Derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide, production thereof and use in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

 

The object of the present invention are compounds ligands of nicotinic receptors. They are suitable for treatment or prevention of disorders associated with dysfunction of the nicotinic receptors.

Compounds according to the invention correspond to the General formula (1)

In which

X denotes a nitrogen atom or a group of General formula C-R2,

P, Q, R and W denote each independently from each other, a nitrogen atom or a group of General formula C-R3,

R1denotes a hydrogen atom or a C1-C6is an alkyl group,

R2represents C1-C6is an alkyl group,

R3denotes a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, nitro, amino, trifluoromethyl, cyano or a group of General formula-NR4R5, -NR4C(=O)R5, -NR4C(=O)NR5R6, -NR4C(=O)OR5, -NR4S(=O)2NR5R6, -OR5, -OC(=O)R5, -OC(=O)OR5, -OC(=O)ONR4R5, -OC(=O)SR5, -C(=O)OR5C(=O)R5, -C(=O)NR4R5, SR5, -S(=O)R5, -S(=O2R5, -C(=O)2NR4R5or phenyl, possibly substituted by one or more groups selected from halogen atoms and C1-C6-alkyl, C1-C6-alkoxy, nitro, amino, trifloromethyl, cyano, or groups total f is rmula-NR 4R5, -NR4C(=O)R5, NR4C(=O)NR5R6, NR4C(=O)OR5, NR4S(=O)2NR5R6, -OR5, -OC(=O)R5, -OC(=O)OR5, -OC(=O)ONR4R5, -OC(=O)SR5, -OC(=O)OR5, -OC(=O)NR4R5, SR5, -S(=O)R5, -S(=O)2R5, -S(=O)2NR4R6or R3denotes a group selected from the cycles of imidazole, pyridine, pyridazine, pyrimidine, pyrazole, pyrazine, triazole, chinoline, ethanolamine, tetrazole, furan, thiophene, thiazole, isothiazole, oxazole, isoxazol, pyrrole, tetrahydroquinoline, tetrahydroisoquinoline, indole, benzimidazole, benzofuran, dihydrobenzofuran, cinnoline, indazole, phthalazine, triazine, isoindole, oxadiazole, thiadiazole, furazane, benzofurazan, benzothiophene, dihydrobenzofuran, benzotriazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, heatline, cinoxacin, naphthiridine, dihydroquinoline, dihydroisoquinoline, properidine, dihydropyrimidine, pyrrolopyridine, thienopyridine, dihydrotriazine, imidazopyridine, pyrazolopyrimidine, oxazolopyridine, isoxazolidine, isoxazolidine, triazolopyridine, isothiazolinone, pyrrolopyrimidine, properidine, dihydropyrimidine, thienopyrimidine, dihydrotriazine, imidazopyrimidines, pyrazolopyrimidine, oxazolam is rimidine, isoxazolidine, triazolopyrimidine, isothiazolinones, foroperating, dihydroporphyrin, pyrrolopyrazine, thienopyridine, dihydrotriazine, imidazopyridine, pyrazolopyrimidine, oxazolopyridine, isoxazolidine, triazolopyridine, isothiazolinone, properidine, dihydropyrimidine, pyrrolopyridine, thienopyridine, dihydrotriazine, imidazopyridine, pyrazolopyrimidine, oxazolopyridine, isoxazolidine, triazolopyridine or isothiazolinone,

R4, R5and R6denote each, independently of one another a halogen atom or C1-C6-alkyl, straight or branched C2-C6alkenyl straight or branched or C2-C6-quinil straight or branched, or C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C3-alkyl, C4-C8-cycloalkenyl or phenyl,

in this case a group of the General formula NR4R5and NR5R6can form with the nitrogen atom to which they are attached, a group selected from aziridinyl, azetidine, pyrrolidine, piperidine, azepine, piperazinil, morpholinyl, thiomorpholine, pyrrolidine, indoline, pyrazoline, pyrazolidine, imidazoline, 3Nindolyl, hinokitiol and chinoiserie.

Compounds according to the invention can be as bases or salts accession acid, hydrate or solvate.

Because diazabicyclo cycles contain asymmetric carbon atom, the compounds according to the invention can be in the form of pure enantiomers or mixtures of enantiomers. Enantiomers can be separated by methods known to the person skilled in the art, such as separation by fractional crystallization diastereoisomeric salts of chiral acids or selection using chromatography on chiral media.

According to the invention compounds of General formula (1) can be obtained by the method, which is illustrated by the following scheme 1.

Enter in the interaction of 1,4-diazabicyclo[3.2.1]octane of formula (II) and the compound of General formula (III)in which X, P, Q, R, W and R1have the above meanings, in the presence of a binding agent, such as N,N'-carbonyldiimidazole in a solvent such as dimethylformamide. At the preliminary stage funkcinalnnuyu the carboxylic acid group present in the compound of General formula (III)can also be converted into the functional group of the acid chloride to interact with 1,4-diazabicyclo[3.2.1]octane in the solvent, such as dichloromethane.

Alternatively, compounds of General formula (I) can be obtained by the method, which is illustrated by the following scheme 2.

Enter in aimogasta 1,4-diazabicyclo[3.2.1]octane of formula (II) and the compound of General formula (IV), in which X, P, Q, R, W and R1have the above meanings and Z represents a bromine atom or iodine, in the presence of carbon monoxide and a catalyst containing palladium, such as bis(triphenylphosphine)dichloropalladium, and bases, such as triethylamine, in a solvent such as, for example, dimethylformamide.

Compounds of General formula (III) are commercially available or can be obtained by methods described in the literature, for example, in Can. J. Chem. 1988, 66, 420-8.

Compounds of General formula (IV) are commercially available or can be obtained by methods described in the literature, for example, in J. Het. Chem. 1983, 475.

Obtaining 1,4-diazabicyclo[3.2.1]octane described in J. Med. Chem. 1977, 20, 133.

The following examples illustrate in detail the production of several compounds according to the invention. Elemental microanalysis and IR spectra and NMR spectra confirm the structures of the obtained compounds. The numbers of the compounds given in parentheses in their names correspond to the numbers indicated in the table below. In the names of compounds dash "-" is part of the word, and the dash "_" only serves to reduce at the end of the line, it must be removed if the reduction is not, and should not replace normal dash or space.

Example 1. (Compound No. 2)

3-(1,4-diazabicyclo[3.2.1]Oct-4-ylcarbonyl)-1the -indazole hydrochloride 1:1

In the reactor of 50 ml volume injected 0,165 g (1,02 mmol) 1N-indazol-3-carboxylic acid and 1 ml of thionyl chloride, the mixture is heated under reflux for 1 hour 30 minutes and concentrate it under reduced pressure. Then inject 1.2 ml of pyridine and 0.30 g (to 2.67 mmol) of 1,4-diazabicyclo[3.2.1]octane and heat the mixture under reflux for 1 hour 30 minutes

The solvent is evaporated under reduced pressure, the residue is treated with 1 ml of chloroform and the residue purified by chromatography on a column of silica gel, elwira a mixture of ethyl acetate, methanol and ammonia in the ratio 70/30/3.

Obtain 0.16 g of product which was dissolved in 10 ml of acetone before you enter to 0.47 ml 5 N hydrochloric acid in isopropyl alcohol. The obtained crystals (0.17 g) was separated by filtration and dried under reduced pressure.

Melting point: 286 and 287°C.

Example 2. (Compound No. 3)

6-chloro-3-(1,4-diazabicyclo[3.2.1]Oct-4-ylcarbonyl)-1-N-indazole bromohydrin 1:1

In a reactor with a volume of 10 ml consistently give 0.25 g (0.9 mmol) of 3-iodo-6-chloro-1N-indazole, 0.09 g (0.13 mmol) of bis(triphenylphosphine)dichloropalladium, 0.25 g (2,24 mmol) of 1,4-diazabicyclo[3.2.1]octane and 0.31 ml (2,24 mmol) of triethylamine in solution in 1 ml of dimethylformamide. The mixture is then blown with carbon monoxide and heated to 70°C for 8 hours. Reaction medium op is equidivium in 10 ml of a saturated aqueous solution of ammonium chloride and the aqueous phase extracted with chloroform. The organic phase is dried, filtered and concentrate them under reduced pressure. The residue is purified by chromatography on a column of silica gel, elwira mixture of chloroform, methanol and ammonia in the ratio of 90/10/1.

Get so 0.2 g of product which was dissolved in 1 ml of isopropyl alcohol and add 0,13 ml 5 N hydrochloric acid in isopropyl alcohol.

The obtained crystals (0,076 g) is separated by filtration and dried under reduced pressure.

Melting point: 285-286°C.

Example 3. (Compound No. 1)

3-(1,4-diazabicyclo[3.2.1]Oct-4-ylcarbonyl)-6-methyl-1N-pyrazole[3,4-b]pyridine bromohydrin 2:1

By analogy with example 2 is injected into the interaction of 0.7 g (3.3 mmol) of 3-bromo-6-methyl-1N-pyrazole[3,4-b]pyridine with 1,1 g (9.9 mmol) of 1,4-diazabicyclo[3.2.1]octane in the presence of 0.35 g (0.5 mmol) of bis(triphenylphosphine)dichloropalladium and 2.3 ml of triethylamine in 10 ml of dimethylformamide under conditions described in example 1, and obtain 0.21 g of product which was dissolved in 20 ml of acetone and added with 0.27 ml of a solution of 5,7-N-Hydrobromic acid in acetic acid.

Crystals debrominate separated by filtration and dried in vacuum.

Melting point: 290-291°C.

Example 4. (Compound No. 4).

3-(1,4-diazabicyclo[3.2.1]Oct-4-ylcarbonyl)-5-fluoro-1N-indazole bromohydrin 2:1

By analogy with example 2 is administered in collaboration is the development of 0.23 g (0.88 mmol) of 3-iodo-5-fluoro-1 N-indazole 0,25g (2,19 mmol) of 1,4-diazabicyclo[3.2.1]octane in the presence of 0,092 g (0.13 mmol) of bis(triphenylphosphine)dichloropalladium and 0.3 ml of triethylamine in 1 ml dimethyformamide under the conditions described in example 2. Get 0,136 g of product which was dissolved in 20 ml of acetone and add to 0.18 ml of a solution of 5,7-N-Hydrobromic acid in acetic acid. Crystals debrominate separated by filtration and dried in vacuum.

Melting point: 283-284°C.

The table below illustrates the chemical structures and physical properties of a few compounds according to the invention.

In column “Q” “Me” denotes a methyl group and “Ms” denotes methanesulfonyl group.

In the column “St.” “(+/-)” refers to the racemate, “(+)” and “(-)” mean respectively clockwise rotating and such enantiomers.

In the column “Salt” (Sel) “-“ denotes a compound in the form of the base, “HBr” means bromohydrin, “HCl” denotes a hydrochloride and “ox” signifies oxalate or tandikat.

Table

Compounds according to the invention were subjected to pharmacological tests which revealed that the compounds are of interest as active substances of medicines.

So I studied their affinity for nicotinic receptors containing sub-unit α4β2the method is mi, described by Anderson and Arneric in Eur.J.Pharmacol.1994, 253, 261, and Hall et coll. in Brain Res. 1993, 600, 127.

Was decapitated male rats Sprague Dawley, weighing from 150 to 200 g, and quickly removed the rest of the brain, homogenized it in 15 volumes of sucrose solution with a concentration of 0.32 M at 4°C, then centrifuged for 10 min, 1000 g of the Precipitate was removed and centrifuged the pooled liquid for 20 min, 20000 G at 4°C. the precipitate was Isolated and homogenized using a homogenizer transmitter stationTM15 volumes of double-distilled water at 4°C, then centrifuged for 20 min, 8000 g Sediment was removed and centrifuged settled solution and the skin layer (buffy coat) for 20 min, 40000 G, were isolated sediment, suspended it in 15 ml of double-distilled water and centrifuged again at 40,000 G and then stored at -80°C. on the day of the experiment was slowly thawed tissue and suspended it in 3 volumes of buffer. Cells were then incubated with 150 μl of this membrane suspension at 4°C for 120 min in the presence of 100 μl of [3H]tsitizina 1Nm in the final volume of buffer equal to 500 μl, in the presence or absence of test compounds. The reaction was stopped by filtration through filters Whatman GF/BTMpre-treated polyethylenimine, rinsed the filters twice with 5 ml of buffer at 4°C and measured the radioactivity on the filter by liquid vs is integratie. Determined nespecificescuu communication in the presence of (-)nicotine, 10 μm; non-specific relationship ranged from 75 to 85% of the total communication received on the filter. For each concentration of the compounds was determined by the percent inhibition of specific [3H]tsitizina, then calculate the concentration CI50connection specific inhibitory connection by 50%.

The concentration CI50compounds according to the invention, having the highest affinity, ranged from 1 to 10 microns.

Also investigated the affinity of the compounds according to the invention to nicotinic receptors containing the subunit α7, the methods described Mark and Collins J. Pharmacol. Exp. Ther. 1982, 22, 564 and Marks et coll. Mol. Pharmacol. 1986, 30, 427.

Was decapitated male OFA rats, weighing 150 to 200 g, and quickly removed the rest of the brain, homogenized it in 15 volumes of sucrose solution with a concentration of 0.32 M at 4°C. using a homogenizer transmitter stationTMthen centrifuged for about 10 min, 1000 g of the Precipitate was removed and centrifuged the pooled liquid for 20 min, 8000 G at 4°C. the precipitate was Isolated and homogenized using a homogenizer transmitter stationTM15 volumes of double-distilled water at 4°C, then centrifuged for 20 min, 8000 g Sediment was removed and centrifuged the pooled liquid and the skin layer (buffy coat) for 20 min, 40000 G. precipitate was Isolated, suspe who was denovali it in 15 ml of double-distilled water at 4°C and centrifuged again at 40,000 G for 20 minutes, and then kept at -80°C.

On the day the experiment was slowly thawed tissue and suspended it in 5 volumes of buffer. Pre-incubated with 150 μl of this membrane suspension at 37°C for 30 min in the dark in the presence of 50 μl of [3H]α-bungarotoxin 1Nm in the final volume of 250 μl of buffer HEPES 20mm, 0,05%polyethylenimine. The reaction was stopped by filtration through filters Whatman GF/BTMpre-processed within 3 hours of 0.05%polyethylenimine. Had rinsed the filters twice with 5 ml of buffer at 4°C and measured the radioactivity on each filter by liquid scintigraphy. Determined nespecificescuu communication in the presence of α-bungarotoxin, 10 μm; non-specific bond was approximately 60% of the total communication received on the filter. For each concentration of the compounds was determined by the percent inhibition of specific [3H]-α-bungarotoxin, then calculate the concentration CI50connection specific inhibitory connection by 50%.

The concentration CI50compounds according to the invention, having the highest affinity was from 0,010 0,10 mm.

The concentration CI50several specific compounds are given in the following table.

Connection # CI50α7μmCI50α7β2
10,056"10
40,055-
70,224-

The above results show that the compounds according to the invention are selective ligands against subunits α7nicotinic receptor.

The results of some experimental tests show the suitability of compounds for treatment or prevention of disorders associated with dysfunction of the nicotinic receptors, in particular, in the Central nervous system.

These violations include cognitive impairment, more specifically musicheskie, as well as in the field of attention, associated with Alzheimer's disease, age of the particular violation memory (Age Association his or her Memory, AAMI), Parkinson's disease, trisomy 21 (down syndrome), alcohol Korsakov's syndrome, vascular dementia (multi-infarct dementia dementia, MDI).

Compounds according to the invention may also be useful in the treatment of motor disorders observed in Bolani Parkinson's or other neurological diseases such as Huntington's chorea, Tourette syndrome, late Diskin the Oia and hyperkinesis.

Compounds according to the invention can also be used for therapeutic treatment or symptomatic therapy of disorders of cerebral circulation and cerebral hypoxic crises. They can also be used in cases of mental pathologies: schizophrenia, depression, anxiety, panic attacks, compulsive and obsessive-compulsive disorder.

They can prevent symptoms associated with tobacco, alcohol dependence, dependence on various substances, addictive, such as cocaine, LSD, cannabis, benzodiazepines.

Additionally, the compounds according to the invention can also be used to treat lower limb ischemia, occlusion of arteries of the lower extremities (PAD: peripheral arterial disease), ischemic heart disease (stable angor), myocardial infarction, heart failure, failure of scarring in patients with diabetes, varicose ulcers with venous insufficiency.

The treatment of each of these pathologies can be performed using only nicotinic agent and/or combination of drugs shown in this pathology.

Therefore, an object of the present invention are also pharmaceutical compositions containing an effective dose of at least one compound according to the invention in the form of a pharmaceutically acceptable base or Soleil of MES, and if necessary in a mixture with acceptable excipients.

These excipients is selected depending on the dosage form and the desired method of administration.

Thus the pharmaceutical compositions according to the invention can be designed for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, vnutritraheinogo, intranasal, transdermal, rectal, intraocular injection.

Forms for a single administration may, for example, be represented as tablets, gelatin capsules, granules, powders, solutions or suspensions for oral administration or for injection, percutaneous patches actions (“patch”), suppositories. Forms for local use may constitute ointments, lotions and lotions for the eyes.

These one-forms are the dosage providing a daily dose of from 0.01 to 20 mg of active substance per 1 kg of body weight depending on the galenical form.

To obtain tablets to fine or reconcisolomon active substance add pharmaceutical filler, which can be composed of diluents, such as lactose, microcrystalline cellulose, starch and prescription additives, such as binders (polyvinylpyrrolidone, hypromellose, etc.), agents, leak, such as on the silicon oxide, lubricants such as magnesium stearate, stearic acid, tribehenin glycerin, sodium fumarate. You can also add wetting means or surfactants such as sodium lauryl sulfate.

Methods of obtaining can be a direct compression, dry granulation, wet granulation or hot melting.

Tablets can be without shell, index, for example, saccharose or coated with various polymers or other suitable substances. They can be designed for fast, slow or sustained release of the active substance due to the used for the shell polymer matrices or specific polymers.

To obtain gelatin capsules mixing the active substance and dry pharmaceutical excipients (simple mixing, dry or wet granulation or hot melting), liquid or semi-liquid pharmaceutical excipients.

Gelatin capsules may be hard or soft, coated or uncoated film and thus provide fast-acting or slow action (for example, intestinal forms).

The composition is in the form of a syrup or elixir or work designed for administration in the form of drops can contain the active substance together with podslastitel is m, preferably low-calorie, methylparaben or propylparaben as antiseptics, a flavoring and coloring.

Powders or granules, dispersible in water, may contain the active ingredient mixed with dispersing additives or surfactants or dispersing additives such as polyvinylpyrrolidone, as well as with sweeteners and additives, corrective taste.

For rectal use of suppositories containing binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration using aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing additives and/or surfactants, for example, propylene glycol or butyleneglycol.

The active substance may also be in the form of microcapsules, possibly with one or more carriers or additives, or with a polymer matrix or with cyclodextrin (plasters for percutaneous actions, forms of slow release).

Compositions for topical application according to the invention contain a medium compatible with the skin. They can in particular be in the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, emulsions, water-in-m the following or oil-in-water in the form of cream or gel, microemulsions, aerosols or in the form of vesicular dispersions containing ionic and/or nonionic lipids. These herbal forms of get methods, traditional for this area.

Finally, the pharmaceutical compositions according to the invention may contain, together with the compound of General formula (1) other active substances which may be suitable for treatment of the above disorders and diseases.

1. Derivatives of 1,4-diazabicyclo[3.2.1]octacarbonyl in the form of a pure enantiomer or mixture of enantiomers corresponding to the General formula (1)

in which X denotes a nitrogen atom,
R and W denote each independently from each other, a nitrogen atom or a group of General formula C-R3,
Q and R represent each independently of each other a group of General formula C-R3,
R1denotes a hydrogen atom,
R3denotes a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms;
as grounds, solvate, or salt of joining with acid.

2. The compound according to claim 1, which is an oxalate 3-(1,4-diazabicyclo[3.2.1]Oct-4-yl-carbonyl)-5-mesilate-1H-indazole.

3. Drug for treatment or prevention of disorders associated with dysfunction of the nicotinic receptors, characterized in that it comprises a compound according to claim 1 or 2

4. Pharmaceutical composition for treatment or prevention of disorders associated with dysfunction of the nicotinic receptors, characterized in that it contains a compound according to claim 1 or 2 in combination with excipients.

5. The use of compounds according to claim 1 or 2 for obtaining a medicinal product intended for the treatment of cognitive disorders, and disorders of attention or for the treatment of motor disorders, neurological, psychiatric disorders or intended for the prevention of symptoms associated with addiction to various substances, addictive, or intended for treatment of cardiac, vascular, arterial or venous pathologies.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: chemistry.

SUBSTANCE: ergot alkaloid is extracted from ergot with high yield and purity level using method including extraction of Claviceps purpurea, i.e. ergot, mix of solvents toluene/ethanol that leads to production of primary extract. The primary extract can be additionally treated within two stages of liquid-liquid extraction to provide alkaloid purification that gives purified toluene extract. Toluene extract can be additionally partially softened by stream, and crystalline product is produced by toluene crystallisation or mixture of toluene and aliphatic hydrocarbon.

EFFECT: development of method of ergot extraction with high yield and purity level.

23 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds of formula I which can be used in photopolymer composition hardening with catalyst, possible during rays, and as photoinitiators for coating preparation. In formulas (I) and (II) $ , in which R1 denotes phenyl, naphthyl, phenanthryl, anthryl, pyrenil 5,6,7,8-tetrahydro-2-naphthyl,5,6,7,8-tetrahydro-1-naphthyl, thienyl, tiantrenyl, anthraquinonyl, xantenyl, thioxantyl, phenoxantyinyl, carbazol, phenantridinyl, akridinyl, fluorenyl or phenoxazinyl, besides radicals is unsubstituted or once or several times substituted by C1-C18alkyl, C2-C18alkenyl, C1-C18haloalkyl, NO2, NR10R11, CN, OR12, SR12, halogen atom or radical of formula II or radical R1 denotes radical of formula III . R2 and R3 independently denote a hydrogen atom; R10, R11 R12 independently denote a hydrogen atom or C1-C18alkyl; R4 and R6 form C2-C12alkylen bridge, which is not substituted or substituted by or several C1-C4alkyl radicals; R15 denotes H or radical of formula II.

EFFECT: production of the nitrogen bases that can be used as a photopolymer composition, hardening with catalyst, and as photoinitiator for coating.

11 cl, 4 tbl, 21 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for synthesis of compounds of the formula (I): wherein one of substitutes A or B means hydrogen atom (H) and another one means aryl substituted optionally with one or two R2, heteroaryl substituted optionally with one or two R2, and so on; R represents H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl or -CHR3-OCO-(C1-C6)-alkyl or salt; R2 represents hydrogen atom, optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, and so on; R3 represents hydrogen atom, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Method for synthesis of these compounds involves the following steps: (a) condensation of substituted aldehyde of the formula: (A'-CHO) (17) wherein A' represents A, such as given above when B represents hydrogen atom; or B, such as given above when A represents hydrogen with derivative of 6-bromopenem of the formula (16): wherein R represents p-nitrobenzyl in the presence of Lewis acid and a weak base at low temperature that results to formation of intermediate aldol product of the formula (18): ; (b) interaction of intermediate compound of the formula (18) with chloroanhydride or acid anhydride of the formula: (R8)Cl or (R8)2O or with tetrahalogen methane of the formula: C(X1)4 and triphenylphosphine wherein R8 represents alkyl-SO2, aryl-SO2, alkyl-CO or aryl-CO; X1 represents Br, J or Cl atoms to form intermediate compound of the formula (19): wherein R9 represents X1 or -OR8, and conversion of intermediate compound of the formula (19) to the end compound of the formula (I). Also, invention relates to 4-nitrobenzyl-(5R,6S)-6-bromopenem-3-carboxylate of the formula (16) and to a method for its synthesis. Method involves the following steps: (A) (i) interaction of 6-aminopenicillanic acid with hydrobromic acid in organic solvent and water to form 6-bromopenicillanic acid of the formula (21): and its conversion to p-nitrobenzyl-6-bromopenicillanate of the formula (22): wherein R represents p-nitrobenzyl by interaction with 4-nitrobenzyl bromide in the presence of a base in organic solvent; (B) oxidation of compound of the formula (22) to form p-nitrobenzyl-6-bromopenicillanate-1-oxide of the formula (23) given in the invention description; (C) boiling compound of the formula (23) with 2-mercaptobenzothiazole in aromatic solvent to form 4-nirobenzyl-(2R)-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-3-enoate of the formula (24) given in the invention description; (D) dissolving compound of the formula (24) in organic solvent and interaction with an organic tertiary base to form 4-nitrobenzyl-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (25) given in the invention description; (E) conversion of compound of the formula (25) to 4-nitrobenzyl-2-[(3S,4R)-3-bromo-4-formylthio-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (26) given in the invention description as result of interaction of with organic acid in aromatic organic medium in the presence of a mixture acetic anhydride/organic tertiary base and trialkyl- or triarylphosphine in the range of temperature from about -10°C to about -30°C, and (F) passing ozonized oxygen through solution of compound of the formula (26) in organic solvent for 3-4 h at temperature from -70°C to -90°C and the following the intramolecular cyclization reaction using a phosphite reagent. Invention provides the increased yield and economy method for synthesis of derivatives of 6-alkylidenepenem.

EFFECT: improved method of synthesis.

41 cl, 2 tbl, 42 ex

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R3 means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH2-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR10-, -NR10C(=O)-, -NR10C(=O)NR11-, -NR10CO2-, -NR10SO2-, -NR10SO2NR11-, -SO2NR10-, -C(=O)NR10, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR20 being wherein Z means -CR20 optionally substituted bicyclic aryl or heteroaryl with R4 or R5; R1 means hydrogen atom, -CH3, -OH, -OCH3, -SH, -SCH3, -OC()=O)R21, -S(=O)R22, -SO2NR23R25, -CO2R21, -C(=O)NR24R25, -NH2, -NR24R25, -NR21SO2NR24R25, -NR21SO2R22, -NR24C(=O)R25, -NR24CO2R25, -NR21C(=O)NR24R25, halogen atom, nitro- or cyano-group; R2 is chosen from the following group: (a) hydrogen atom under condition that R2 doesn't mean hydrogen atom if X means -S(=O)-, -SO2-, -NR10CO2- or -NR10SO2-; (b) alkyl, alkenyl and alkynyl comprising up to four R26 groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R27 as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R27 as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R2 is absent if X means halogen atom, nitro- or cyano-group; R4 means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R5 means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R5 is absent, or R4 and R5 in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R6 means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR7R8, -OR7 or halogen atom; R10 and R11 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R7, R8, R21, R24 and R25 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R20 means hydrogen, lower alkyl or substituted alkyl, or R20 can absent if carbon atom to which is bound and in common with R4 and R5 represents part of bicyclic aryl or heteroaryl; R22 means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R26 is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR28, -OR28, -NR28R29, -NR28SO2, -NR28SO2R29, -SO2R28, -SO2NR28R29, -CO2R28, -C(=O)R28, -C(=O)NR28R29, -OC(=O)R28, -C(=O)NR28R29, -NR28C(=O)R29, -NR28CO2R29,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R27 groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R27 groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R27 groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R28 and R29 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl and (C3-C7)-heterocycle, or they can form in common (C3-C7)-heterocycle; and each R28 and R29, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R27 is chosen from the following group: alkyl, R32 and (C1-C4)-alkyl comprising as substitutes from one to three R32groups and wherein each R32 group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR30, -OR30, -NR30R31, -NR30SO2, -NR30SO2R31, -SO2R30, -SO2NR30R31, -CO2R30, -C(=O)R30, -C(=O)NR30R31, --OC(=O)R30, -OC(=O)NR30R31, -NR30C(=O)R31, -NR30CO2R31 and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R30 and R31 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl, and heterocycle, or they in common can form (C3-C7)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) , methods for their synthesis and their using for therapeutic treatment of the nervous system disorders associated with 5-HT-6 receptor. Invention provides synthesis of novel biologically active substances of the formula (I) and pharmaceutical compositions based on thereof used in treatment of the nervous system disorders and controlled by 5-HT-6 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 tbl, 82 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to novel individual compounds of series 2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates, namely, to isopropyl-12-aroyl-2-hydroxy-1,6-dioxo-4-(3-pyridinyl)-7-phenyl-1,3,6,7-tetrahydro-2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates of the formula (1) wherein Ar means phenyl or p-methoxyphenyl, and to a method for their synthesis. Method for synthesis of compound of the formula (1) involves interaction of 3-aroyl-5-phenylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with isopropyl-3-amino-3-(3-pyridinyl)-2-propenoate in an inert aprotonic solvent medium and the following isolation of end substances. The proposed method provides synthesis of novel compounds of the formula (1) possessing antibacterial effect with high yield and selectivity.

EFFECT: improved method of synthesis.

4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

Up!