (4H, d)

Compound IV-18: Z is a simple bond, R5H, R6OH, m 1, n 2, R7R8H, R9PNZ, R10H, 2S,

1,2 2,3 (5H, m), 2,5 4,5 (15H, m), 4,5 4,8 (1H, m), 5,20 (2H, m) to 7.50 (4H, d), to 8.20 (4H, d)

Compound IV-19: Z is a simple bond, m is 0, n is 3, R7R8H, R9PNZ, R10H,

1,3 2,0 (5H, m), 2,1 2,5 (2H, m), 2,5 3,0 (1H, m), 3,0 4,3 (13H, m), 4,5 4,8 (1H, m), 5,20 (4H, s) to 7.50 (4H, d), to 8.20 (4H, d)

Compound IV-20: Z is a simple bond, m is 0, n is 4, R7R8H, R9PNZ, R10H, 1,0 2,1 (7H, m), 2,1 2,4 (2H, m), 2,5 4,2 (14H, m), 4,5 4,9 (1H, m), 5,20 (2H, s), 5,23 (2H, s) to 7.50 (4H, d), to 8.20 (4H, d)

In each of the above compounds IV-4, IV-5, IV-6, IV-11, IV-12, IV-13, IV-14, IV-15 and IV-18 configuration of a partial structure (IVa) shown together with the number that indicates the position number of the corresponding atom in the partial structure (IVa), where the carbon atom of the carbonyl group (carbonyl carbon) is defined as the 1-position.

Inventive example 1.

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-/2-aminoacetyl/piperazine - 4-yl-carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carbiener in acetonitrile, added 83 mg of diisopropylethylamine and 173 mg of diphenylphosphinylchloride in this order in a stream of argon at 0oC, followed by reaction for 1 h at the same temperature. After cooling to -35oC there was added 80 mg of diisopropylethylamine and 390 mg /2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-/2-/p-nitrobenzenesulfonyl/aminoacetyl/piperazine-4 - yl/carbonitriding in this order, then carry out the reaction for 2 h at the same temperature. After concentrating the reaction solution, the residue is mixed with chloroform, washed with aqueous sodium bicarbonate solution, aqueous citric acid solution and water in this order, then dried over sodium sulfate, the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel, get 416 mg p-nitrobenzyl- /1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-p-nitrobenzenesulfonyl/-2-//2-/p-nitrobenzenesulfonyl/aminoacetyl/piperazine-4 - yl/carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl 3-carboxylate as a yellow foam.

NMR /CDCl3/ d 1,0 1,4 /6H, m/, 1,6 2,1 /1H, m, 2,5 3,0 /1H, m, 4,5 4,8 /1H, m, 5,0 5,6 /6H, m/, 7,3 7,8 /6H, m/, by 8.22 /6H, d/.

2. Suspended portion 416 mg of the compound obtained in the article is under 150 mg of platinum oxide under a pressure of 5 ATM. After removal of catalyst by filtration and removal of the tetrahydrofuran by evaporation under reduced pressure the residue is purified by chromatography on a column using Diaion HP-20, then purified HPLC, the result of 21.1 mg of target compound.

NMR /D2O/ d 1,23 /3H, d/, 1,32 /3H, d/, 1,6 1,7 /1H, m, 2,65 2,85 /1H, m, 3,0 3,1 /1H, m, 3,1 3,2 /1H, m, 3,3 3,4 /2H, m, 3,5 3,9 /1H, m, 4,15 4,05 /1H, m, 4,15 4,30 /2H, m/.

Inventive example 2.

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-//2-N,N - dimethylaminoacetyl/piperazine-4-yl/carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

1. Add to 199 mg p-nitrobenzyl-/1R, 5S, 6S, 8R/-6-/1-oxyethyl/-1-methyl-2-exacerbating-3-carboxylate, dissolved in acetonitrile, 85 mg of diisopropylethylamine and 177 mg of diphenylphosphinylchloride in this order in a stream of argon in an ice bath, then carry out the reaction for 1 h at the same temperature. After cooling to -35oC to the solution was added 82 mg diisopropylethylamine and 303 mg /2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-//N, N-dimethylglycine/piperazine-4-yl/carbonyl/pyrrolidine in this order, followed by reaction for 2 h at the same temperature. After concentration of the solvent, the resulting residue solution is hinnon pressure. The resulting residue is purified by chromatography on a column of silica gel, receive 429 mg foam p-nitrobenzyl-/1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-/p-nitrobenzenesulfonyl/-2-/1-//2-N,N - dimethylaminoacetyl/piperazine-4-yl/carbonyl/pyrrolidine-4-yl/-ist/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate.

NMR /CDCl3/ d 1,0 1,4 /6H, m/, 1,7 2,3 /7H, m/, 2,5 4,4 /14H, m/, 4,5 4,8 /1H, m, 5,0 5,6 /4H, m/ 7,4 7,7 /4H, m/, 8,20 /4H, m/.

2. Suspended portion 429 mg p-nitrobenzyl- /1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-/p-nitrobenzenesulfonyl/-2-/1-//2, N, N - dimethylaminoacetyl/piperazine-4-yl/carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/1-methylcarbamoyl-3-carboxylate obtained in stage 1/above, in a mixture of 10 ml of tetrahydrofuran and 10 ml of phosphate buffer, conduct hydrogenation for 2 h in the presence of 150 mg of platinum oxide under a pressure of 5 ATM. After removal of catalyst by filtration and removal of the tetrahydrofuran by evaporation under reduced pressure the residue is distilled chromatographytandem on the column using Diaion HP-20 and the target fraction additionally cleaned HPLC, the result of 18.3 mg of target compound.

NMR/D2O/ d 1,22 /3H, d/, 1,30 /3H, d/, 1,65 1/75 /1H, m, 2,75 2,85 /1H, m/ 2,87 /6N,, 3,10 3,20 /1H, m, 3,27 /1H, DD/ 3,35-3,55 /2N, m/, 3,50 3,60 /2N, m/, 3,60 3,75 /6N, m/, 3,80 3,90 /1H, m, 4,15 - 4,30 /5H, m/.

DIN-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

1. To 199 mg p-nitrobenzyl-/1R, 5S, 6S, 8R/-6-/1-oxyethyl/-1-methyl-2-oxocarbon-3-carboxylate, dissolved in acetonitrile, are added dropwise 85 mg diisopropylethylamine and 177 mg of diphenylethylamine in this order in a stream of argon at 0oC, then carry out the reaction for 1 h at the same temperature. After cooling to -35oC to the solution was added 82 mg diisopropylethylamine and 416 mg /2S, 4S/-4-mercapto-1-/p-nitrobenzenesulfonyl/-2-//1-/4-/p - nitrobenzenesulfonyl/aminobutyryl/piperazine-4-yl/carbonyl/pyrrolidine in this order, then carry out the reaction for 2 h at the same temperature. After concentration of the solvent, the resulting residue is mixed with chloroform, washed with aqueous citric acid solution and aqueous sodium chloride solution in this order, then dried over sodium sulfate, then the solvent is evaporated under reduced pressure and applying the obtained residue on chromatographic column filled with silica gel get 489 mg p-nitrobenzyl-/1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-/- nitrobenzisoxazole/-2-//1-/4-/p-nitrobenzenesulfonyl/aminobutyryl/-piperazine-4 - yl/carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate.

NMR/CDCl3/ d 1,0 1,4 /6N, the I, obtained in the above stage, suspended in a mixture of 10 ml of tetrahydrofuran and 10 ml of phosphate buffer and carry out hydrogenation for 2 h in the presence of 150 mg of platinum oxide under a pressure of 5 ATM. After removal of catalyst by filtration and removal of the tetrahydrofuran by evaporation the residue is purified by chromatography on a column using Diaion HP-20 with subsequent target HPLC fractions, the result of 50.7 mg of target compound.

NMR /D2O/ d 1,21 /3H, d/, 1,30 /3H, d/, 1,6 1,7 /1H, m, 1,8 1,9 /2N, m/, 2,5 2,6 /2N, m/, 2,6 2,8 /1H, m, 2,9 3,0 /3H, m/, 0 3,0 3,1 /1H, m, 3,3 3,4 /2N, m/, 3,5 3,7 /6N, m, 3,7 3,8 /1H, m, 4,1 4,3 /3H, m/.

Inventive example 4.

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-//2-/1-//2S/-4-amino-2-oxobutyric/-piperazine-4-yl/carbonyl/piperidine-4-yl/thio/-6-/1-oxyethyl/- 1-methylcarbamoyl-3-carboxylic acid

1. To 204 mg p-nitrobenzyl-/1R, 5S, 6S, 8R/-6-/1-oxyethyl/-1-methyl-2-oxycarbonyl-3-carboxylate, dissolved in acetonitrile, was added 80 mg of diisopropylethylamine and 166 mg of diphenylphosphinylchloride in this order in a stream of argon at 0oC, followed by reaction for 1 h at the same temperature. After cooling to -35oC to the solution was added 80 mg of diisopropylethylamine and 418 mg /2S, 4S/4 mehrabani/pyrrolidine in this order, then carry out the reaction for 5 h at the same temperature. After concentration of the solvent, the resulting residue is dissolved in chloroform, washed with water and then dried over sodium sulfate, then the solvent is evaporated under reduced pressure and purify the resulting residue by chromatography on a column of silica gel, receive 468 mg p-nitrobenzyl- /1R, 5S, 6S, 8R, 2'S, 4'S/-2-//1-/p-nitrobenzenesulfonyl/-2-//1-//2S/-4-p-nitrobenzenesulfonyl/amino-2 - oxobutyric/piperazine-4-carbonyl/pyrrolidine-4-yl/thio/-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate.

NMR /CDCl3/ d 1,0 1,4 /6N, m/, 1,4 2,2 /3H, m/, 2,4 2,9 /1H, m, 3,0 4,5 /N, m/, 4,5 4,9 /1H, m, 5,20 /4H/, 5,38 /2N, K/, 7,50 /4H, m/, 7,63 /2N, q/.

2. Portion 468 mg of the compound obtained in the above stage, suspended in a mixture of 7 ml of tetrahydrofuran and 7 ml of phosphate buffer, conduct hydrogenation for 4 h in the presence of 300 mg of 10% palladium on coal at a pressure of 4 ATM. After removal of catalyst by filtration and removal of the tetrahydrofuran by evaporation under reduced pressure the residue chromatographic on the column using Diaion HP-20, and then purify the target faction additionally HPLC, the result is 11 mg of the target compound.

Below is shown the replacement group (IVa), the compound (I) obtained in the above inventive examples, the replacement group (IVa), other compounds obtained in the same manner, and the results of NMR analysis. In these compounds: R1is 1-oxyethyl-/6S, 8R/ and R2is stands /1R/,

Compound I-1: Z is a simple bond, m n 0, R7R8R9R10H,

Compound I-2: Z is a simple bond, m n 0, R7R8H, R9R10CH3,

Compound I-3: Z is a simple bond, m is 0, n is 2, R7R8R9R10H,

Compound I-4: Z is a simple bond, R5H, R6OH, m n 1, R7R8R910H, 2S,

Compound I-5: Z is a simple bond, m n 0, R7CH3, R8R9R10H, 2R,

to 1.22 (3H, d), of 1.30 (3H, d), the 1.44 (3H, DD), 1,69 1,63 (1H, m), 2,75 - 2,82 (1H, m), 3,11 (1H, m), 3,21 (1H, DD), 3,37 of 3.45 (2H, m), 3,61 of 3.75 (8H, m), 3,81 3,88 (1H, m), 4,17 the 4.29 (3H, m), 4,35 of 4.44 (1H, m)

Compound I-6: Z is a simple bond, m n 0, R7CH3, R8R9R10H, 2S,

to 1.22 (3H, d), of 1.30 (3H, d), of 1.47 (3H, DD), 1,68 1,72 (1H, m), was 2.76 - to 2.85 (1H, m) and 3.15 (1H, m), or 3.28 (1H, DD), 3,35 3,45 (2H, m), 3,60 of 3.78 (8H, m), 3,83 3,91 (1H, m), is 4.21 or 4.31 (3H, m), of 4.45 (1H, m)

Compound I-7: Z is a simple bond, m n 0, R7R8H 3,6 3,7 (6H, m), 3,8 3,9 (1H, m), 4,10 (2H, d), 4,1 4,3 (3H, m)

Compound I-8: Z is a simple bond, m n 0, R7R8CH3, R9R10H,

to 1.22 (3H, d), of 1.30 (3H, d), 1,63 of 1.74 (1H, m) to 1.70 (6H, s), 2,73 is 2.80 (1H, m), of 3.12 (1H, DD), up 3.22 (1H, DD), to 3.36 to 3.45 (2H, m), 3,63 3,88 (9H, m), 4,18 to 4.28 (3H, m)

Compound I-9: Z is a simple bond, m n 0, R7R8-(CH2)2-, R9R10H,

0,87 1,07 (4H, m) to 1.22 (3H, d), of 1.30 (3H, d), 1,59 of 1.66 (1H, m), 2,70 and 2.79 (1H, m), 3.04 from is 3.08 (1H, m), 3,12 3,17 (1H, m), to 3.36 to 3.45 (2H, m), 3,47 a 3.87 (9H, m), 4,10 4,15 (1H, m)

Compound I-10: Z is a simple bond, m is 0, n is 1, R7R8H, R9R10H,

to 1.21 (3H, d), of 1.30 (3H, d), 1,6 1,7 (1H, m), 2,7 2,8 (1H, m), 2,8 - 2,9 (2H, m), 3,9 (1H, d), 3,19 (1H, DD), 3,2 3,3 (2H, m), 3,3 3,4 (2H, m), 3,5 3,7 (8H, m), 3,8 3,9 (1H, m), 4,1 4,3 (3H, m)

Compound I-11: Z is a simple bond, m n 0, R7H, R8CH2OH, R9R10H, 2R,

to 1.22 (3H, d), of 1.30 (3H, d), 1,75 1,84 (1H, m): 2,83 to 2.94 (1H, m) of 3.25 (1H, dt), 3,36 3,44 (2H, m), of 3.46 (1H, DD), 3,63 of 3.80 (8H, m), 3,80 - of 3.95 (3H, m), 4,21 be 4.29 (2H, m), 4,40 4,47 (2H, m).

Compound I-12: Z is a simple bond, m n 0, R7H, R8CH2OH, R9R10H, 2S,

to 1.22 (3H, d), of 1.30 (3H, d), 1,75 1,84 (1H, m), 2,83 of 2.93 (1H, m) of 3.25 (1H, m), 3,36 3,44 (2H, m), of 3.45 (1H, DDE, 3,63 of 3.78 (8H, m), 3,78 - of 3.95 (3H, m), 4,21 be 4.29 (2H, m), 4,40 4,47 (2H, m).

Compound I-13: Z is a simple bond, R5H, R6OH, m 1, n 0, R7R8R9R10H, 2S,

of 1.23 (3H, d), of 1.32 (3H, d), 1,6 1,7 (1H, m), 2,65 2,85 R8R9R10H, 2R,

to 1.22(3H, d), is 1.31 (3H, d), 1,72 1,90 (1H, m), 2,81 2,89 (1H, m), 3,22 3,19 (1H, m), 3,32 of 3.48 (5H, m), 3,60 is 3.82 (8H, m), of 3.85 to 3.92 (1H, m), 4,21 be 4.29 (2H, m), 4,32, however, 4.40 (1H, m), 5,63 of 5.68 (0.5 H, m), 5,75 5,80 (0.5 H, m)

Compound I-15, Z is a simple bond, m is 0, n is 2, R7H, R8CH2OH, R9R10H, 4S,

to 1.22 (3H, d), of 1.30 (3H, d), 1,64 1,58 (1H, m), 1,92 1,77 (2H, m), 2,56 2,77 (3H, m), 3,02 of 3.07 (1H, m), 3,07 of 3.27 (1H, m), 3,37 of 3.45 (2H, m), 3.45 was 3,82 (12H, m), 4,03 to 4.14 (1H, m), 4,20 4,30 (2H, m)

Compound I-16: Z CR11R12, R5R6H, m 2, n 0, R7R8R9R10R11H, R12CH3,

of 1.20 (3H, d), of 1.29 (3H, d), is 1.31 (3H, d), 1,59 of 1.66 (1H, m), 1,78 - of 1.88 (1H, m), 1.93 and 2,02 (1H, m), 2,53 of 2.68 (2H, m), 2,69 2,79 (1H, m), 3.04 from to 3.09 (1H, m), 3,19 3,14 (1H, m) 3,37 3,47 (3H, m), 3,60 3,71 (8H, m), 3,78 is 3.82 (1H, m), 4,12 to 4.28 (3H, m).

The connection I 17: Z CR11R12, R5R6H, m 1, n 0, R7R8R9R10R11H, R12OH,

to 1.22 (3H, d), is 1.31 (3H, d), 1,64 of 1.74 (1H, m), 2,64 (a 2.71 (1H, m), 2,71 to 2.85 (2H, m), to 3.02 (1H, DD), 3,14 (1H, m), up 3.22 (1H, DD), 3,26 (1H, DD), 3,40 (1H, m), of 3.45 (1H, DD), 3,57 is 3.82 (8H, m), 3,86 (1H, m), 4,20 4,36 (4H, m).

Connection 1 18: Z is a simple bond, R5H, R6OH, m 1, n 2, R7R8R9R10H, 2S,

to 1.19 (3H, d), of 1.28 (3H, d), 1,3 1,8 (5H, m), 2,65 2,80 (1H, m), 3,00 3,15 (3H, m), 3,15 3,20 (2H, m), 3,35 3,45 (2H, m), 3,50 of 3.85 (9H, m), 4,10 of 4.25 (3H, m), 4,70 4,65 (1H, m)

The connection I 19: Z is a simple bond, m is 0, n is 3, R7R8, ,8 of 3.9 (1H, m), 4,1 4,3 (3H, m).

Compound I 20: Z is a simple bond, m is 0, n is 4, R7R8R9R10H,

of 1.20 (3H, d), of 1.29 (3H, d), of 1.35 to 1.45 (2H, m) of 1.55 to 1.75 (5H, m) of 2.50 (2H, t), 2,65 2,80 (1H, m) to 2.99 (2H, t), 3,00 3,10 (1H, m), and 3.16 (1H, DD), 3,35 3,45 (2H, m), 3,55 3,75 (8H, m), 3,75 3,85 (1H, m), 4,10 - 4,30 (3H, m).

In each of the above compounds I 4, I 5, I 6, I 11, I 12, I 13, I 14, I 15 and I 18, the configuration of the partial structure (IVa) shown together with the number that indicates the position number of the corresponding atom in the partial structure (IVa), when the carbonyl carbon is defined as 1-position.

Inventive example 5.

/1R, 2S, 6S, 8R, 2'S, 4'S/-2-/2-/4-/2-/2-aminoethoxy/-acetyl-piperazine-1-Il/carbonyl/pyrrolidine-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid.

< / BR>
1. To 181 mg p-nitrobenzyl-/1R, 5S, 6S, 8R/-6-/1-oxyethyl/-1-methyl-2-oxocarbon-3-carboxylate, dissolved in acetonitrile and cooled in an ice bath, is added dropwise 0,131 ml diisopropylethylamine and 0,155 ml diphenylphosphinylchloride, then 3 h and stirred at the same temperature. After cooling to -35oC there is added 272 ml /2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-/p-nitrobenzenediazonium/ethoxyacetic/piperazine-1-Il/carbonyl/-4-mercaptopyrimidine and 0.087 ml is P> After evaporation of the solvent under reduced pressure the residue is purified by chromatography on a column of silica gel, receive 546 mg p-nitrobenzyl-/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/1-/p - nitrobenzenesulfonyl/-2-/2-/4/2-/2-p-nitrobenzenediazonium/ amoxi/acetyl/piperazine-1-yl-carbonitriding-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate.

NMR /CDCl3/ 1,10 1,60 /6H, m), 1,70 2,20 /1H, m, 2,50 - 2,90 /1H, m, 2,90 3,95 /15H, m/, 3,95 4,40 /5H, m/, 4,55 4,90 /1H, m, 5,19 /4H/, 5,20 /1H, d/, 5,51 /1H, d/, of 5.92 6,23 /1H, m, 7,50 / 4H, m/, 7,60 /4H, m/, 8,19 /6H, d/.

2. Dissolve a portion 546 mg p-nitrobenzyl- /1R, 5S, 6S, 8R, 2'S, 4'S/-2-/-1-/p-nitrobenzenesulfonyl/-2-/2-/4-/2-/2-p-nitrobenzenediazonium/amoxi/acetyl/piperazine-1-Il/carbonitriding-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate in a mixture of 30 ml of tetrahydrofuran and 40 ml of phosphate buffer, the solution is subjected to catalytic hydrogenation for 3 h in the presence of 180 mg of platinum oxide at a pressure of 4 ATM.

After removal of catalyst by filtration and concentration of the filtrate thus obtained residue chromatographic on the column using Diaion HP-20, the eluate then further purified HPLC, obtain 21 mg of the target compound.

NMR /D2O/ d 1,21 /3H, d/, 1,29 /3H, d/, 1,69 1,62

Inventive example 6.

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/2/-4/-/2//2S/-2-carboxy-2-amino-ethyl-thio/acetyl/piperazine-1-Il/carbonitriding-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

< / BR>
1. To 272 mg p-nitrobenzyl-/1R,5S,6S,8R/-6-/1-oxyethyl/-1-methyl-2-oxocarbon-3-carboxylate, dissolved in acetonitrile and cooled to 0oC, add 0,222 ml diphenylphosphinylchloride and 0,194 ml diisopropylethylamine, then carry out the reaction for 2 h at this temperature.

After cooling to -30oC there was added 680 mg /2S, 4S/-1-p-nitrobenzenesulfonyl/-2-/4-/2-//2S/-2-p-nitrobenzenesulfonyl/-2-/p-nitrobenzenediazonium/editio/acetyl/pyrazin-1-yl/carbonyl/-4-mercaptopyrimidine and 0,196 ml diisopropylethylamine, then hold for 2.5 h reaction at the same temperature. After this obtain a reaction solution was purified by chromatography on silica gel, to obtain 630 mg of p-nitrobenzenesulfonyl-/1R, 5S, 6S, 8R, 2'S, 4'S/2-/1-p-nitrobenzenesulfonyl/-2-/4-/2-//2S/- 2-/p-nitrobenzenesulfonyl/-2-/p - nitrobenzenediazonium/ethylthio/acetyl/piperazine-1-Il/carbonyl/-pyrrolidin-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate.

NMR /CDCl3/ 1,1 1,4 /6H, m/, 1,6 2,1 /1H, m, 2,4 2,9 /1H, M, 2,9-4,4 /19H, m/, ensil-/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/1-p-nitrobenzenesulfonyl-2-/4-/2-//2S/-2-/p - nitrobenzenesulfonyl/-2-/p - nitrobenzenediazonium/ethylthio/acetyl/piperazine-1-ylcarbonyl/pyrrolidin-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylate in a mixture solvent consisting of tetrahydrofuran and phosphate buffer, the resulting solution was subjected to catalytic recover for 2 h in the presence of 270 mg of platinum oxide in a stream of hydrogen at a pressure of 4.5 ATM. After removal of catalyst by filtration and concentration of the filtrate thus obtained residue chromatographic on the column using Diaion HP-20, the fraction containing the target compound additionally cleaned HPLC, get 118,5 mg of target compound.

NMR /D2O/ d 1,20 /3H, d/, 1,28 /3H, d/ a, 1,75 1,85 /1H, m, 2,80-2,95 /1H, m, 3,05 3,15 /1H, m, 3,15 3,20 /1H, m, 3,20 3,30 /1H, m, 3,35 3,50 /3H, m/, 3,60 3,75 /10H, m/, 3,90 3,95 /2H, m, 4,20 - 4,30 /2H, m, 4,40 4,50 /1H, m/.

The following compounds were obtained in the same way.

Inventive example 7.

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/2-/4-/2-//2R/-2-carboxy-2-aminoacetic/acetyl/piperazine-1-Il/carbonitriding-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

< / BR>
NMR /D2O/ 1,20 /3H, d/, 1,28 /3H, d/ a, 1,75 1,85 /1H, m, 2,85 2,95 /1H, m, 3,05 3,15 / the example 8

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/2-/4-/2-aminoacetic/acetyl/piperazine-1-Il/carbonitriding-4-yl/tio/6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

< / BR>
NMR /D2O/ 1,22 /3H, d/, 1,30 /3H, d/, 1,64-1,70 /1H, m/ 2,74 2,85 /1H, m, 2,92-2,95 /2H, m, 3,13 /1H, d/, 3,17 3,26 /3H, m/, 3,39 - 3,45 /2H, m/, to 3.58 3,72 /10H, m/, 3,86 3,84 /1H, m, is 4.21 or 4.31 /3H, m/, 4,76 4,85 /1H, m/.

Inventive example 9

/1R, 5S, 6S, 8R, 2'S, 4'S/-2-/2-/4-/2-/2-aminoacetyl/aminoacetyl/-piperazine-1-Il/carbonitriding-4-yl/thio-6-/1-oxyethyl/-1-methylcarbamoyl-3-carboxylic acid

< / BR>
Reference example 5.

/2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-/p - nitrobenzenediazonium/amoxi/acetyl/piperazine-1-Il/carbonyl-4-mercaptopyrimidine

< / BR>
1. Mix a portion of 6.11 g ethanolamine and 14,81 g of phthalic anhydride in 100 ml of toluene for 3 hours under heating. After concentrating the reaction solution, the residue is crystallized from chloroform, filtered and dried, obtaining and 17.2 g of white 2-phthalimidomethyl.

NMR /CDCl3/ 3,84 /4H/, 7,6 8,0 /4H, m/.

Add gradually the portion of 3.00 g of sodium hydride to 9,65 g of 2-phthalimidomethyl, which was dissolved in 200 ml of tetrahydrofuran, the mixture is refluxed for 2 hours, then added dropwise 7,65 g methylpropane the first material by filtration, the remaining filtrate is concentrated and extracted with chloroform, the organic layer washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure and purify the resulting residue by chromatography on a column of silica gel, the result is to 4.81 g of methyl 2-/2-phthalimidomethyl/acetate as a yellow oil.

NMR /CDCl3/ d 3,63 /3H/, 3,7 4,0 /4H, m, 4,10 /2H, m, 7,6 8,0 /4H, m/.

3. Suspended methyl-2-/2-phthalimidomethyl/acetate in 50 ml 6H hydrochloric acid and refluxed for 17 hours the resulting crystals Filtered off and washed 1H hydrochloric acid, the filtrate is concentrated. Thus obtained residue is dissolved in 1H hydrochloric acid, treated with cation exchange resin 1P 120, washed with water and then elute 2H aqueous ammonia, then concentrate elyuirovaniya fraction under reduced pressure, received 873 mg /2-/2-aminoethoxy/acetic acid.

NMR /D2O/ d 3,20 /2H, t/, 3,76 /2H, t/, 3,97 /2H,/.

4. While cooling in an ice bath to 596 mg 2-/2-aminoethoxy/-acetic acid dissolved in 100 ml of water, add essential solution 883 mg of sodium bicarbonate and 1.29 g of p-nitrobenzotrifluoride dropwise. After 17 h per conc. hydrochloric acid and extracted with ethyl acetate, the obtained organic layer is washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure to obtain 1.48 g of 2-/2-/p-nitrobenzenediazonium/amoxi/acetic acid.

NMR /CDCl3/ d 3,26 3,80 /4H, m/, 4,12 /2H,/, 5,20 /2H,/, 5,65 to 5.93 /1H, m, 7,50 /2H, d/, 8,18 /2H, d/.

5. To 100 ml of tetrahydrofuran was added 14.9 g/2S, 4R/-1-/p-nitrobenzenesulfonyl/-4-hydroxyproline, 12.4 g of dicyclohexylcarbodiimide and 6.75 g of N-oxybisethanol, then carry out the reaction for 1 h at room temperature, receive /2S, 4R/-1-/p-nitrobenzenesulfonyl/-4-oxypropyl-N-oxibendazole ether. To the solution was added 16.5 g of 1-/p-methoxybenzenesulfonyl/piperazine, then 2 h the reaction mixture is stirred at room temperature. After completion of the reaction, filtered dicyclohexylamine and the filtrate is evaporated under reduced pressure, the obtained residue is dissolved in chloroform and washed with 10% citric acid and water, dried over sodium sulfate, the solvent is evaporated under reduced pressure to obtain an oily residue. It is applied on a column of silica gel and elute with chloroform and a mixture of chloroform and methanol, to obtain 16.5 g /2S, 4R/-1-/p-nitrobenzenesulfonyl/-2-/4-/p-m the l3/ d 0,90 1,40 /2H, m/. 3,00 3,90 /11H, m/ 3,80 /3H/, 4,40 4,70 /1H, m, 4,90 5,44 /4H, m/ 6,75 7,02 /2H, m, 7,20 - 7,60 /4H, m/ 8,08 8,30 /2H, m/.

6. Dissolve a portion of 11.8 g of triphenylphosphine in 200 ml of tetrahydrofuran and cooled at -20oC added dropwise 7,06 ml of diethylazodicarboxylate to the solution.

After 40 minutes there is gradually added dropwise 200 ml of tertrahydrofuran ring solution containing 15.9 g /2S, 4R/-1-/p-nitrobenzenesulfonyl/-2-/4-/p-methoxybenzenesulfonyl/piperazine-1-Il/carbonyl-4-oxopyrrolidin and 5.2 ml thiobenzoic acid. After the reaction over night under stirring at room temperature tetrahydrofuran is evaporated under reduced pressure, the residue is dissolved in 500 ml ethyl acetate and washed with aqueous sodium bicarbonate solution, the organic layer washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure. Thus get /2S, 4R/-1-/p-nitrobenzenesulfonyl/-2-/4-/p-methoxybenzenesulfonyl/piperazine-1-Il/carbonyl-4-benzoyl-cooperrider, which is used in the next reaction without purification.

The crude compound, obtained above, was added to a chilled on ice mixture consisting of 200 ml triperoxonane acid is Noah acid under reduced pressure the residue is dissolved in ethyl acetate and neutralized with an aqueous solution of sodium bicarbonate, collect an ethyl acetate layer is washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure. Thus obtained residue chromatographic on a column of silica gel, collecting fractions, erwerbende with a mixture of chloroform and methanol, which are 12 g /2S, 4R/-1-/p-nitrobenzenesulfonyl/-2-/piperazine-1-Il/carbonyl-4-benzoylpiperidine.

NMR /CDCl3/ d 1,8 2,3 /1H, m, 2,6 3,3 /5H, m/, 3,3 4,0 /5H, m/ 4,0 4,4 /2H, m, 4,6 5,0 /1H, m, 5,23 /2H,/, 7,3 7,7 /5H, m/, 7,8 8,0 /2H, m, 8,23 /2H, d/.

8. Dissolved in 10 ml of tetrahydrofuran 209 mg 2-/2-/p-nitrobenzenediazonium/amoxi/acetic acid, then stirred in an ice bath. Add back 161 mg of 1-oxibendazole and 433 mg dicyclohexylcarbodiimide, then after 1 h of stirring at the same temperature give 523 mg /2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/piperazine-1-Il/carbonyl-4-benzoylpiperidine and 0,146 ml of triethylamine, then stirred for 1 h After removal of insoluble materials by filtration the resulting filtrate is evaporated under reduced pressure and the residue chromatographic on a column of silica gel, receive 402 mg of (2S, 4S)1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-/p-nitrobenzenediazonium/amoxi/aceti d 1,80 2,30 /1H, m/, 2,60 3,00 /1H, m, 3,20 - 4,00 /13H, m/ 4,00 4,40 /4H, m/, 4,60 5,00 /1H, m, 5,00 5,35 /5H, m/, 7,35 7,65 /7H, m/ 7,83 8,00 /2H, m, 8,00 8,33 /4H, m/.

9. To 402 mg /2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-/p-nitrobenzenediazonium/amoxi/acetyl/piperazine-1-yl-carbonyl-4-benzoylpiperidine dissolved in 5 ml of tetrahydrofuran, add 5 ml of methanol, and then stirred in an ice bath. To the solution obtained above was added portion 69 mg of sodium methoxide and stirred for 30 minutes. After neutralizing the reaction solution with concentrated hydrochloric acid and subsequent evaporation of the solvent under reduced pressure, the resulting residue chromatographic on a column of silica gel, get 272 mg of the target compound.

NMR /CDCl3/ d 1,70 2,16 /1H, m, 2,50 2,95 /1H, m, 2,95 - 3,93 /13H, m/, 3,93 4,30 /4H, m/, 4,50 4,85 /1H, m, 5,00 5,32 /5H, m/, 7,51 /4H, m/, 8,20 /4H, m/.

Reference example 6

/2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-//2S/-2-/p-nitrobenzenesulfonyl/-2-/p - nitrobenzenediazonium/ethylthio/acetyl/piperazine-1-Il/carbonyl-4-mercaptopyrimidine

< / BR>
1. To of 5.05 g of D-cysteine hydrochloride, dissolved in 4H, sodium hydroxide and cooled in an ice bath, is added dropwise 9,39 ml p-methoxybenzylamine, then 2 hours and stirred at the Noah acid, filter the crystals, get 7.78 g S-p-methoxybenzyl-D-cysteine in the form of light yellow crystals.

Portion 7,025 g thus obtained S-p-methoxybenzene compounds dissolved in aqueous acetonitrile and cooled in an ice bath was added there was 12.75 g of sodium bicarbonate and 7,09 g p-nitrobenzotrifluoride, the mixture is stirred for 1.5 h at room temperature. The reaction solution is washed with ether, acidified with concentrated sulfuric acid and extracted with ethyl acetate, the obtained organic layer is washed with water and dried over sodium sulfate, then the solvent is distilled off under reduced pressure, the result is 6,47 g S-p-methoxybenzyl-N-p-nitrobenzisoxazole in the form of butter.

Portion 2,31 ml of triethylamine was added to a cooled on ice to a solution in dimethylformamide of 5.81 g obtained above p-nitrobenzisoxazole connection and 3.28 g of p-nitrobenzylamine, the mixture is stirred for 1 h at the same temperature and then for 3 h at room temperature. After removal of the solvent by evaporation under reduced pressure the resulting residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate, then evaporated rauchut 7,31 g S-p-methoxybenzyl-N-p-nitrobenzenesulfonyl-D-cysteine-p - nitrobenzyl ether.

NMR /CDCl3/ 2,89 /2H, d/, 3,66 /2H,/, of 3.77 /3H/, 4,5 - 4,6 /1H, m/, to 5.21 /2H,, 5,26 /2H,/, 5,5 5,7 /1H, m, 6,80 /2H, d/, 7,16 /2H, d/, 7,4 7,6 /4H, m/, 8,18 /4H, m/.

2. Portion 766 mg S-p-methoxybenzyl-N-p-nitrobenzenesulfonyl-D-cystein-p-nitrobenzyl ether dissolved in a mixture triperoxonane acid and anisole and cooled in an ice bath, then add 0,183 ml triftormetilfullerenov acid and the resulting mixture was stirred for 5 h at room temperature. After evaporation of the solvent under reduced pressure the resulting residue is mixed with ethyl acetate, washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride in this order, then dried over sodium sulfate, the solvent is evaporated under reduced pressure to obtain 920 mg of N-p-nitrobenzenesulfonyl-D-cysteine-p-nitrobenzyl ether.

Portion 0,186 ml of triethylamine are added to a dichloromethane solution containing 319 mg of the thus obtained compound and 217 mg of 1-p - methoxybenzyloxy-4-/2-chloroacetyl/piperazine a mixture of 2 h refluxed. After removal of the solvent under reduced pressure the residue is purified by chromatography on silica gel, to obtain 453 mg of 1-p - methoxybenzyloxy-4-/2-//2S/-/n-nite.

NMR /CDCl3/ d 3,11 /2H, d/, 3,3 3,7 /10H, m/ 3,80 /3H, 4,5 4,9 /1H, m, 5,08 /2H,, 5,22 /2H,, 5,28 /2H,/, 5,5 5,7 /1H, m, 6,89 /2H, d/, 7,29 /2H, d/, 7,52 /4H, m/, 8,17 /2H, d/, 8,19 /2H, d/.

3. To 193 g /2S, 4R/-1-/tert.butoxycarbonyl-2-etoxycarbonyl-4-oxopyrrolidin dissolved in 500 ml of pyridine and cooled in an ice bath, was added 213 g of p-toluensulfonate, then stirred for 20 h at room temperature. The reaction mixture was concentrated and the resulting residue is dissolved in ethyl acetate, washed with water, 10% aqueous citric acid solution, 5% aqueous sodium bicarbonate solution and water in this order, then the solvent is evaporated under reduced pressure, get 289 g /2S, 4R/-1-/tert. butoxycarbonyl/-2-etoxycarbonyl-4-/p-toluensulfonate/pyrrolidine.

Then dissolve of 36.4 g thiobenzoic acid in 300 ml of dimethylformamide and cooled in an ice bath, then added back gradually to 10.5 g of sodium hydride. Add back 102 g /2S, 4R/-1-/tert.butoxycarbonyl/-2-etoxycarbonyl-4-/p - toluensulfonate/pyrrolidine dissolved in 200 ml of dimethylformamide, and 37.5 g of sodium iodide, then 3 hours, heated at 80oC. After concentrating the reaction mixture thus obtained residue is dissolved in benzene, received orgai water in this order, then dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel, get 66 g /2S, 4S/-1-/tert.butoxycarbonyl/-2-etoxycarbonyl-4-benzoylpiperidine.

While cooling in an ice bath was added 66 g of the thus obtained compound to ethoxide sodium prepared from 300 ml of ethanol and 4.4 g of sodium, the mixture was subjected to reaction at the same temperature for 30 minutes. To the reaction solution are added while cooling in an ice bath 27,4 g p-methoxybenzylamine and the resulting mixture stirred for 2 h at the same temperature. After concentration of the reaction mixture, the resulting residue is mixed with ethyl acetate, the obtained organic layer is washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure and purify the resulting residue by chromatography on a column of silica gel, get 56 g /2S, 4S/-1- /tert.butoxycarbonyl/-2-Atarbekyan-4-/p-methoxybenzyl/tierralinda.

A portion of 3.95 g of the thus obtained compound was dissolved in 20 ml triperoxonane acid and conduct the reaction at room temperature for 1 h, evaporated solution is the atrium and extracted with ethyl acetate, the resulting organic layer is washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure to obtain 2.8 g /2S, 4S/-2-ethoxycarbonyl-4-/p-methoxybenzyl/tierralinda.

Thus obtained compound was dissolved in 20 ml of tetrahydrofuran and the resulting solution was added under cooling in an ice bath and 1.4 ml of triethylamine and 2.2 g of p-nitrobenzotrifluoride, conduct the reaction for 3 hours After removal of the solvent by evaporation under reduced pressure the resulting residue is mixed with ethyl acetate and the organic layer washed with water and dried over sodium sulfate, then the solvent is evaporated under reduced pressure, get a 4.5 /2S, 4S/-1-p-nitrobenzenesulfonyl-2-etoxycarbonyl-4-/p-methoxybenzyl/tierralinda. It is dissolved in 50 ml of ethanol, mixed with 24 ml of 1H of sodium hydroxide and stirred for 15 h, then the solvent is evaporated under reduced pressure and then dilute the concentrated solution with water and washed with ethyl acetate. The information collected during this aqueous layer was acidified with aqueous citric acid solution and extracted with ethyl acetate, the obtained organic layer is washed with water and dried over sodium sulfate ethoxybenzyl/thioproline.

NMR /CDCl3/ d 1,8 2,8 /2H, m, 2,9 3,6 /3H, m/, to 3.73 /2H,/, 3,80 /3H/, 4,34 /1H, t/, 5,24 /2H,/, 6,21 /1H/, 6,86 /2H, d/, of 7.23 /2H, d/, 7,4 7,6 /2H, m, 8,1 8,3 /2H, m/.

4/ To 278 mg /2S, 4S/-1-p-nitrobenzenesulfonyl/-4-/p-methoxybenzylthio/Proline dissolved in 5 ml of dichloromethane, are added 0,109 ml oxalicacid and one drop of dimethylformamide, then carry out the reaction for 1.5 h and then the solvent is evaporated under reduced pressure, get /2S, 4S/-1-/p-nitrobenzenesulfonyl/-4-/p-methoxybenzyl/theprolonged.

Conduct the reaction between the portion 453 ml 1-/p-methoxybenzenesulfonyl/-4-/2-//2S/-2-/p-nitrobenzenesulfonyl/-2-/p-nitrobenzenediazonium/ethylthio/acetyl/piperidine obtained in the previous phase 2/, and 3 ml triperoxonane acid for 30 min, then remove the solvent under reduced pressure. The resulting residue is dissolved in dichloromethane, mixed with 2,18 ml of triethylamine and conduct the reaction with just obtained the acid chloride of the acid at an elevated temperature, the resulting product was then purified by chromatography on a column of silica gel, receive 494 mg /2S, 4S/-1- /p-nitrobenzeneboronic/-2-/4-/2-//2S/-2-/p-nitrobenzenesulfonyl/-2- /p-nitrobenzenediazonium/ethylthio/acetyl/piperazine-1-ylcarbonyl/, 4,4 4,8 /2H, m, 5,18 /2H,/, 5,23 /2H,/, of 5.29 /2H,/, 6,85 /2H, d/, of 7.23 /2H, d/, 7,4 7,6 /6H, m/, 8,1 - 8,3 /6H, m/.

5/ To 774 mg /2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-//2S/-2-/p-nitrobenzenesulfonyl/-2-/p - nitrobenzenediazonium/ethylthio/acetyl/piperazine-1-ylcarbonyl/-4-/p - methoxybenzyl/tierralinda obtained in stage 4/ above and dissolved in a mixture triperoxonane acid and anisole are added 0,021 ml triftormetilfullerenov acid at room temperature, conduct the reaction mixture for 4 h

After evaporation of the solvent at low temperature, the obtained residue is purified by chromatography on a column of silica gel, get the target connection.

NMR /CDCl3/ d: 1,6 2,1 /2H, m, 2,5 2,8 /1H, m, 2,8 4,2 /15H, m/, 4,4 4,8 /2H, m, 5,23 /4H/, from 5.29 /2H,/, 7,4 7,6 /6H, m/, 8,1 8,3 /6H, m/.

Reference example 7

/2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4- /2-//2S/-2-/p-nitrobenzenesulfonyl/-2-/p-nitrobenzenediazonium/- ethylthio/acetyl/piperazine-1-Il/carbonyl-4-mercaptopyrimidine

NMR /CDCl3/ d 1,6 2,2 /2H, m, 2,5 2,9 /1H, m, 2,9 4,2 /15H<m/, 4,5 4,8 /2H, m, 5,23 /4H/, from 5.29 /2H,/, 7,4 7,6 /6H, m/, 8,1 8,3 /6H, m/.

Reference example 8

/2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-/p-nitrobenzenesulfonyl/aminoacylation/acetyl/paparazi the/1H, m/, 5,19 /4H,, 5,31 - 5,59 /1H, m, 7,51 /4H, m/, 8,21 /4H, m/.

Reference example 9

/2S, 4S/-1-/p-nitrobenzenesulfonyl/-2-/4-/2-/2-p-nitrobenzenesulfonamide/aminoacetyl/piperazine-1-Il/carbonyl/-4-mercaptopyrimidine

NMR /CDCl3/ d 1,70 2,13 /1H, m, 2,50 2,95 /1H, m, 3,10 - 4,30 /15H, m/, 4,50 4,90 /1H, m, 5,00 5,40 /4H, m/ 5,64 5,93 /1H, m, 6,92 7,25 /1H/, 7,50 /4H, m/, 8,20 /4H, m/.

The invention can provide an antibiotic that is effective against various bacterial strains, including Pseudomonas aeruginosa, excellent security and stable against hydrolases, such as BPH, and the like.

1. Derivatives carbapenem General formula I

< / BR>
where R1lower alkyl which may be substituted by hydroxyl or protected hydroxyl;

R2lower alkyl;

R3carboxyl, which may be esterified;

R4aminoamides group or a hydrogen atom;

R5and R6the same or different, hydrogen atom, hydroxyl and halogen atom;

R7a hydrogen atom, lower alkyl or carboxyl;

R8a hydrogen atom, lower alkyl or hydroxylase alkyl, or R7and R8together may form a C2- C6-alkylenes group;

R9Rasta communication, an oxygen atom, a sulfur atom or a group

CR11R12,

where R11and R12the same or different, hydrogen atom, hydroxyl or lower alkyl,

or group

< / BR>
where R13a hydrogen atom;

m and n are integers from 0 to 6;

and their pharmaceutically acceptable salts.

2. The compound and its salt under item 1, wherein R1- 1-hydroxyethyl group.

3. The compound and its salt under item 1 or 2, characterized in that the said compound is (6S,8R)-6-(1-oxyethyl)a carbapenem derivative.

4. The compound and its salt under item 1 or 2, characterized in that the said compound is (1R,5S,6S,8R)-6-(1-oxyethyl)-1-methylcarbamoyl derived.

5. The compound and its salt under item 1 or 2, characterized in that the said compound is (1R,5S,6S,8R, 2'S, 4'S)-2-[2-((4-((2S)-5-amino-2-oxopentanoic) piperazine-1-yl)carbonyl)pyrrolidin-4-yl)-thio] -6-(1-oxyethyl)- 1-methylcarbamoyl-3-carboxylic acid.

6. The compound and its salt under item 1 or 2, characterized in that the said compound is (1R, 5S, 6S, 8R, 2'S, 4'S)-2-[2-(4-(2-(2- aminoethoxy)acetyl)piperazine-1-yl) carbonyliron-4-yl]-thio-6-(1-oxyethyl)-1-methylcarbamoyl-3 - carboxylic acid.

 

Same patents:

The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents

Anti-inflammatory // 2086239
The invention relates to medicine, namely to the use of new anti-inflammatory drugs from the class alkanolammonium salts hetarylthioacyl acids, specifically to indolyl-3-diacetate Tris/2-hydroxyethyl/ammonium

The invention relates to new chemical compounds, particularly to derivatives of 2-aminoindole that exhibit hepatoprotective activity and can find application in medical practice

The invention relates to the field of new biologically active compounds, in particular to 1-benzyl-2-oxitriptan hydrochloride and its derivatives, possess hepatoprotective activity, which can be used as potential drugs in medical practice

The invention relates to pharmaceutical chemistry and relates to crystalline salts of substituted tetrahydrobenzo[cd]indole and its applications

The invention relates to medicine, namely to the use of Tris(2-hydroxyethyl) ammonium salt of 3-IntelliTouch acid having the following formula

< / BR>
as a highly effective protective means in cardiogenic shock and toxic stress

The invention relates to medicine, in particular to the experimental cardiology and the treatment of congestive heart failure

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves intravitreously introducing two electrodes into intraocular neoplasm after carrying out vitrectomy and retinotomy to expose the intraocular neoplasm. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with current intensity of 100 mA during 1-10 min or 10 mA during 10 min in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2.The transformed retina and tumor destruction products are intravitreally removed. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. Another embodiment of the invention involves adjusting position and size of the intraocular neoplasm in trans-scleral diaphanoscopic way. Rectangular scleral pocket is built above the intraocular neoplasm to 2/3 of sclera thickness with its base turned away from limb. Several electrodes are introduced into intraocular neoplasm structure via the built bed. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with the same current intensity in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. Superficial scleral flat is returned to its place and fixed with interrupted sutures. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg after having carried out vitrectomy and retinotomy. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2. The transformed retina and tumor destruction products are intravitreally removed using vitreotome. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. The number of electrodes is equal to 4-8.

EFFECT: reduced risk of metastasizing.

4 cl, 13 dwg

FIELD: medicine.

SUBSTANCE: method involves building tunnel to posterior eyeball pole in inferoexterior and superexterior quadrants. The tunnel is used for implanting flexible polymer magnetolaser implant to the place, the subretinal neovascular membrane is localized. The implant has a permanent magnet shaped as a cut ring and is provided with drug delivery system and a short focus scattering lens of laser radiator connected to light guide. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 5-7 mTesla units intensity. It is arranged with its north pole turned towards sclera at the place of the subretinal neovascular membrane projection with extrascleral arrangement of laser radiator lens membrane being provided in the subretinal neovascular membrane projection area. The other implant end is sutured to sclera 5-6 mm far from the limb via holes made in advance. The implant is covered with conjunctiva and retention sutures are placed thereon. Light guide and drug supply system lead is attached to temple with any known method applied. Drugs are supplied via the implant drug supply system in retrobulbary way in any order. Triombrast is given in the amount of 0,4-0,6 ml and dexamethasone or dexone in the amount of 0,4-0,6 ml during 3-4 days every 12 h. 0.1-1% aqueous solution of khlorin is intravenously introduced at the third-fourth day after setting the implant as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, at a bolus dose of 0.8-1.1 mg/kg. Visual control of subretinal neovascular membrane cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the subretinal neovascular membrane with the photosensitizer to maximum saturation level, intravitreous, transretinal laser radiation of 661-666 nm large wavelength is applied at general dose of 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the subretinal neovascular membrane via laser light guide and implant lens, repeated laser irradiation of the subretinal neovascular membrane is carried out with radiation dose of 30-60 J/cm2.

EFFECT: accelerated subretinal edema and hemorrhages resorption; regression and obliteration of the subretinal neovascular membrane; prolonged vision function stabilization.

6 cl

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

Up!