Quinoline derivatives, particularly 6,7-substituted 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ols, method for production thereof and use of compounds to treat infectious mycobacterial dieseases, particularly tuberculosis

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 1-(2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol of general formula I or their pharmaceutically acceptable salts with acids, where R1 denotes H, R2+R3 denotes -O-(CH2)n-O-, where n=1-2, which forms additional dioxane and 1,3-dioxolane rings. The invention also relates to a method of producing a compound of formula I and to use of the compound of formula I in treating infectious mycobacterial diseases.

EFFECT: obtaining novel compounds with useful biological activity.

4 cl, 2 tbl, 3 ex

 

The invention relates to biologically active substances, in particular derivatives of substituted quinoline with cytostatic and cytotoxic activity against mycobacteria, namely substituted derivatives of 1-(2-chlorhydrin-3-yl)-4-dimethylamino-2-(naphthalene-1-yl)-1-phenylbutane-2-tins of General formula (I), method of production thereof, and use them as antimycobacterial agents, in particular substances and pharmaceutical preparations (funds) for the treatment of tuberculosis and other infectious diseases mycobacterial nature.

According to who, every year, more than 8-9 million people become ill with tuberculosis, the causative agent of which is bacterial wand Micobacterium Tuberculosis. The number of deaths from drug-resistant and not to be resistant forms ranges from 20 to 30% (2-3 million). Currently used approaches to the treatment of this disease is based on the combination therapy near drugs, such as ethambutol, isoniazid, rifampicin, pyrazinamide, cycloserine, etc. Taking account of the increasing worldwide incidence of resistant forms of TB, as well as the relatively high toxicity of the aforementioned drugs and long enough, the search for new chemical substances with high protivokataralnoe activity, t is aetsa urgent task of modern medicine and pharmacology.

Recently synthesized and evaluated for activity against M. the number of derivatives diarylquinolines number of General formula (II) [WO 2004/011436, 05.02.2004, WO 2008068270, 12.06.2008, WO 2006/125769, 30.11.2006], the structure of which is related used since the early 17th century for the treatment of infectious diseases quinine

where R1-H, halogen, haloalkyl, cyano, hydroxy, aryl, hetaryl, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthiomethyl, arylalkyl;

R2- H, hydroxy, thio, alkyloxy, alkyloxyalkyl, alkylthio-, mono - and dialkylamino-;

R3is hydrogen, halogen, alkyl;

R4- naphthyl, aloneftis, phenyl, halodrol, arylalkyl, pyridinyl, alkyl, thienyl;

R5, R6- alkyl, N, benzyl, imidazolyl, hetaryl, alkylthio, pyrimidyl.

From RU 2404971, 27.11.2010 known quinoline derivatives of General formula (III)

where R1means halogen, R2means halogen, R3means hydroxy, R4, R5mean C1-C3-alkyl, R6means aryl, R7means aryl, n=1 or 2, and their pharmaceutically acceptable salts with acids, possessing activity against mycobacteria.

In these patents describes how to obtain these derivatives, which consists in the interaction of 2-arylmethylidene relevant acetophenone and acetylation under the action of metallurugic agents, in particular diisopropylamide lithium.

Compounds of General formula (III), based on patent No. 2404971, 27.11.2010, can be obtained from the intermediates (VI) and (IV) using metalliser reagent, such as diisopropylamide lithium, in particular, obtained in situ from utility and Diisopropylamine in a suitable solvent, preferably ether type, such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl tertiary butyl ether and mixtures thereof and mixtures with other solvents or co-solvents (Scheme 1). All radicals have the definitions as in the formula (III). The reaction can be easily carried out in the temperature range from -70 to +20°C., preferably from -70 to -20°C.

Formed during reaction mixture of diastereomers can be separated using known methods such as chromatography or crystallization of diastereomeric salts.

The presence of R2chlorine atom ceteris paribus does not critically affect the cytotoxic activity of the compounds against Mycobacterium, while their chemical synthesis is simplified at one stage, which affects the practical yield of the target products.

At the same time, the presence of two halogen substituents in the quinoline nucleus is the cause of the low solubility suitable for the proposed originalnew in a series of solvents, applied ORGANOMETALLIC chemistry (such as THF, diethyl ether), resulting in poor reproducibility of the process conditions of litrovaya when scaling reactions, accompanied, as a rule, low yields of final compounds.

The present invention is the introduction of a quinoline nucleus originalia instead of a halogen atom, electron-donating substituents increase the solubility of the intermediates of General formula (VI) in THF at temperatures below -50°C, as well as obtaining new compounds of the formula (I) with high reproducible practical application, as well as with improved antibacterial activity.

Thus, an object of the invention is to provide new compounds - derivatives of quinoline [General formula (I)] with reproducible practical output with enhanced antibacterial activity, as well as their pharmaceutically acceptable salts with acids, resulting in the expansion of the means to treat tuberculosis and other infectious diseases mycobacterial nature.

The technical result is achieved by obtaining substituted derivatives of 1-(2-chlorhydrin-3-yl)-4-dimethylamino-2-(naphthalene-1-yl)-1-phenylbutane-2-tins with antimycobacterial activity, namely, quinoline derivatives such as 5,6,7-protected the s 1-(2-chlorhydrin-3-yl)-4-dimethylamino-2-(naphthalene-1-yl)-1-phenylbutane-2-Ola General formula (I)

where R1means N

R2+R3means-O-(CH2)n-O-, where n=1-2, what forms

additional dioxane and 1,3-dioxolane cycles and their farmatsevticheskii acceptable salts with acids.

Specific examples that meet the General formula (I)are the compounds listed below:

The invention also relates to a method of obtaining these new substituted derivatives of 1-(2-chlorhydrin-3-yl)-4-dimethylamino-2-(naphthalene-1-yl)-1-phenylbutane-2-tins with antimycobacterial activity, by reacting substituted 2-arylmethylidene, for example, the General formula (VI)

where R1-R3mean values above;

and 2-(N,N)-dimethylaminoethyl-1-naftalene (IV)

in the environment of an organic solvent under action of metallurugic agents in the form of organic amides of metals at temperatures in the range from -70 to +20°C for 1-3 hours. In the method of obtaining the above substituted quinoline General formula (I) according to the invention as metallurugic agents can be used organic amides of metals such as diisopropylamide lithium, diethylamid lithium 2,2,6,6-tetramethylpiperidine lithium etc.

Pharm is citiesi acceptable salts with acids mentioned substituted quinoline derivatives of General formula (I) are characterized by the fact that that contain therapeutically active non-toxic salt forms, formed by the compounds of formula (I)with acids. These salts with acids can be obtained by treating substances in the form of free bases, represented by the formula (I), suitable inorganic and organic acids.

Such acids are, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzosulfimide, p-toluensulfonate acid, reklamowa acid, salicylic acid, p-aminosalicylic acid.

It was found that the compounds according to the invention have antimycobacterial activity, and therefore can be used for the treatment of infectious diseases caused by Mycobacterium tuberculosis, in particular, can be used as a biologically active component (applicable beginning) upon receipt of medicinal products (funds) for the treatment of tuberculosis, that is, for anti-TB medicines.

General description the Intesa

Compounds according to the invention of formula (I) can be obtained from intermediates of formula (VI) and intermediate compounds of the formula (IV) using metalliser reagent, such as diethylamid lithium, in particular, obtained in situ from n-utility and diethylamine in a suitable solvent, such as THF, diethyl ether, diisopropyl ether, methyl tertiary butyl ether and their mixtures and in mixtures with other solvents and co-solvents (Scheme 2). All radicals have the definitions as in the formula (I). The reaction is carried out in the temperature range from -70 to +20°C, preferably at -70°C for 1 -3 hours.

Formed in the reaction mixture of diastereomers (I-1+I-2) can be separated using known methods such as chromatography or crystallization of diastereomeric salts.

The initial compounds and intermediates of formulae (VI) and (IV) are compounds that are either commercially available or can be obtained by conventional methods known in the literature [D.Mabire, et al., Med. Chem., 2005, 48, 2134-2153].

For example, intermediate compounds of formula (I) can be obtained according to scheme 3:

where R1means N

R2+R3means-O-(CH2)n-O-, where n=1-2, which forms an additional dioxane and 1,3-dioxol the new cycles.

The synthesis presents the scheme includes a step (a), in which the substituted arylamine subjected to interaction with 3-phenylpropionic acid in the presence of suitable catalyst (strong Lewis acid and an inert solvent, such as benzene or toluene. The process is carried out in the temperature range from 20 to 110°C, preferably at boiling of the reaction mixture.

At the next stage (b) the product of accession, obtained in stage (a), is subjected to the interaction with phosphorus oxychloride (POCl3in the presence of N,N-dimethylformamide (formirovanie on Vilsmeier-khaak with subsequent cyclization). The reaction can be carried out in the temperature range from 20 to 80°C., preferably at 75°C.

The products of reactions (a) and (b) can be selected individually and purified using solvent extraction, crystallization or chromatography. The reaction products (I), existing in the form of the diastereomers, can be purified by the method of chiral preparative high-performance liquid chromatography.

The following examples explain the invention without its limitations.

A. Obtaining intermediates (General method)

Example 1

The intermediate compound (Va).

To a mixture of 123 g (0.9 mol) of 3,4-(methylenedioxy)aniline and 135 g (0.9 mol) of 3-phenylpropane acids are added to 200 m is benzene, 7,01 g (0.05 mol) of epirate boron TRIFLUORIDE or 5 g (0.08 mol) of boric acid and boiled under stirring for 5 hours. The resulting product is cooled, filtered off, washed with toluene, rectified alcohol and water. Dried to constant weight. The practical output of the intermediate compound (Va) - 224 g (92,5%).

Example 1'

Obtaining the compounds (VIa)

To a cooled to 10°With a mixture of 79 g (1,08 mol) of dimethylformamide and 160 g (0.59 mol) of the intermediate compound (Va) in 600 ml of chloroform is added dropwise 274 ml (451,6 g, 2,95 mol) of phosphorus oxychloride, and then the resulting solution is boiled for the night. Cooled to room temperature, the reaction mass is then poured into a mixture of ice water, the organic layer was washed with aqueous solution of Na2CO3distilled water, dried over MgSO4, filtered and the solvent is distilled off in vacuum. The residue is crystallized from methanol. The practical output of the intermediate compound (VIa) - 93 g (53%).

Example 2

Obtaining the compound (IV)

A mixture of 340 g (2 mol) of 1-acetonaphthone, 56 g (1,86 mol) of paraform and 200 g (2,07 mol) of dimethylamine hydrochloride in 700 ml of dichloroethane is boiled for 1.5 hours, cooled to room temperature, the precipitation is filtered off, treated with aqueous ammonia and diethyl ether. Organicheskikh washed with water, dried over MgSO4, filtered and the solvent evaporated to dryness. The output of the intermediate compounds (IV) - 335 g (79%).

B. Obtaining the compounds according to the invention

Example 3. 1-(6,7-(methylenedioxy)-2-chloro-quinoline-3-yl)-4-dimethylamino-2-(1-naphthyl-yl)-1-phenyl-butane-2-ol (I-1a+I-2A).

To a cooled to -30°C. a solution of 180 g (0,79 mol) of intermediate naftalene (IV) in 2 l of absolute THF in a stream of argon sprinkled 51,3 g (of 0.65 mol) of lithium diethylamide. The mixture is stirred for 1 hour, cooled to -70°C. and added dropwise 129 g (0.43 mol) of intermediate originalia (VIa) in 500 ml THF. The mixture is kept for 30 minutes, then warmed to 20°C, then add 120 ml of glacial acetic acid. Otogretogo to room temperature the reaction mass is evaporated to dryness, dissolved in chloroform, washed several times with water. The organic layer is dried over MgSO4and the solvent is distilled off. Target products (I-1A and I-2A) in the form of a separate diastereoisomeric pairs allocate using preparative high performance liquid chromatography. Practical yield a mixture of diastereomeric acetates pairs (I-1a+I-2A) in a 1:1 ratio amounted to 74.2 g (29,5%).

The compounds obtained in the form of diastereoisomeric pairs to separate the enantiomers were separated. While the Arab designation "1" connections characterizes diastereomers couple with minimal time UD is Rivonia on chromatographic system (RRSS-configuration diastereomeric center), while the designation "2" characterizes diastereomers couple with RSSR-configuration, and accordingly, the maximum retention time.

The compound (I-1b+I-2b) were obtained in a way analogous to that described for (I-1a+I-2A). Practical outputs the synthesized compounds and their mass spectral characteristics are given in table 1 below:

Table 1
ConnectionR1R2+R3[M+H]+*Output %**
I-1a, I-2aN-O-CH2-O-52629,5
I-1b+I-2bN-O-(CH2)2-O-54035,7
* The main peak in electrospray mass spectrum (ESI-MS) with positive ionization mode.
** Practical yield a mixture of diastereomeric pairs

Description of the methods of determination of antibacterial activity the security of the obtained compounds

Antimycobacterial action are listed in table 1 compounds studied in the dynamics of growth of strain .tuberculosis H37Rv in enriched liquid medium Middlebrook 7H9 broth suspensions in the presence of various concentrations (0,312 µg/ml of 0.625 μg/ml to 1.25 mg/ml, 2.5 μg/ml, 5 μg/ml, 10 μg/ml, 20 μg/ml, 40 μg/ml) compared with the growth of these strains on the environment, not containing compounds, and the medium containing the drug is the 1st of a number of rifampicin in the same concentrations.

Mycobacterial suspension was planted in the amount of 105CFU/ml of Each concentration, including the control tube without connecting tube and rifampicin, were studied triplicate.

Detection of crop growth of mycobacteria was performed using an automated accounting system crop growth Bactec MGIT 960 (Becton Dickenson, USA) in a special MGIT tubes containing the bound fluorophore under a semi-permeable membrane on the bottom of the tube. Detection of mycobacterial growth of the cultures was carried out every hour with Epicenter software (Becton Dickenson, USA). The dynamics of the division of mycobacterial cells was expressed in relative fluorescence units (OEF).

The experiment duration was 42 days, according to the Protocol Becton Dickinson. After that, all grown culture were analysed at the species specificity (belonging to the Mycobacterium tuberculosis).

Bacteriostatic Akti is the ability of the compounds were evaluated:

1) the delay in growth compared to control without drugs;

2) duration of active phase of division.

The research results of the above compounds on antimycobacterial activity, expressed in the unit MIC100shown in table 2:

Table 2
ConnectionMIC100µg/ml*
I-1A**>25
I-2A5
I-1b>20
I-2b10
* concentration of compound at which there is complete loss of crop growth .tuberculosis within 42 days.
** each compound was tested in the form diastereomeric couples and single enantiomers were not separate.

From the results in table 2 shows that the compound (I-2A) and (I-2b) showed rather high antituberculosis activity against strains of Mycobacterium H37Rv comparable (same order) with the same when using rifampicin (1 μg/ml). Polucen the e results is the basis for further testing of selected substances to infected animals and their subsequent use as an active start new and promising anti-TB drugs.

1. Derivatives of quinoline, in particular 6,7-substituted 1-(2-chlorhydrin-3-yl)-4-dimethylamino-2-(naphthalene-1-yl)-1-phenylbutane-2-Ola General formula (I)

where R1means N
R2+R3means-O-(CH2)n-O-, where n=1-2, which forms an additional dioxane and 1,3-dioxolane cycles, or their pharmaceutically acceptable salts with acids having antimycobacterial activity.

2. The method of obtaining compounds of formula (I) according to claim 1 by reacting substituted 2-chloro-3-alkalinising and arylketones under the action of metallurugic agents.

3. The method according to claim 2, characterized in that as metalliser agent use diethylamid lithium.

4. The use of compounds according to claim 1 for the treatment of infectious diseases mycobacterial nature, in particular tuberculosis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula

,

where R1 is an alkoxy group; R2 is H or F; each of R3, R4, R5 and R6 is independently H or D; V is CH and W is CH or N, or V is N and W is CH; Y is CH or N; Z is O, S or CH2 and A is CH2, CH2CH2 or CD2CD2; or a salt of said compound. The invention also describes a antibacterial pharmaceutical composition which contains the compound of formula (I) as a basic component, and use of the compound of formula (I).

EFFECT: obtaining novel compounds possessing useful biological properties.

25 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives general formula I, where: when R2+R3=-C(CH3)2- or -CH(CH3)-; , when R1=H; R2=H; , when R1=H; R3=H; , .

EFFECT: pyridoxine derivatives, having high anti-inflammatory activity and low toxicity.

2 cl, 2 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives of general formula

,

where R1-is a hydrogen atom or methyl, R2 is a hydrogen atom, methyl, linear, branched or cyclic alkyl or R1 and R2 together form a cyclic alkyl capable of powder second-harmonic generation (SHG).

EFFECT: invention can be used in laser technology and communication equipment.

1 cl, 1 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate which possess strong antibacterial activity. This compound is highly safe and applicable in the production of pharmaceutical preparations as a parent drug. What is furthermore described is a method for preparing 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluor-1,5-naphthyridin-2(1H)-one monohydrate of formula 19 and methods for preparing intermediate compounds.

EFFECT: preparing the compounds possessing strong antibacterial activity.

8 cl, 1 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: for treatment of patients with pulmonary tuberculosis with accompanying non-specific bronchitis at the background of carrying out standard anti-tuberculosis therapy from the first day of treatment additionally daily for 3 months the preparation Wobenzym is introduced in a dose of 1 tablet 2 times per day, 30 minutes before meal, and inhalation with a solution of the preparation Hixozide in a dose of 350 mg in 10 ml of water for injections is performed 2 times per week, the course constitutes 24 procedures.

EFFECT: method makes it possible to increase treatment efficiency by indices of infiltration resorption, closing of the decay cavities and abacillation.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: for complex therapy of the first time identified pulmonary tuberculosis traditional anti-tuberculosis therapy is carried out. After two weeks of anti-tuberculosis chemotherapy, complex physiotherapy is performed. In the morning 40-60 minutes after meal ultrasound inhalation with an inhibitor of proteases contrykal in a dose of 5000 UNITS, diluted in 3-4 ml of an isotonic solution of sodium chloride is carried out. Inhalation is carried out at a temperature of the solution of 35°C for 10 minutes on the apparatus "Vulkan-1". 20 minutes after inhalation magnetic infrared laser therapy (MIL-therapy) is performed from the apparatus "Rikta-04/4" on affected zones of the lungs by contact method of the application of the apparatus emitter. Frequency of the laser impact constitutes 5-50 Hz. Average power of infrared light-diode radiation is 60±30 mW, an impact with constant magnetic field is realised with induction 35±10 mT for 1-5 min. The course of treatment constitutes 30-40 daily procedures as well.

EFFECT: enhancement of infiltration resorption, closing decay cavities in the shorter period, arrest of intoxication symptoms by the end of the first month of treatment, reduction of terms of elimination of clinical and laboratory manifestations of tuberculosis.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: drug preparation for treating tuberculosis contains an active substance isoniaside, and a pharmaceutical carrier tiozol gel with the isoniaside concentration of 5.7-54.5 wt % and the tiozol gel concentration of 45.5-94.3 wt %.

EFFECT: higher clinical effectiveness in tuberculosis and lower toxicity.

2 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed is a cocrystalline form of fenbufen with pyrazinamide, where molar ratio of fenbufen with pyrazinamide constitutes 1:1, which has an endothermal peak from 148 to 152°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 7.38, 10.43, 11.04, 21.67 by the data of measurement of polycrystal X-ray radiation diffraction.

EFFECT: increased rate and level of solubility of the crystalline form of fenbufen and its suitability for application in the pharmaceutical industry.

2 ex, 7 dwg

FIELD: medicine.

SUBSTANCE: with underlying antituberculous therapy from the first day of treatment, a therapeutic course is added with an oral administration of preparations Wobenzym and Thiotriazoline; Wobenzym is administered for 4 months in a dose of 1 tablet once a day 30 minutes before breakfast, while Thiotriazoline is administered for the first 15 days in a dose of 100 mg 2 times a day, from the 16th to 45th day in a dose of 100 mg 1 time a day, on the 46th day, Thiotriazoline is withdrawn.

EFFECT: method enables higher clinical effectiveness and reduced rate of an adverse hepatotoxic response to the antituberculous preparations due to improving the immune status and peroxidation values.

6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: rifabutin is dissolved in a water-miscible solvent which dissolves rifabutin better than water does; a rifabutin solution is prepared; gelatin is dissolved in water to prepare a gelatin solution; the rifabutin solution is slowly added to the gelatin solution while stirring to prepare a semi-product. The semi-product is dried in a spray drier or lyophilised to prepare a product. The prepared product is used as a part of a pharmaceutical composition for treating mycobacteriosis and Helicobacter pylori infection.

EFFECT: higher bioavailability of rifabutin.

46 cl, 8 tbl, 5 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention represents 3-aminosubstituted 6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazines, which applied as anti-tuberculosis medications make it possible to increase activity and specificity of antimicrobacterial action, extend its spectrum (impact on atypical strains of mycobacteria) as well as reduce toxicity in comparison with analogues.

EFFECT: toxicity of claimed compounds is 10-20 times lower than toxicity of anti-tuberculosis medications applied in medicine.

5 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: in an intensive phase of the therapeutic course, a conventional anti-tuberculosis therapy is added with the oral preparation Thiotriazoline 100 mg 2 times a day daily for 45 days. Besides, pulmonary administration of the preparation Hixozide 350 mg dissolved in 10 ml of water for injection every second day in the number of 20 procedures is added.

EFFECT: infiltrate resolution, cavity closure and abacillation with no hepatotoxic reaction ensured by creating high concentrations of drug preparations directly in the lesion and increased activity of the immune system.

2 ex, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to dialkyl(2-methyl-4-oxopent-2-yl) phosphine oxide pyridinoyl hydrazones (Ia-c) for treating tuberculosis, which can be used in medicine and veterinary: la Py-4-Py, R=Et; Ib Py=4-Py, R=Pr; 1c Py=3-Py, R=Et.

EFFECT: novel efficient antituberculous preparations with low toxicity, which do not exhibit neurotoxic activity.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

Up!