Intermediate products - methyl 7-aryl-4, 9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1, 7-diazaspiro[4,4]none-3, 8-diene-8-carboxylates; methyl 6, 9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3, 4,10-trioxo-7-oxa-2, 9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates; method of producing methyl 6, 9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3, 4, 10-trioxo-7-oxa-2, 9-diazatricyclo [6.2.1.01,5]undec-5-ene-8-carboxylates; methyl 11-benzoyl-2-o-hydroxyphehyl-3, 4, 10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2, 9-diazatricyclo [6.2.1.01,5]undec-5-ene-8-carboxylate having antimicrobial activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III Ar1=Ar2=Ph, Ar3=C6H4Me-n (IIIa); and Ar1=C6H4Br-n, Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-6-ene-8-carboxylates of formula IV where Ar1=Ar2=Ph, Ar3=C6H4Me-n (IVa); Ar1=C6H4Br-n Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 ex

 

"Intermediate products - methyl-7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates; Methyl-6,9-diaryl-1 1-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates; the Method of obtaining methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates; Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylate having antimicrobial activity.

The technical field

The invention relates to the field of organic chemistry, namely the synthesis and release of intermediate products (individual compounds) 1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates having antimicrobial activity, to the synthesis of individual compounds functionalized bridged heterocyclic system 7-oxa-2,9-diazatricyclo[6.2.1.01,5]undecane having antimicrobial activity, which can be used as starting products for the synthesis of new heterocyclic systems.

The level of technology

Known structural analogues of the claimed compounds (5-methyl-2-oxo-1-phenyl-4-etoxycarbonyl-2,3-dihydro-1H-pyrrol-3-Spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydropyrrole)received vzaimode esteem 3-aroyl-2,4-dihydro-1H-pyrrolo[2,1-C] [1,4]benzoxazine-1,2,4-trions with ethyl 3-arylamino-2-butenoate (ethyl esters 3 arylamino-2-butenova acid) (RF Patent for the invention №2294330, priority 11.10.05, the application 2005131264, registered in the State. The registry of the Russian Federation 27.02.2007,).

The disadvantages of this method include the inability to obtain methyl 7-aryl-4,9-derail-(3-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates, which are an intermediate product for the synthesis of more complex bridged heterocyclic system 7-oxa-2,9-diazatricyclo[6.2.1.01,5]undecane having antimicrobial activity.

Known structural analogues of the claimed compounds (7-oxa-2,9-diazatricyclo[6.2.1.01,5]undecane), obtained by the interaction of 3-aroyl-5-phenyl-1,2,4,5-tetrahydro-1H-pyrrolo[2,1-a]cinoxacin-1,2,4-trions with 3-amino - and 3-benzylamino-5,5-dimethyl-2-cyclohexen-1-areas (RF Patent for the invention №2257386, priority 05.05.04, the application 2004113761, registered in the State. The registry of the Russian Federation 27.07.2005,). Synthesis of structural analogues is performed according to the following scheme:

The disadvantages of this method include the inability to obtain methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates. Structural analogues have a weak antimicrobial activity. The compound (IIIa) has the minimum inhibitory concentration against the stamp of Escherichia coli .li M171000 µg/ml and Golden state is okocha P-209 1000 µg/ml

Disclosure of inventions

The objective of the invention is to develop a simple method for the synthesis of intermediate product methyl-7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates and develop a method for the synthesis of these intermediates - methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates, exhibiting antimicrobial activity, which can be used as starting products for the synthesis of new heterocyclic systems and find application in medical practice.

The task is carried out by boiling 3-aroyl-2,4-dihydro-1H-pyrrolo[2,1-C][1,4]benzoxazine-1,2,4-trions with methyl 4-aryl-2-arylamino-4-oxo-2-butenoate taken in the ratio 1:1, in an inert aprotic solvent to obtain intermediate products - substituted methyl

7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates, cyclicality by recrystallization from ethyl acetate in methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates, according to the scheme:

I, AG1=Ph (a), (C6H4VG-p (b); II, Ar2=Ph, Ar3=C6H4IU-p (a), Ar2=C6H 4OEt-p, Ar3=C6H4IU-p (b); III, IV, Ar1=AG2=Ph, Ar3=C6H4IU-p (a), Ar1=C6H4VG-p, Ar2=C6H4OEt-p, Ar3=C6H4IU-p (b).

The process is conducted at a temperature of 79-80°C, and the solvent used absolute benzene. As a solvent for recrystallization using ethyl acetate.

From the patent and technical literature were identified ways of getting similar to methyl 7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates connection, but when using these ways to get the products, which cannot be used for the synthesis of bridged heterocyclic systems.

From the patent and technical literature were not identified methods of synthesis of methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates having similar characteristics with the claimed method, and it has not been used for the original products, solvents in which the reaction takes place, and the temperature, on what basis is it possible to make a conclusion on the compliance of the claimed technical solution the criterion of "novelty" and "inventive step".

The invention is illustrated by the following examples.

Example 1 (an intermediate product). Methyl 4,9-dibenzo the l-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-7-p-methoxyphenyl-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylate (IIIa).

A solution of 1.0 mmol of 3-benzoyl-2,4-dihydro-1H-pyrrolo[2,1-C][1,4]benzoxazine-1,2,4-trione(Ia) and 1.0 mmol of methyl (2E)-4-oxo-4-phenyl-2-(4-toluidine)-2-butenoate (IIA) in 10 ml of absolute benzene was boiled for 20 minutes (before bleaching), cooled, precipitated precipitate was filtered, washed 2 times in 1 ml ethyl acetate and 5 ml of hexane. Yield 85%, TPL 184-185°C.

The compound (III a) C36H26N2O8.

Found %: at 70.32; N, 4.16; N, 4.58.

Calculated %: C 70.35; N, 4.26; N, 4.56.

Example 2 (intermediate product). Methyl 4-p-bromobenzoyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-7-p-methoxyphenyl-9-n-ethoxybenzoyl-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylate(IIIB).

A solution of 1.0 mmol of 3-p-bromophenyl-2,4-dihydro-1H-pyrrolo[2,1-C][1,4]benzoxazine-1,2,4-trione (1B) and 1.0 mmol of methyl (2E)-4-oxo-2-(4-toluidine)-(4-ethoxyphenyl)-2-butenoate (IIB) in 10 ml of absolute benzene was boiled for 25 minutes (before bleaching), cooled, precipitated precipitate was filtered, washed 2 times in 1 ml ethyl acetate and 5 ml of hexane. Yield 86%, TPL 209-210°C.

The compound (IIIB), C38H29BrN2O9.

Found, %: C at 61.76; H 3.92; VG 10.84; N, 3.76.

Calculated, %: C 61.88; H 3.96; VG 10.83; N, 3.80.

Compound (III a, b) - light yellow crystalline substance with a high melting temperature, melting with decomposition, soluble in DMF and DMSO, insoluble in the usual organic solvents, insoluble in alkane and water, giving positive sample (cherry staining) in the presence of enol and phenolic hydroxyl with an alcoholic solution of ferric chloride (III).

In the IR spectra of compounds (III a, b) are the bands of stretching vibrations of the groups HE is in the form of a broad peak in the region 3150-3170 cm-1group the Sooma in the field 1760-1770 cm-1two lactam carbonyl groups in the form of two peaks in the area 1723-1736 cm-1, acetyl and arolina carbonyl group in the form of two peaks in the area 1620-1675 cm-1.

In NMR spectra1N solutions of helical compounds (III a, b) in DMSO-d6in addition to the signals of the protons of aromatic rings and related groups is the singlet protons metoxygroup in the field 3.23-3.30 ppm, a singlet proton of the phenolic group HE is in the area of 9.83-9.84 ppm, broadened singlet proton enol group HE is in the field 12.50-12.60 ppm

The proposed method is quite simple, one-step and allows you to get undescribed in the literature methyl 7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates, in almost quantitative yield, which can be used as starting products for the synthesis of new heterocyclic systems.

Example 3. Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carbox the lat (IVa). A solution of 1.0 mmol of methyl 4,9-Dibenzoyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-7-p-methoxyphenyl-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylate was recrystallize from 10 ml of ethyl acetate, cooled, precipitated residue was filtered. Yield 90%, TPL 190-191°C (from ethyl acetate).

The compound (IVa) C36H26N2O8.

Found, %: C 70.28; N, 4.21; N, 4.49.

Calculated, %: C 70.35; N, 4.26; N, 4.56.

Example 4. Methyl 6-n-bromophenyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-p-tolyl-11-p-ethoxybenzoyl-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylate (IV6).

A solution of 1.0 mmol of methyl 4-p-bromobenzoyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-7-p-methoxyphenyl-9-p-ethoxybenzoyl-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylate was recrystallize from 10 ml of ethyl acetate, cooled, precipitated residue was filtered. Yield 93%, TPL 210-211°C (from ethyl acetate).

Connection (IV6)38H29rN2O9.

Found, %: C 61.85; H 3.94; VG 10.79; N, 3.82.

Calculated, %: C 61.88; H 3.96; VG 10.83; N, 3.80.

Compounds (IV (a,b) is a colourless, crystalline substance with a high decomposition temperatures, soluble in DMF and DMSO, insoluble in the usual organic solvents, insoluble in alkanes and water, giving a positive test (cherry staining) in the presence of a phenolic hydroxyl with an alcoholic solution of ferric chloride (III).

In the IR spectra of compounds (IV (a,b) have I the bands of stretching vibrations of the group HE is in the form of a broad peak in the region 3220-3230 cm -1group the Sooma in the field 1767-1770 cm-1two lactam and ketone carbonyl group in position 4 in the form of one or two peaks in the area 1721-1755 cm-1, aroline carbonyl group in the field 1700-1707 cm-1.

In NMR spectra1N solutions of the compounds (IV, a,b) in DMSO-d6besides the signals of the protons of aromatic rings and related groups, there is a singlet proton OMe group in the field 3.23-3.34 ppm, singlet methine proton With11N in the field 5.15-5.25 ppm, a singlet proton of the phenolic group HE is in the field 9.91-10.01 ppm

The NMR spectrum13With a solution of the compound (IV) in DMSO-d6there are the following signals of carbon atoms (δ, ppm): 189.11 (WITHWith6H4t), 176.95 (4=O), 167.87, 163.07 (10=O,3=O), 159.80 (WithOON3), 154.07 (5), 137.68-106.49 hrs (Ar), 92.44 (8), 65.29 (Spiro), 63.72 (11), 53.76 (och2), At 44.52 (och3), 20.49 (CH3), 14,40 (CH2CH3).

Example 5.

Study of the antimicrobial action of the claimed compounds was carried out on gram-positive microorganisms Staphylococcus aureus (strain 906) and Escherichia coli (strain 1275), method twofold serial dilutions in accordance with the methodology of the study of antimicrobial drugs [Henderson. Methods of experimental chemotherapy. - M.,1971, p.100, 109-117].

the La culturing bacteria used mastopathy agar and broth (pH 7,2-7,4). Prepared initial cultivation of microbial bodies on the optical standard turbidity of daily agar culture. To determine the antimicrobial activity of the microbial load corresponded to 2.5·105microbial cells in 1 ml of medium. The microbial suspension was made in the prepared diluted drugs in a nutrient medium. The results of the experiments considered after 20 hours (inhibitory effect) and 7 day (bactericidal effect) incubation at 37°C. Antimicrobial (bacteriostatic - MIC and bactericidal MBq) activity was estimated by the minimum valid concentration. The maximum tested concentration of compounds was 1000,0 µg/ml Standard of comparison served as is known in medical practice fenilsalitsilat (Medmaravis "Drugs". - M.: Medicine, 1993, Vol.2 str).

Studies have shown (see Table 1)that the claimed compound (IVa) exhibits antimicrobial properties against gram-positive and gram-negative bacteria, i.e. inhibitory activity against cultures of Staphylococcus aureus at a concentration of 125,0 µg/ml, which exceeds the average concentration of standard fenilsalitsilata 6 times against E. coli - 1000,0 µg/ml.

Bactericidal effect of compound (IVa) was observed against Staphylococcus aureus at a concentration of 250.0 µg/ml, which exceeds the average concentration of standard fenilsalitsilata 8 times.

Due to the fact that the proposed connection has a strong antimicrobial effect on gram-positive and gram-negative microflora and its activity against Staphylococcus aureus in 8 times higher than the structural analogue, it can find application in practical medicine.

Table 1
Study of antimicrobial activity of compounds
The connection numberE. coliStaphylococcus aureus
MIC, mcg/mlIBC, ug/mlMIC, mcg/mlIBC, ug/ml
IVa1000,0-125,0250,0
Standard-fenilsalitsilat--750,02000,0

1. Intermediate products - methyl-7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]Nona-3,8-diene-8-carboxylates of General fo the mules III:

where AG1and AG2mean Ph, Ar3means6H4IU-p (IIIA); AG1means6H4VG-p, AG2means6H4OEt-p, AG3means6H4IU-p (IIIB).

2. Methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates of General formula IV:

where Ar1and AG2mean Ph, AG3means6H4IU-p (IV); AG1means6H4VG-p, AG2means6H4Ot-p, AG3means6H4IU-p (IV).

3. The method of obtaining methyl-6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylates IV a, b:

where AG1and AG2mean Ph, Ar3means6H4IU-p (IVa); Ar means6H4Br-p, Ar2means6H4Ot-p, Ar3means6H4IU-p (IV), characterized in that methyl 7-aryl-4,9-derail-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro [4.4] Nona-3,8-diene-8 carboxylates of the formula III a, b:

where Ar1and Ar2mean Ph, AG3means6H4IU-p (IIIa); Ar1means6H4VG-p, Ar2means H4Et-p, Ar3means6H4IU-p (IIIB), is subjected to recrystallization from ethyl acetate, followed by separation of the desired products.

4. The method according to claim 3 characterized in that the solvent used in ethyl acetate.

5. Methyl 11-benzoyl-2-o-hydroxyphenyl-3,4,10-trioxo-9-n-tolyl-6-phenyl-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-5-ene-8-carboxylate having antimicrobial activity.



 

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FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

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14 cl, 6 dwg, 63 ex

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EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

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8 cl, 1 ex

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73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 3-aminorifampicin-S representing semi-product in synthesis of anzamycine antibiotics, such as rifabutin - an anti-tuberculosis antibiotic with prolonged effect. Invention describes a method for preparing3-aminorifampicin-S that involves interaction of 3-bromorifampicin-S with hexamethylenetetramine in the amount 2-6-fold molar excess of hexamethylenetetramine with respect to 3-bromorifampicin-S at temperature 40-65°C in organic solvent medium and isolation of the end product. Trichloroethylene is used as a solvent in preparing 3-aminorifampicin-S followed by its change for butyl acetate by addition of butyl acetate to reaction mass in the amount 2-5-fold excess with respect to trichloroethylene volume followed by distilling off trichloroethylene. Prepared 3-aminorifampicin-S butyl acetate solution is filtered through aluminum oxide layer and 3-aminorifmapicin-S is isolated by evaporation until dry. Also, invention describes variant of method for preparing 3-aminorifampicin-S. Invention provides reducing reaction time in preparing the end product, reduced cost and simplified reaction, enhanced yield and purity of the end product.

EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: for treatment of patients with pyoinflammatory diseases of lower extremities at the background of diabetes complex treatment is realised, which includes introduction of insulin, antiaggregants and antibacterial therapy. As antibacterial therapy, cell-associated introduction of preparations is realised. For this purpose isolated autoblood formed elements in amount 1-1.45 ml per 1 kg of patient's weight are mixed with 5 ml of 20% ceftriaxone solution and 0.3 ml of dymethylsulfoxide, incubated during 30 minutes, 1 ml of distilled water is added per 5 ml of isolated autoblood formed elements, and stood during 10-15 minutes. Obtained solution is introduced into artery, feeding affected region, 1 time a day during 7-10 days.

EFFECT: increase of concentration of antibacterial preparations in affected tissues due to reversible depositing of erythrocytes in microcirculatory channel of lower extremities.

2 ex

FIELD: veterinary science.

SUBSTANCE: invention refers to veterinary science, particularly to agents and methods of treating keratoconjunctivitis in cattle. A preparation for treatment and prevention of infectious keratoconjunctivitis in cattle contains an aqueous solution of Sulfur, Echinacea purpurea, Hepar sulphur, Belladonna albus, Apis melifelica and tissue nosode in the following relation, wt %: Belladonna albus C6 - 10, Sulfur C6 - 20, Echinacea purpurea C6 - 10, Apis melifelica C6 - 30, Hepar sulphur C6 - 15, tissue nosode D6 - 15. The method for treatment and prevention of infectious keratoconjunctivitis in cattle involves intramuscular introduction of said preparation to calves, cows and heifers once a day every 3-5 days, and to calves to 80 kg of live weight the preparation is introduced in a dose 1-2 ml/10-15 kg of live weight, and to cows and heifers in a dose 1-2 ml/100 kg of live weight.

EFFECT: preparation and method exhibit high therapeutic efficiency in comparison with analogues.

4 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: substance of the invention involves sterile liquid or dry specifically active F(ab')2-fragments of anti-anthrax antibodies containing (35±5) mg·cm3 of protein and at least 96% of F(ab')2-fragments of antibodies recovered from liquid equine anti-anthrax immunoglobulin prepared of blood serum of horses preliminary immunised with strains B anthracis "СТИ"-1 and Ichtiman, and also a anthrax toxin produced by the Kohn's spirit deposition method.

EFFECT: lower reactogenicity and improved immunogenicity.

1 tbl

FIELD: medicine.

SUBSTANCE: present invention concerns a derivative of pyridonecarboxylic acid presented by formula (1): or its salts where R1 represents methyl group, fluorine atom or chlorine atom; R2 represents hydrogen atom or lower alkyl group; R3 represents isopropyl group or tert-butyl group; R4 represents methyl group or halogen atom; and R5 represents fluorine atom or chlorine atom, and also an antibacterial preparation and a pharmaceutical composition, containing specified derivative or its salt as an active component. Besides the invention describes application of the compound under item 1 and the method of treating the infectious disease.

EFFECT: new compound shows excellent antibacterial activity, low toxicity, improved biological availability and low speed of binding with serum proteins.

10 cl, 4 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention can be used in manufacturing of vaccines for Streptococcus pyogenes - streptococci of group A (SGA) and Streptococcus agalactiae - streptococci of group B (SGB). Substance of the invention involves development of recombinant DNA pB1 derived from PCR with using chromosomal DNA of strain 090R Ia of serotype SGB, primers Pb1 and Pb2 and following cloning with using expression plasmid pQE-30 in E coli M15. Recombinant DNA pB1 codes recombinant protein PB1 expressing protective properties in relation to specified streptococci which has no enzymatic activity and causes synthesis of anti-Pb1 antibodies expressing protective properties in relation to Streptococcus pyogenes and Streptococcus agalactiae. In the invention there is developed recombinant plasmid DNA pQE-pB1 representing plasmid DNA pQE-30 that bears recombinant DNA pB1, and strain-producer E. coli M15-PB1 enabling to express recombinant protein PB1.

EFFECT: no enzymatic activity of produced recombinant protein allows application as an ingredient of the vaccine for Streptococcus pyogenes and Streptococcus agalactiae.

7 cl, 7 dwg, 4 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: conjugated capsular saccharides of serogroups B, C, W135 and Y N.meningitidis are safe and immunogenic when combined in a single dose. This effect is retained when a conjugated capsular saccharide of serogroup A is added. Given conjugated antigens can be stably combined in a single aqueous dose without lyophilisation required. A wide spectrum of protection against serogroup B infection can be assured by additional application of certain polypeptide antigens - protein NadA in the oligomeric form, proteins '741', '936' ,'953', '287' which can be combined with saccharide Neisseria antigens without loosing protective efficiency of any of five serogroups. Efficiency of the vaccine remains, e.g. when Hib-conjugate added. Efficiency of a conjugate of serogroup W135 increases when proteantigens derived from Neisseria stain of serogoup D added. When Hib-conjugate added to meningococcal conjugate, total activity against serogroup W135 increases. The aqueous immunogenic meningococcal compositions (versions) derived from the capsular antigens are intended for immunisation against bacterial meningitis, inducing a specific immune response in a mammal. When antigen Hib and antigen Str. pneumoniae are used as a part of the composition, preventive protection of a mammal against the disease caused H.influenzae type B and Str. pneumoniae is provided.

EFFECT: produced aqueous vaccine compositions provide a wide spectrum of immunologic protection against meningococcal infection of serogroup B.

19 cl

FIELD: medicine.

SUBSTANCE: invention provides use of polypeptide antigens and/or automembrane vesicles (OMV) Neisseria meningitidis for immunisation against meningococci of serogroup A, C, W135 and Y (and particularly against meningococci of serogroup Y). According to the invention, polypeptides of meningococci of serogroup B are able to provide protection from meningococci of all serogroups A, B, C, W135 and Y, preferentially Y. These polypeptides and/or automembrane vesicles provide a basis to created immunogenic compositions for immunisation from infection caused by Neisseria meningitidis of serogroup Y and the other. Said immunogenic compositions under the invention provide protection against infection Neisseria meningitides of serogroups A, B, C, W135 and/or Y.

EFFECT: application of the invention allows for protection against the diseases caused by Neisseria meningitides with using as active component polypeptides Neisseria of serogroup B only, instead of a number of capsulat polysaccharide antigens which do not provide protection from Neisseria of serogroup B.

5 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to antibacterial therapy, namely to medications for infectious diseases caused by multiresistant bacteria. The invention can be used for treatment of hospital mainly, and also severe heavy and extremely severe infectious diseases. The preparation represents mixed cephalosporin antibiotic Cefepime and beta-lactamase inhibitor Sulbactam in the ratio 1:1 to 1:2, respectively.

EFFECT: application of the preparation allows improving clinical effectiveness for infectious diseases essentially.

4 tbl, 2 dwg

FIELD: pharmacology.

SUBSTANCE: it is shown that 2,4,6-tri-(p-methoxyphenyl)selenopyrilium in concentration 10-1 to 10-4 mg/ml taking action on E. coli, has suppressed bacteria reproduction 3.6 to 25.7%; while acting on growing culture K oxytoca, it has suppressed the growth 6.7 to 18.4 %; on growing culture P. aeruginosa, it has suppressed the growth 7.4 to 16.2 %.

EFFECT: it is established that for given compound LD50=183+56 mg/kg.

1 cl, 3 tbl, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

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