2h- or 3h-benzo[e]indazol-1-yl-carbamate derivatives and use thereof in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

 

The object of the invention are compounds - derivatives of 2H or 3H-benzo[e]indazol-1-yl-carbamate, which have an affinityin vitroandin vivoto the receptors of the peripheral benzodiazepine type (sites R or PBR).

The first object of the invention are compounds of General formula (I)below.

Another object of the invention are methods of obtaining compounds of General formula (I).

Another object of the invention is the use of compounds of General formula (I), in particular, drugs or pharmaceutical compositions.

Compounds according to the invention correspond to the General formula (I):

in which

W represents an oxygen atom or sulfur;

X1, X2, X3and X4represent, each independently from each other, hydrogen atom or halogen or cyano group, With1-C6-alkyl, C1-C6-alkyl fluoride With1-C6-alkoxy, C1-C6-feralcode;

Y is in position (N2) or (N3);

when Y is in position (N2), Y represents C1-C6-alkyl, C1-C6-alkyl fluoride, aryl or heteroaryl group,

when Y is in position (N3), Y denotes an aryl or heteroaryl group,

however aryl or heteroaryl group possibly substituted by one or n is the number of atoms or groups, selected from halogen atoms, With1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio,1-C6-alkyl-S(O)-, C1-C6-alkyl-S(O)2-With1-C6-alkyl fluoride groups;

the relationship in position C4-C5 is double or simple; R1and R2denote, each independently of one another, aryl, benzyl or1-C6is an alkyl group; or R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, possibly substituted by one or more1-C6-alkyl or benzyl groups.

In the framework of the present invention is meant

- Ct-Czwhere t and z can have a value from 1 to 6 carbon chain which can have from t to z carbon atoms, for example, C1-3- carbon chain that may contain from 1 to 3 carbon atoms;

- alkyl: saturated aliphatic linear or branched group. As examples are methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, tert-boutelou, pentelow, etc. groups;

- perakyla: alkyl group, one or more hydrogen atoms of which is substituted by fluorine atom;

- alkoxy: a radical-O-alkyl in which the alkyl group is as defined above;

- feralcode: group ALK is XI, one or more hydrogen atoms of which is substituted by fluorine atom;

- alkylthio: radical-S-alkyl, in which alkyl group is as defined above;

- heterocycle: a cyclic group containing from 4 to 7 units and containing the nitrogen atom and possibly other gererator, such as nitrogen, oxygen or sulfur. As examples of the heterocycles can be called azetidinol, pyrrolidinyloxy, piperidinyloxy, morpholinyl, thiomorpholine, sepanlou, piperazinilnom or homopiperazine group;

- aryl: an aromatic cyclic group containing from 6 to 10 carbon atoms. As examples of aryl groups can be called phenyl or naftalina group;

- heteroaryl: aromatic cyclic group containing from 5 to 6 units and containing from 1 to 2 heteroatoms, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups can be called pyridinyl, thienyl, fornillo, pyrimidinyl, personilnya or pyridazinyl group;

- link: cyclic group indicates the bond between two adjacent atoms;

the halogen atom: a fluorine, chlorine, bromine or iodine.

Compounds of General formula (I) may contain one or more asymmetric carbon atoms. They can be in the form of enantiomers or diastereoisomers. These enantiomers and diaster the isomers, as well as mixtures thereof, including racemic mixtures, belong to the invention.

The compounds of formula (I) can be in the form of bases or of salts of Association with an acid. Such salts are joining to the invention.

These salts mainly get with pharmaceutically acceptable acids but the salts of other acids that are suitable, for example, for the purification or separation of the compounds of formula (I), also belong to the invention.

Compounds of General formula (I) can be in the form of a hydrate or of a solvate and in the form of associations or combinations with one or more water molecules or with a solvent. Such a hydrate or solvate also belong to the invention.

Of the compounds of formula (I), which is the object of the invention, a first subgroup of compounds consists of compounds in which:

W represents an oxygen atom or sulfur; and/or

X1, X2and X3represent, each independently from each other, hydrogen atom or halogen, more particularly fluorine, chlorine or bromine, or cyano, With1-C6-alkyl, more specifically methyl,1-C6-alkoxy, more particularly a methoxy group; and/or

X4denotes a hydrogen atom; and/or

Y is in position (N2) or (N3);

when Y is in position (N2), Y represents C1-C6-alkyl, more particularly methyl or ethyl, With -C6-alkyl fluoride, more specifically triptoreline, aryl, more particularly phenyl, or heteroaryl, more specifically pyridinio or personilnya group;

when Y is in position (N3), Y denotes an aryl, more particularly phenyl, or heteroaryl, more specifically pyridinoline or pyrimidinyl group;

however aryl or heteroaryl group possibly substituted by one or more atoms or groups, more specifically one or two atoms or groups selected from halogen atoms, more particularly fluorine, chlorine, C1-C6-alkyl, more specifically methyl, and C1-C6-alkoxy, more specifically methoxypropane; and/or

the relationship in position C4-C5 is double or simple; and/or

R1and R2represent, each independently from each other aryl, more particularly phenyl,1-C6-alkyl, more specifically methyl, ethyl, n-sawn, tert-boutelou, ISO-propyl group; or R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, more specifically pyrrolidinyl, piperidinyl, morpholinyl or piperazinil, possibly substituted by one or two1-C6-alkyl, more specifically methyl groups.

Of the compounds of formula (I), which is the object of the invention, the second under the group of compounds consists of compounds in which:

W represents an oxygen atom or sulfur; and/or

X1, X2and X3represent, each independently from each other, hydrogen atom or halogen, more particularly fluorine, chlorine or bromine, or With1-C6-alkyl, more specifically methyl,1-C6-alkoxy, more particularly a methoxy group; and/or

X4denotes a hydrogen atom; and/or

Y is in position (N2) or (N3) and denotes aryl, more particularly phenyl or heteroaryl, more specifically pyridinoline, personilnya or pyrimidinyl group;

however aryl or heteroaryl group possibly substituted by one or more atoms or groups, more specifically one or two atoms or groups selected from halogen atoms, more particularly fluorine, chlorine, C1-C6-alkyl, more specifically methyl, and C1-C6-alkoxy, more particularly methoxy groups; and/or

the relationship in position C4-C5 is double or simple; and/or

R1and R2represent, each independently from each other aryl, more particularly phenyl,1-C6-alkyl, more specifically methyl, ethyl, n-sawn, tert-boutelou, ISO-propyl group; or R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, more specifically pyrrolidinyl, Piperi inil, morpholinyl or piperazinil, possibly substituted by one or two1-C6-alkyl, more specifically methyl groups.

Of the compounds of formula (I), which is the object of the invention, a third subgroup of compounds consists of compounds in which:

W represents an oxygen atom or sulfur; and/or

X1, X2and X3represent, each independently from each other, hydrogen atom or halogen, more particularly fluorine, chlorine or bromine, or With1-C6-alkyl, more specifically methyl,1-C6-alkoxy, more particularly a methoxy group; and/or

X4denotes a hydrogen atom; and/or

Y is in position (N3) and denotes aryl, more particularly phenyl, or heteroaryl, more specifically pyridinoline or pyrimidinyl group;

however aryl or heteroaryl group possibly substituted by one or more atoms or groups, more specifically one or two atoms or groups selected from halogen atoms, more particularly fluorine, chlorine, C1-C6-alkyl, more specifically methyl, and C1-C6-alkoxy, more particularly methoxy groups; and/or

the relationship in position C4-C5 is double or simple; and/or

R1and R2represent, each independently from each other aryl, more particularly phenyl,1- 6-alkyl, more specifically methyl, ethyl, tert-boutelou, ISO-propyl group; or R1and R2form together with the nitrogen atom to which they are bound, a heterocycle, more specifically piperidinyl, possibly substituted by one or two1-C6-alkyl, more specifically methyl groups.

Compounds of General formula (I) can be obtained by methods which are illustrated in the following schema.

In accordance with the first variant get (scheme 1), the compound of General formula (II)in which X1, X2, X3and X4are as defined in General formula (I)enter into interaction with methylcarbonate in the presence of catalytic amounts of a base, such as methanolic sodium or sodium hydride to produce complex keeeper General formula (III). Condensation of complex keeeper (III) with hydrazine, for example, in a polar solvent such as DMF or acetic acid, allows you to select a pyrazole of the General formula (IV). The latter are then subjected to selective N-substitution effect of the aryl halide or heteroaryl General formula Y-hal, in which Y is as defined in General formula (I)and hal is a halogen atom, such as iodine or bromine, in the presence of a base such as potassium carbonate or cesium or potassium triphosphate, a catalytic amount of copper salt and dia is on (S.L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727).

Then the resulting mixture, containing positional isomers of General formula (Va) and (Vb), in which the group Y is respectively in positions 2 and 3 pyrazol cycle, is subjected to the action of a derivative of chloride carbamoyl General formula CIC(W)NR1R2in which W, R1and R2are as defined in General formula (I), in the presence of a base such as potassium carbonate, sodium hydride or triethylamine, to obtain carbamates of General formula (Ia) and (Ib), which at this stage is separated by methods known to the person skilled in the art, such as chromatography on a column of silica gel.

Alternatively, the second option allows you to obtain compounds of General formula (Ia) (scheme 2).

It consists in condensing complex keeeper General formula (III), such as defined above, with a hydrazine of General formula Y-NH-NH2in which Y is as defined in General formula (I), for example, in a polar solvent such as DMF or acetic acid, and allows you to select a pyrazole of the General formula (VA), such as defined above. This last then subjected to acylation by the action of a derivative of chloride carbamoyl General formula CIC(W)NR1R2such as defined above, in prisutstvuyuschuyu, such as potassium carbonate, sodium hydride or triethylamine, to obtain carbamates of General formula (Ia).

A simple link in position C4-C5 compounds of General formula (I) may possibly be digidrirovanne to obtain the double bond by a method known to the expert, for example, by analogy with the method described Kozo, Shishido et al. Tetrahedron, 1989, 45, 18, 5791-5804. Alternatively, compounds of General formula (I)containing a simple link in position C4-C5, you can degidrirovanii by interacting with a halogenation agent such as N-bromosuccinimide, in the presence of an initiator, such as 2,2'-azobis(2-methylpropionitrile). Under these conditions, compounds of General formula (I)containing a simple link in position C4-C5, is first subjected to galogenirovannyie, then the resulting intermediate product is subjected to the reactions of elimination to obtain the compound (I)containing a double bond in position C4-C5.

The reagents in schemes 1 and 2, the method of obtaining them is not described, are commercially available or described in the literature, or they can be obtained by the methods described there, or that well-known specialist in this field.

Compounds of General formula (II) can be obtained from commercial sources or obtained by the methods described in the literature (Sims, J.J. et al. Tetrahedron Lett. 1971, 951).

In accordance with another of its aspects the invention relates so is e to compounds of formulas (Va) and (Vb). These compounds may be suitable as intermediate products for the synthesis of compounds of formula (I).

The following table 1 illustrates the chemical structures and physical properties of several compounds of the General formulae (Va) and (Vb) according to the invention. In the column “PF” indicates the melting point of the products.

Table 1
No.X1X2X3X4YPF (°C)
Va.1HHHH2-(4-were)221-222
Vb.1HMeHH3-(pyridin-4-yl)315-316
Va.2HFHH2-(4-forfinal) 220-221
Vb.2HClHH3-(pyridin-4-yl)336-342
Va.3HClHH2-(pyridin-4-yl)190-216

In the following examples describe some of the compounds according to the invention. These examples are not limiting, but only illustrative of the invention. The numbers of the compounds in the examples correspond to the numbers shown in tables 1 and 2. Elemental microanalysis, analyses LC-MS (liquid chromatography coupled with mass spectrometry), IR spectra and NMR confirmed the structure of the compounds obtained.

Example 1 (compound 1)

7-fluoro-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl

1.1 Methyl-6-fluoro-2-hydroxy-3,4-dihydronaphthalene-1-ILOAT

In a reactor with a volume of 2 l enter 12,66 g (316 mmol) of 60%sodium hydride in oil, 900 ml of toluene and 17,69 ml (210 mmol) of dimethylcarbonate. The reaction mixture is stirred for 1 hour under reflux. Then introduce a solution of 19 g (115 mmol) of 6-fluoro-3,4-dihydro-1H-naphthalene-2-it in 350 ml of toluene. Rea is operating, the mixture is heated under reflux for 24 hours. Then the reaction mixture was cooled to 0°C., then acidified by adding 114 ml of acetic acid. Enter 114 ml of water and the organic phase is separated by settling, washed with twice 150 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride. Then the organic phase is dried on magnesium sulfate, then concentrated under reduced pressure to obtain of 26.1 g of product, which is used as such in the next stage.

1.2 7-fluoro-2-(4-forfinal)-1-hydroxy-4,5-dihydro-2H-benzo[e]indazol (Va.2)

In a reactor with a volume of 100 ml is administered 2 g (9 mmol) of the product obtained in stage 1.1, and 2,73 g (16,8 mmol) of 4-tortenelmitradiciokban. The mixture is dissolved in 100 ml of acetic acid and heated under reflux for 4 hours. Then the reaction mixture is cooled, and then concentrated under reduced pressure. The residue is treated with 150 ml of ethyl acetate and 100 ml of water. The organic phase is advocated, washed twice with 100 ml water, then once with 100 ml saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 3.5 g of the target product.

Melting point: 220-221°C

1H-NMR (DMSO-d6): δ (ppm) 2,72 (DCD, 2H), 2.95 and (DCD, 2H), 7,01 (m, 2H), and 7.3 (m, 2H), to 7.75 (m, 3H).

1.3 7-fluoro-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-dietiker the Mat (compound 1)

In a reactor of 500 ml is injected 3.5 g (9 mmol) of the product obtained at stage 1.2, 3,48 g (25 mmol) of potassium carbonate and 2.66 ml (21 mmol) of N,N-diethylcarbamoyl. The reaction mixture is heated under reflux for 24 hours, then concentrated under reduced pressure. The resulting product is treated with 100 ml of ethyl acetate. The organic phase is washed twice with 100 ml water, then once with 100 ml saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 5,96 g of raw product. The mixture is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane and ethyl acetate. Thus 2.2 g of the desired product is isolated and recrystallized in isopropanol and get 1.5 g (of 3.77 mmol) of the final product.

Melting point: 141-142°C

1H-NMR (CDCl3): δ (ppm) 1,95 (t, 3H), 2,6 (t, 3H), of 2.97 (t, 2H), 3,98 (t, 2H), 3,4 (kV, 2H), 3,52 (kV, 2H), 7,00 (m, 2H), 7,2 (m, 2H), 7,32 (m, 1H), 7,56 (m, 2H).

Example 2 (compound 2)

7-fluoro-2-(4-forfinal)-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl

A solution of 0.7 g (1,76 mmol) of 7-fluoro-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl obtained in stage 1.3 of example 1 and 1.2 g (5.2 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 25 ml of toluene is stirred for 2 hours, then cooled. mesh tilt 100 ml of ethyl acetate. This organic phase is washed with twice 100 ml of a saturated aqueous solution of hydrogencarbonate sodium, 100 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride. The organic phase is separated by settling, dried on magnesium sulfate and concentrated under reduced pressure. Purify by chromatography on a column of silica gel (eluent: a mixture of methylene chloride and ethylacetate) and recrystallized in isopropanol and receive 500 mg (of 1.26 mmol) of the target product.

Melting point: 159-160°C

1H-NMR (DMSO): δ (ppm) was 1.04 (t, 3H), of 1.21 (t, 3H), of 3.28 (q, 2H), 3,55 (kV, 2H), 7,45 (m, 3H), and 7.7 (m, 5H), 7,9 (DCD, 1H).

Example 3 (compound 3 and 4)

The hydrochloride of 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 3), and hydrochloride of 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 4)

3.1 Methyl-6-chloro-2-hydroxy-3,4-dihydronaphthalene-1-ILOAT

In the reactor of 2 l enter the 10.1 g (252 mmol) of 60%sodium hydride in oil, 621 ml of toluene and 14,18 ml (163 mmol) of dimethylcarbonate. The reaction mixture is stirred for 1 hour under reflux. Then introduce a solution of 15.2 g (84 mmol) of 6-chloro-3,4-dihydro-1H-naphthalene-2-it in 268 ml of toluene. The reaction mixture is heated under reflux for 24 hours. Then the reaction mixture was cooled to 0°C., then acidified by adding the Oia 92 ml of acetic acid. Enter 114 ml of water and the organic phase is separated and defend, washed with three times 150 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride. Then the organic phase is dried on magnesium sulfate, then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (elwira with a mixture of cyclohexane and dichloromethane) and obtain 12.8 g (53.6 mmol) of the target product, which is used as such in the next stage.

3.2 7-chloro-1-hydroxy-4,5-dihydro-2H-benzo[e]indazol

In the reactor of 2 l enter 28 g (117 mmol) of product obtained in stage 3.1, and 28.6 ml g (586,6 mmol) hydrazinoacetate. The mixture is dissolved in 782 ml of acetic acid and heated under reflux for 4 hours. Then the reaction mixture is cooled, and then concentrated under reduced pressure. The resulting product is treated with 300 ml of ethyl acetate and 300 ml of water. The organic phase is advocated, washed twice with 200 ml water, then once with 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is ground to powder in 200 ml of a simple ethyl ether, then filtered and receive a 25 g (113,3 mmol) of the target product.

Melting point: 232-233°C.

3.3 7-chloro-1-hydroxy-2-(pyridin-4-yl)-4,5-dihydro-2H-BAA is zo[e]indazol and 7-chloro-1-hydroxy-3-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol

In the reactor of 2 l is introduced into an inert atmosphere of 15.2 g (of 68.8 mmol) of the product obtained at stage 3.2, 16,95 g (82,66 mmol) of 4-iopidine, 4,14 ml (34,44 mmol) of TRANS-1,2-diaminocyclohexane, 1.31 g (6,89 mmol) of copper iodide and 36,55 g (172,2 mmol) of potassium phosphate. The reaction mixture is suspended in 690 ml of dioxane and heated under reflux for 24 hours, then cooled. The mixture is concentrated under reduced pressure, then treated with 200 ml of water. This aqueous phase is acidified to pH 5 by successive additive acetic acid. The suspension is stirred for 30 minutes, then the precipitate is filtered, washed with water, then dried under reduced pressure and obtain 16.6 g (55,7 mmol) of the desired product N-arilirovaniya in the form of mixtures of isomers.

LC-MS: 2 peak at 60.4% and 38%, corresponding to [MH]+=298.

3.4 hydrochloride of 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 3), and hydrochloride of 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 4)

In the reactor of 2 liters of introducing inert atmosphere 13 g (43,66 mmol) of the mixture of isomers obtained at stage 3.3, 18,1 g (131 mmol) of finely ground potassium carbonate and 11,07 ml (87,32 mmol) of N,N-diethylcarbamoyl. The reaction mixture was suspended in 1 ml of acetonitrile is heated under reflux for 24 hours then cooled. The reaction mixture was concentrated under reduced pressure. The resulting product is treated with 300 ml of ethyl acetate and 300 ml of water. The organic phase is advocated, washed twice with 200 ml water, then once with 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting product contains both isomers position (compounds 3 and 4). Separated by chromatography on a column (300 g of silica gel Merck 15-40 microns, eluent: a mixture of heptane and ethyl acetate).

The hydrochloride of 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 3)

Product # 3 allocated thus converted into the hydrochloride by dissolving in a solution of 0.1 G. of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. Grind to a powder in a simple ethyl ether, then filtered and dried under reduced pressure to obtain 2.3 g (5,79 mmol) of the final product.

Melting point: 250-251°C

1H-NMR (DMSO): δ (ppm) of 1.08 (t, 3H), of 1.31 (t, 3H), 2,98 (m, 4H), and 3.3 (q, 2H), 3,68 (kV, 3H), 7,27 (d, 1H), 7,38 (DCD, 1H), 7,46 (DCD, 1H), 7,92 (d, 2H), 8,87 (d, 2H).

The hydrochloride of 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 4)

Product # 4 allocated thus transformed into the hydrochloride by dissolving in the solution is 0.1 N. hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. Grind to a powder in a simple ethyl ether, filtered and dried under reduced pressure and obtain 6.2 g (15.62 wide mmol) of the final product.

Melting point: 224-226°C

1H-NMR (DMSO): δ (ppm) of 1.18 (t, 3H), of 1.29 (t, 3H), to 3.02 (t, 2H), and 3.31 (m, 4H), 3,51 (kV, 2H), 7,20 (m, 1H), 7,32 (DCD, 1H), 7,45 (d, 1H), 8,08 (d, 2H), 8,98 (d, 2H).

Example 4 (compound 5)

The hydrochloride of 8-methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl

4.1 Methyl-6-methoxy-2-hydroxy-3,4-dihydronaphthalene-1-ILOAT

In the reactor of 1 liter of injected 3.4 g (85,12 mmol) of 60%sodium hydride in oil, 180 ml of toluene and 4,78 ml (56,75 mmol) dimethylcarbonate. The reaction mixture is stirred for 1 hour under reflux. Then injected a solution of 5 g (28,37 mmol) 7-methoxy-3,4-dihydro-1H-naphthalene-2-it in 100 ml of toluene and then stirred. The reaction mixture is heated under reflux for 24 hours. Then the reaction mixture was cooled to 0°C., then acidified by adding 30 ml of acetic acid. Inject 30 ml of water and the separated organic phase is advocated, washed with twice 50 ml of water, then 50 ml of a saturated aqueous solution of sodium chloride. Then the organic phase is dried on magnesium sulfate, then concentrated under reduced pressure. The residue is purified chromatographia column of silica gel (eluent: a mixture of methylene chloride and heptane) and gain of 3.9 g (16,64 mmol) of the target product, which is used as such in the next stage.

4.2 1-hydroxy-8-methoxy-4,5-dihydro-2H-benzo[e]indazol

In a reactor with a volume of 0.5 l enter 3,9 g (16,65 mmol) of product obtained in stage 4.1, and 4,06 ml (83,24 mmol) hydrazinoacetate. The mixture is dissolved in 166 ml of acetic acid and heated under reflux for 4 hours. Then the reaction mixture is cooled, and then concentrated under reduced pressure. The resulting product is treated with 100 ml of ethyl acetate and 100 ml of water. The organic phase is advocated, washed twice with 100 ml water, then once with 100 ml saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue is ground to powder in 50 ml of a simple ethyl ether, then filtered and obtain 2.4 g (11.1 mmol) of the target product.

4.3 1-hydroxy-8-methoxy-2-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol

In a reactor with a volume of 0.1 l injected into an inert atmosphere 1.2 g (5,55 mmol) of product obtained in stage 4.2, 1,36 g (6,66 mmol) of 4-iopidine, 0.33 ml (2.77 mmol) of TRANS-1,2-diaminocyclohexane, 0,105 g (0.55 mmol) of copper iodide and 2.94 g (13,87 mmol) of potassium phosphate. The reaction mixture was suspended in 55 ml of dioxane and heated under reflux for 24 hours, then cooled. Then the mixture is treated with 1 l of 1/1 mixture of water and ethyl acetate. The organic phase is advocated, then washed with water (50 ml). This organic phase is acidified to pH 5 by successive additive acetic acid. The precipitate is filtered and washed with water, then dried under reduced pressure and obtain 0.2 g (of 0.68 mmol) of the expected product N-arilirovaniya. The organic phase is dried on magnesium sulfate, then concentrated under reduced pressure. The resulting product was then purified by chromatography on a column of silica gel (eluent: a mixture of dichloromethane and methanol) and receive an additional 0,57 g (1.94 mmol) of the desired product N-arilirovaniya.

1H-NMR (DMSO-d6): δ (ppm) 2,89 (DCD, 3H), 3,09 (DCD, 2H), of 3.73 (s, 3H), 6,2 (DCD, 1H), and 7.1 (m, 2H), of 7.48 (m, 2H), and 8.6 (m, 2H).

4.4 8-methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl-N,N-diethylcarbamyl (compound 5)

In a reactor with a volume of 0.1 l injected into an inert atmosphere of 0.77 g (2,63 mmol) of the product obtained at stage 4.3, 1,09 g (7,88 mmol) of finely ground potassium carbonate and 0.67 ml (the 5.25 mmol) of N,N-diethylcarbamoyl. The reaction mixture was suspended in 30 ml of acetonitrile is heated under reflux for 24 hours, then cooled. The reaction mixture was concentrated under reduced pressure. The resulting product is treated with 100 ml of ethyl acetate and 100 ml of water. The organic phase is advocated, washed twice with 50 ml water, then once with 50 ml of NASA the n aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting product was then purified by chromatography on a column (90 g silica gel Merck 15-40 microns, eluent: a mixture of heptane and ethyl acetate). The selected product is recrystallized in isopropanol, and then re-dissolved in a solution of 0.1 G. of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. Grind to a powder in a simple ethyl ether, filtered and dried under reduced pressure and obtain 234 mg (0.59 mmol) of the target product.

Melting point : 225-227°C

1H-NMR (DMSO): δ (ppm) to 1.15 (t, 3H)and 1.3 (t, 3H), of 2.92 (t, 2H), 3,2-3,4 (m, 4H), 3,51 (kV, 2H), 3,71 (s, 3H), 6,8 (m, 2H), 7,2 (d, 1H), 7,98 (d, 2H), 8,82 (d, 2H).

Example 5 (compound 82)

The hydrochloride of 7-chloro-4,5-dihydro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl-N,N-Diisopropylamine

In the reactor of 1 l in an inert atmosphere injected dropwise and at 0°C in a suspension of 0.4 g (10,04 mmol) of sodium hydride in 17 ml of dimethylformamide, 23 g (7,72 mmol) of the mixture of isomers obtained at stage 3.3 example 3, in solution in 30 ml of dimethylformamide. Stirred for 1 hour at room temperature, and then introduced dropwise 1.39 g (8.5 mmol) of N,N-diisopropylcarbodiimide in 30 ml of dimethylformamide. The reaction mixture is stirred for 18 hours at room temperature, then the concentration of irout under reduced pressure. The resulting product is treated with 300 ml of ethyl acetate and 300 ml of water. the pH of the aqueous phase was adjusted to 5 by adding acetic acid. The organic phase is advocated, washed twice with 200 ml water, then once with 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting product was then purified by chromatography on a column (300 g of silica gel Merck 15-40 microns, eluent: a mixture of dichloromethane and ethyl acetate). The selected product is converted into the hydrochloride by dissolving in a solution of 0.1 G. of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. Grind to a powder in a simple ethyl ether, filtered and dried under reduced pressure and obtain 1.2 g (2.6 mmol) of the target product.

Melting point: 237-269°C

1H-NMR (DMSO): δ (ppm) of 1.29 (m, N), to 3.02 (m, 2H), 3,19 (m, 2H), 3,91 (m, 1H), 4,2 (m, 1H), 7,2 (d, 1H), 7,35 (DCD, 1H), 7,42 (s, 1H), and 7.6 (d, 2H), and 8.7 (d, 2H).

Example 6 (compound 84)

The hydrochloride of 7-chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl-N,N-Diisopropylamine

In a reactor with a volume of 100 ml is injected 1,65 g (3,38 mmol) 7-chloro-4,5-dihydro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl-N,N-diisopropylcarbodiimide, obtained by the method described in example 5 1,105 g (6.21 mmol) of N-bromosuccinimide and to 0.127 g (0.78 mmol) of 2,2'-azobis(2-methylpropionitrile). With the ect dissolved in 40 ml of carbon tetrachloride, stirred for 24 hours under reflux under reduced pressure. The resulting product is treated with 300 ml of dichloromethane and 2 ml of concentrated aqueous ammonia. The organic phase is separated, washed with 200 ml of water, and then 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is then dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting product was then purified by chromatography on a column of aluminum oxide (eluent: a mixture of dichloromethane and methanol), and then on a column of silica (eluent: a mixture of dichloromethane and ethyl acetate).

The selected product is converted into the hydrochloride by dissolving in a solution of 0.1 G. of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. Grind to a powder in a simple ethyl ether, filtered and dried under reduced pressure and obtain 1.2 g (2.6 mmol) of the target product.

Melting point: 234-248°C

1H-NMR (DMSO): δ (ppm) to 1.42 (m, N), was 4.02 (m, 1H), to 4.41 (m, 1H), 7,6 (DCD, 1H) and 7.8 (m, 3H), 7,92 (d, 2H), 8,15 (d, 1H), 8,79 (d, 2H).

The following table 2 illustrates the chemical structures and physical properties of several compounds of the General formula (I) according to the invention.

In the column "Salt" this table "Hcl" denotes a hydrochloride, "-" denotes a compound in the base condition. Molar ratio Ki of the lot:the basis is specified in the same column. In the column "PF" indicates the melting point products, amorphous compounds characterized by the results of their analysis by mass spectrometry (MS).

2-(2-chloro phenyl) N HCl 1:1
Table 2
No.X1X2X3X4WNR1R2Connection C4-C5YSolPF (°C)
1NFNHON(CH2CH3)2simple2-(4-fluoro phenyl)-141-142
2NFNHON(CH2CH3)2DV is ina 2-(4-fluoro phenyl)-159-160
3NCLNHON(CH2CH3)2simple2-(pyridin-4-yl)HCl 1:1250-251
4NCLNHON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1224-226
5NNOCH3HON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1225-227
6 NNNNON(CH3)2simple2-(4-methyl phenyl)-130-131
7NNNNON(CH2CH3)2simple2-(4-chloro phenyl)-148-149
8NNNNOsimple2-(3-chloro phenyl)-150-151
9NNNNON(CH3)2 simple2-(3-chloro phenyl)-128-129
10NNNNON(CH2CH3)2simple2-(3-chloro phenyl)-111-113
11NNNNOsimple2-(3-chloro phenyl)-155-157
12NNNNON(CH(CH3)2)2simple2-(3-chloro phenyl)-116-118
13 NNNNON(CH2CH3)2simple2-phenyl-124-125
14HClHNON(CH2CH3)2simple2-phenyl-114-116
15NHHHON(CH3)Phsimple2-(3-chloro phenyl)-75-78
16NHHHON(CH2CH3)2simple-396*
17NHHHON(CH2CH3)2simple2-ethyl-60-61
18NHHHON(CH3)Phsimple2-ethyl-348*
19NHHHON(CH3)Phsimple2-(2,2',2”-trifter ethyl)-402*
20NHH HON(CH2CH3)2simple2-(4-fluoro phenyl)-132-133
21NHHHON(CH(CH3)2)2simple2-(4-fluoro phenyl)-95-96
22NHHHON(CH3)Phsimple2-(4-fluoro phenyl)-197-198
23NHHHOsimple2-(4-fluoro phenyl)- 211-212
24NHHHOsimple2-(4-fluoro phenyl)-174-175
25NHHHOsimple2-(4-fluoro phenyl)-175-176
26NHHHON(CH3)2simple2-(4-chloro phenyl)-211-212
27NHHHO N(CH(CH3)2)2simple2-(4-chloro phenyl)-203-204
28NHHHON(CH3)Phsimple2-(4-chloro phenyl)-202-203
29NHHHOsimple2-(4-chloro phenyl)-212-213
30NHHHOsimple2-(4-chloro phenyl)-200-201
31NHHHOsimple2-(4-chloro phenyl)-185-186
32NHHHOsimple2-(4-chloro phenyl)-157-158
33NHHHON(CH3)2simple2-(4-fluoro phenyl)-216-217
34NHHHO simple2-(4-fluoro phenyl)-167-168
35NHNNON(CH3)2simple2-phenyl-158-159
36NHNNON(CH(CH3)2)2simple2-phenyl-146-147
37NHNNON(CH3)Phsimple2-phenyl-169-170
38N HNNOsimple2-phenyl-176-177
39NClNNON(CH2CH3)2simple2-(4-fluoro phenyl)-155-156
40NHNNON(CH3) (CH2)2CH3simple2-(4-fluoro phenyl)-143-144
41NHNNON(CH2CH3)2about the Tay 2-(3-chloro-4-methyl phenyl)-99-101
42NHNNON(CH2CH3)2simple2-(3-chloro-4-fluoro phenyl)-148-150
43NClNNON(CH2CH3)2simple2-(3-chloro-4-methyl phenyl)-131-133
44NClNNON(CH2CH3)2simple2-(2,4-debtor phenyl)-78-80
45HNNON(CH2CH3)2simple2-(pyridin-4-yl)HCl 1:1298-299
46NClNNON(CH2CH3)2simple2-(pyridin-2-yl)-108-110
47NOCH3NNON(CH2CH3)2simple2-(4-fluoro phenyl)-161-162
48NBrNNON(CH2CH3) 2simple2-(4-fluoro phenyl)-162-163
49NClNNON(CH2CH3)2simple2-(3-chloro-4-fluoro phenyl)-108-110
50NClNNON(CH2CH3)2simple2-methyl-117-118
51NNNNON(CH2CH3)2double2-(3-chloro phenyl)-125-126
52NNNNON(CH2CH3)2double2-(4-fluoro phenyl)-125-126
53NNNNON(CH3) (CH2)2CH3double2-(4-fluoro phenyl)-154-155
54NNNNON(CH2CH3)2double2-(3-chloro-4-fluoro phenyl)-412*
55NNNNO N(CH2CH3)2double2-(3-chloro-4-methyl phenyl)-118-120
56NClNNON(CH2CH3)2double2-(4-fluoro phenyl)-151-153
57NClNNON(CH2CH3)2double2-(3-chloro-4-fluoro phenyl)-141-143
58NClNNON(CH2CH3)2double2-(3-chloro-4-methyl phenyl)- 141-143
59NClNNON(CH2CH3)2double2-(2,4-debtor phenyl)-144-146
60NOCH3NNON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1208-220
61NCH3NNON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1222-225
62NClN NON(CH2CH3)2simple3-(pyridin-3-yl)HCl 1:1194-197
63NClNNON(CH2CH3)2simple2-(pyridin-3-yl)HCl 1:1155-157
64NFNNON(CH2CH3)2simple2-(pyridin-4-yl)HCl 1:1324-326
65NFNNON(CH2CH3)2simple3-(pyridin-4-yl)233-242
66NClNNON(CH2CH3)2simple3-(4-fluoro phenyl)-131-132
67NClNNON(CH2CH3)2simple3-(pyridin-2-yl)HCl 1:1122-123
68NClNNON(CH2CH3)2simple2-(3-fluoro phenyl-128-130
69NClN/td> NON(CH2CH3)2simple3-(3-fluoro phenyl-124-126
70NBrNNON(CH2CH3)2simple2-(pyridin-4-yl)HCl 1:1300-310
71NBrNNON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1233-238
72NClNNON(CH2CH3)2simple 3-(4-methyl phenyl)-155-159
73NClNNON(CH2CH3)2simple2-(4-methyl phenyl)-118-121
74NClNNON(CH2CH3)2simple2-(2-fluoro phenyl)414*
75NClNNON(CH2CH3)2simple3-(4-chloro phenyl)-177-178
76N ClNNON(CH2CH3)2simple2-(4-chloro phenyl)-148-149
77NClNNON(CH2CH3)2simple2-(4-methoxy phenyl)-131-132
78NClNNON(CH2CH3)2simple3-(4-methoxy phenyl)-185-187
79NClNNON(CH2CH3)23-(3-fluoro phenyl)-142-144
80NClNNON(CH3)Phsimple3-(pyridin-4-yl)-213-215
81NClNNON(CH(CH3)2)2simple2-(pyridin-4-yl)-184-185
82NClNNON(CH(CH3)2)2simple3-(pyridin-4-yl)-146-18
HCl 1:1237-269
83Och3HNNON(CH2CH3)2simple3-(pyridin-4-yl)HCl 1:1238-240
84NClNNON(CH(CH3)2)2double3-(pyridin-4-yl)HCl 1:1234-248
85NClNNOsimple2-(pyridin-4-yl)HCl 1:1153-173
86N ClNNOsimple3-(pyridin-4-yl)HCl 1:1243-248
87NClNNON(CH(CH3)2)2simple2-(pyridin-3-yl)HCl 1:1243-260
88NClNNON(CH(CH3)2)2simple3-(pyridin-3-yl)HCl 1:1209-213
89NClNNSN(CH(CH3)2)23-(pyridin-4-yl)HCl 1:1290-318
90NClNNOsimple3-(pyridin-4-yl)HCl 1:1228-252
91NClNNONCH3C(CH3)3simple2-(pyridin-4-yl)HCl 1:1350-360
92NClNNON(CH(CH3)2)2double3-(pyridin-3-yl)HCl 1:1238-240
93 NClNNON(CH(CH3)2)2simple3-(pyridin-2-yl)-193-195
94NFNNON(CH(CH3)2)2simple3-(pyridin-4-yl)HCl 1:1255-260
95NClNNON(CH(CH3)2)2simple3-(pyrimi DIN-2-yl)-220-222
96NClNNO N(CH(CH3)2)2simple2-(pyrazin-2-yl)-175-176
97NFNNON(CH(CH3)2)2double3-(pyridin-4-yl)HCl 1:1272-280
98NClNNON(CH(CH3)2)2double3-(pyridin-2-yl)-213-215
99NClNNON(CH3) (C(CH3)3)simple3-(pyridin-4-yl)HCl 1:1 411*
100NClNNON(CH2CH3)2double3-(pyridin-4-yl)HCl 1:1227-229
101NClNNON(CH3)Phdouble3-(pyridin-4-yl)HCl 1:1248-268

* [MH]+

Compounds according to the invention were subjected to pharmacological tests which revealed that they are of interest as substances with therapeutic activity.

Compounds according to the invention also have the property to dissolve in water, which contributes to their high activityin vivo.

Study of the binding of [3H]Ro5-4864 to receptors perifericheskogo type of benzodiazepines (sites p or PBR)

Determined the affinity of the compounds according to the invention to sites p or PBR (sites communications periphery is a mini type with benzodiazepines).

The receptor sites R selectively marked in renal membranes of rats, incubated in the presence of [3H]Ro5-4864. The affinity of the compounds according to the invention in respect of these receptors was investigatedin vitro.

Used male rats Sprague Dawley (Iffa Credo) weighing from 180 to 300 mg After the military removed the kidney and the tissue homogenized at 4°C using a homogenizer transmitter stationTMwithin 2 minutes at a rate equal to 6/10 maximum speed, 35 volumes of phosphate buffer Na2HPO450 mm, pH is brought to 7.5 with NaH2PO4. The membrane homogenate was filtered through gas (sur gaze) and subjected to a tenfold dilution buffer. [3H]Ro5-4864 (specific activity: 70-90 CI/mmol; New England Nuclear) at a concentration of 0.5 nm were incubated in the presence of 10 μl of membrane homogenate in a final volume of 1 ml of the buffer containing the test compound.

After incubation for 3 hours at 0°C. the membrane was separated by filtration through filters Whatman GF/BTM, washed 2 times with 4.5 l of cold buffer incubation (0°C). The amount of radioactivity on the filter was measured by liquid scintigraphy.

For each concentration of the compounds was determined by the percentage inhibition of [3H]Ro5-4864, then the concentration of CI50, the concentration which inhibits the specific binding by 50%.

Znaczenia compounds according to the invention, possessing the greatest activity was from 0.5 nm to 300 nm. In particular, compounds 14, 20 and 56 in table 2 have the CI50 values of 1.6 nm to 2.8 nm and 1.4 nm, respectively.

Compounds according to the invention are thus ligands having affinity to the receptors of the peripheral benzodiazepine type.

The study of the neuroprotective activity

The test of the survival of motor neurons after transection of the facial nerve in rats aged 4 days

After the defeat of the facial nerve of the four-day rat motoneurons of the facial nucleus were subjected to neuronal death by apoptosis. Evaluation of the survival of neurons was performed histological methods and counting neurons.

Conducted a four-day anaesthesia of rats pentobarbital (3 mg/kg by I.P. Pavlova.).

The right facial nerve was removed and cut at its exit from the stylomastoid foramen. Awake rat was returned to the mother and within 7 days treated by oral and intra-abdominal injection of doses from 1 to 10 mg/kg once or twice a day.

7 days after dissection, animals were decapitated and froze the marrow in isopentane at -40°C. the Facial nucleus completely cut by cryostat section size of 10 μm. The motoneurons were stained purple kresila and counted using HistoTM(BiocomTM).

In this fashion the and compounds according to the invention increased the survival of neurons in 38-78%. In the following table 3 shows the test results on the survival of motor neurons in relation to compounds 14, 20, and 56 from table 2.

Table 3
No.142056
% increase in survival of neurons (10 mg/kgpo)38%59%74%

The test results show that the compounds according to the invention, with the greatest activity, contribute to neuroprotection.

Thus, the compounds according to the invention can be used to obtain drugs, in particular, for obtaining a medicinal product intended for the prevention or treatment of pathologies involving receptors of peripheral-type benzodiazepines.

Thus, the invention in accordance with another of its aspects relates to pharmaceuticals which contain a compound of the formula (I) or salt of the accession of the latter and pharmaceutically acceptable acid or hydrate or MES.

These drugs are used in therapy, in particular for the prophylaxis and/or treatment is not what ropati different types, such as traumatic or ischemic neuropathy, infectious, alkogolnye, diabetic, medical or genetic neuropathy, as well as destruction of motor neurons, such as vertebral disease and amyotrophic lateral sclerosis. These medicines are also used in the treatment of neurodegenerative diseases of the Central nervous system or the acute type, such as stroke and traumatic brain injury, or chronic type, such as autoimmune diseases (multiple sclerosis), Alzheimer's disease, Parkinson's disease and any other disease in which the use of neuroprotective/neurotrophic factors should have a therapeutic effect.

Compounds according to the invention can also be used for getting medicines for the prevention and/or treatment of anxiety, epilepsy and sleep disorders. Indeed, the ligands sites R or R stimulate the production of neurosteroids, such as pregnenolone, dehydroepiandrosterone and 3 alphahydroxy-5-alfamega-20-he, facilitating the transfer of cholesterol from the outside of the mitochondrial membrane. These neurosteroids modulate the activity of the macromolecular complex GABAAthe chloride channel and thus can produce activity, bulk, Tr is the Vogue, anticonvulsant and sedative.

Compounds according to the invention can also be used in the treatment of acute or chronic renal, nedostatocnosti, glomerulonephritis, diabetic nephropathy, ischemic heart and nedostatocnosti, myocardial infarction, lower limb ischemia, vasospasm of the coronary arteries, angina, pathologies associated with heart valves, inflammatory heart disease, side effects associated with cardiotoxic drugs or the effects of operations on the heart, atherosclerosis and thromboembolic complications, restenosis, rejection of transplants, conditions associated with proliferation or incorrect migration of smooth muscle cells.

In addition, published new data show that the benzodiazepine receptor, peripheral type, apparently, plays a fundamental role in the regulation of cell proliferation and in the processes of cancerization. Usually compared with normal tissues increased density of receptors of peripheral benzodiazepine type is observed in various types of tumors and cancer.

In human astrocytoma the expression level of the receptor of peripheral benzodiazepine type is correlated with the degree of malignancy of the tumor, the index of proliferation and survival of patients. In tumors of the human brain is Velicina number of receptors of the peripheral benzodiazepine type is used as a diagnostic criterion in medical imaging and as a therapeutic target for conjugates, formed from the receptor ligand of peripheral benzodiazepine type and cytostatic drug. Increased density of receptors of peripheral benzodiazepine type is also observed in ovarian carcinomas and malignant breast tumors. Concerning the latter, it was shown that the expression level of the receptors of the peripheral benzodiazepine type is associated with aggressive potential of the tumor; in addition, the presence of an agonist of the receptor of peripheral benzodiazepine type stimulates the growth of cancerous cell lines of the breast.

The combination of these results, which points to a function deletions receptor of peripheral benzodiazepine type in the processes of cancerization, is fundamental to search for specific synthetic ligands of the benzodiazepine receptor, peripheral type, capable of blocking its action.

Thus, the compounds can be used to treat tumors and cancer.

Receptors of peripheral benzodiazepine type are present also at the level of the skin, and in this regard, the compounds according to the invention can be used for prevention or treatment of skin stress.

Under the skin stress understand the different situations that may cause disturbance, particularly at the level of the epidermis independently of the agent that causes this stress. what the agent can be internal and/or external to the body, such as chemical or containing free radicals agent, or external, such as ultraviolet radiation.

Thus, the compounds used according to the invention, intended for the prevention or treatment of skin irritations, lichen, erythema, perversion sensitivity, burning sensation, pruritus and/or itching mucous membranes, aging and can also be used for skin disorders such as psoriasis, diseases that cause itching, herpes, photo, atopic dermatitis, contact dermatitis, lichen, prurigo, pruritus, insect bites, when fibrosis and other disorders of maturation of collagens, immunological disorders or dermatological diseases such as eczema.

Compounds according to the invention can also be used for the prevention and treatment of chronic inflammatory diseases, particularly rheumatoid arthritis and pulmonary inflammatory diseases.

In accordance with another of its aspects the present invention relates to pharmaceutical compositions containing as active substance a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, hydrate or MES specified connection, and hence the it least one pharmaceutically acceptable excipient. These excipients are chosen according to the pharmaceutical form and the desired method of administration of the conventional excipients known to the expert.

In the pharmaceutical compositions according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local, local, intratracheal, intranasal, transdermal or rectal introduction of the active substance of the above formula (I), or maybe its salt, MES or hydrate, can be entered in the form for a single reception, mixed with classical pharmaceutical excipients, to animals or humans for the prophylaxis or treatment of the above disorders or diseases.

Acceptable forms for a single administration include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules and solutions or suspensie for oral administration, the forms for the introduction of sublingual, oral, intratracheal, intraocular, intranasal, by inhalation, forms for local, percutaneous, subcutaneous, intramuscular or intravenous administration, the forms for rectal injection or implants. For local use, you can apply the compounds according to the invention in creams, gels, ointments or lotions.

As an example, the form for the gas introduction compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention50.0 mg
Mannitol223,75 mg
The sodium croscarmellose6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

These one-forms are the dosage that provides a daily dose of from 0.001 to 20 mg of active substance per kg of body weight in accordance with the galenical form.

In some cases, may require higher or lower doses, these doses are not beyond the invention. In accordance with conventional practice, the dosage required for each patient is determined by the doctor depending on the method of administration, body weight and individual response of the patient.

In accordance with another of its aspects the present invention relates also to method of treatment for these pathologies, which includes the introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically p is jemimah salt or hydrate or solvate.

1. The compound corresponding to formula (I)

in which
W represents an oxygen atom or sulfur;
X1and X3denote, each independently of one another, hydrogen or C1-C6-alkoxy;
X2denotes a hydrogen atom, halogen, C1-C6-alkyl or C1-C6-alkoxygroup and
X4denotes a hydrogen atom,
Y is in position (N2) or (N3);
when Y is in position (N2), Y represents C1-C6-alkyl, C1-C6-alkyl fluoride, phenyl, pyridinyl or personilnya group;
when Y is in position (N3), Y denotes phenyl, pyridinyl or pyrimidinyl group,
this phenyl group, possibly substituted by one or more atoms or groups selected from halogen atoms, C1-C6-alkyl, C1-C6-CNS group;
the relationship in position C4-C5 is double or simple;
R1and R2denote, each independently of one another, phenyl, and C1-C6is an alkyl group; and at least one of R1and R2stands With1-C6is an alkyl group; or R1and R2form together with the nitrogen atom to which they are bound, a cyclic group containing from 4 to 7 units and containing the nitrogen atom and possibly other is heteroatom, such as nitrogen or oxygen, possibly substituted by one or more C1-C6-alkyl groups;
or its pharmaceutically acceptable salt.

2. The compound of formula (I) according to claim 1, characterized in that
W represents an oxygen atom or sulfur;
X1and X3denote, each independently of one another, hydrogen or C1-C6-alkoxy;
X2denotes a hydrogen atom, halogen, C1-C6-alkyl or C1-C6-alkoxygroup and
X4denotes a hydrogen atom,
Y is in position (N2) or (N3);
when Y is in position (N2), Y represents C1-C6-alkyl, C1-C6-alkyl fluoride, phenyl, pyridinyl or personilnya group;
when Y is in position (N3), Y denotes phenyl, pyridinyl or pyrimidinyl group;
this phenyl group, possibly substituted by one or more atoms or groups selected from halogen atoms, With1-C6-alkyl and C1-C6-CNS group;
the relationship in position C4-C5 is double or simple;
R1and R2denote, each independently of one another, phenyl or C1-C6is an alkyl group; or R1and R2form together with the nitrogen atom to which they are bound, a cyclic group containing from 4 to 7 parts and sotiriadou the nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted by one or two1-C6-alkyl groups;
or its pharmaceutically acceptable salt.

3. The compound of formula (I) according to any one of claims 1 and 2, which is a
N,N-Diethylcarbamyl 7-fluoro-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-fluoro-2-(4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 8-methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Dimethylcarbamate 2-(4-were)-4,5-dihydro-2H-benzo [e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Morpholinyl-4-carboxylate 2-(3-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Dimethylcarbamate 2-(3-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Pyrrolidinyl-1-carboxylate 2-(3-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 2-(3-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-(3-chlorophenyl)-4,5-dihyd the on-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(2-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-ethyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-ethyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-(2,2',2"-triptorelin)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Pyrrolidinyl-1-carboxylate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Piperidinyl-1-carboxylate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Morpholinyl-4-carboxylate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Dimethylcarbamate 2-(4-chlorophenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Pyrrolidinyl-1-carboxylate 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Piperidinyl-1-carboxylate 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Morpholinyl-4-carboxylate 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
4-Methyl-piperazinil-1-carboxylate 2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Dimethylcarbamate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;br/> 4-Methyl-piperazinil-1-carboxylate 2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Dimethylcarbamate 2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
Pyrrolidinyl-1-carboxylate 2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N-Methyl-N-propylgallate 2-(4-forfinal)-4,6-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chloro-4-were)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chloro-4-forfinal)-4,6-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(3-chloro-4-were)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(2,4-differenl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-2-(pyridin-2-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-methoxy-2-(4-forfinal)-4,5-dihydro-2H-benzo [e]indazol-1-yl;
N,N-Diethylcarbamyl 7-bromo-2-(4-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(3-chloro-4-(forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-methyl-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chlorophenyl)-2H-benzo[e]indazol-sludge;
N,N-Diethylcarbamyl 2-(4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Methyl-N-propylgallate 2-(4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chloro-4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 2-(3-chloro-4-were)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(3-chloro-4-forfinal)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(3-chloro-4-were)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(2,4-differenl)-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-methyl-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-3-(pyridin-3-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-2-(pyridin-3-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-fluoro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-fluoro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-3-(4-forfinal)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-3-(pyridin-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-2-(3-forfinal)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl-chloro-3-(3-forfinal)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-bromo-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-bromo-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-3-(4-were)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(4-were)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(2-forfinal-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-3-(4-chlorophenyl)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-2-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-3-(4-methoxyphenyl)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diethylcarbamyl 7-chloro-3-(3-forfinal)-3H-benzo[e]indazol-1-yl;
N-Methyl-N-phenylcarbamate 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 7-chloro-4,5-dihydro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 6-methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl, hydrochloride;
Piperidinyl-1-carboxylate 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
Piperidinyl-1-carb is xelat 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-2-(pyridin-3-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-3-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
CIS-2,6-Dimethyl-piperidine-1-carboxylate 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N-methyl-N-tert-BUTYLCARBAMATE 7-chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-3-yl)-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 7-fluoro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyrimidine-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 7-chloro-2-(pyridin-2-yl)-4,5-dihydro-2H-benzo[e]indazol-1-yl;
N,N-Diisopropylamine 7-fluoro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diisopropylamine 7-chloro-3-(pyridin-2-yl)-3H-benzo[e]indazol-1-yl;
N-methyl-N-tert-BUTYLCARBAMATE 7-chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-yl, hydrochloride;
N,N-Diethylcarbamyl 7-chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl, hydrochloride;
N-methyl-N-phenylcarbamate 7-chloro-3-(pyridin-4-yl)-3H-benzo[e]indas the l-1-yl, the hydrochloride.

4. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 3, characterized in that it is injected into the interaction of a mixture of positional isomers of General formula (Va) and (Vb)

in which X1, X2, X3, X4and Y are as defined in General formula (I) according to claim 1, in which the group Y is respectively in position (N2) and (N3) pyrazol cycle
and derived carbamoylated General formula CIC(W)NR1R2in which W, R1and R2are as defined in General formula (I) according to claim 1, in the presence of base
to obtain, after separation of the compounds of General formulas (Ia) and (Ib)

with a simple link in position C4-C5 then maybe digitalout for the formation of double bonds.

5. The method of obtaining the compounds of formula (Ia)

in which
W represents an oxygen atom or sulfur;
in which X1, X2, X3, X4and Y are as defined in General formula (I) according to claim 1,
Y is in position (N2), Y represents C1-C6-alkyl, C1-C6-alkyl fluoride, phenyl, pyridinyl or personilnya group;
this phenyl group, possibly substituted by one or more of the atoms or groups, selected from halogen atoms, C1-C6-alkyl, C1-C6-CNS group;
the relationship in position C4-C5 is double or simple;
R1and R2denote, each independently of one another, phenyl, and C1-C6is an alkyl group; or R1and R2form together with the nitrogen atom to which they are bound, a cyclic group containing from 4 to 7 units and containing the nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted by one or more C1-C6-alkyl groups;
characterized in that it is injected into the interaction of the compound of General formula (Va)

in which
X1, X2, X3, X4and Y are as defined above in General formula (Ia),
and derived carbamoylated General formula CIC(W)NR1R2in which W, R1and R2are as defined above in General formula (Ia), in the presence of a base,
with a simple link in position C4-C5 then maybe digitalout for the formation of double bonds.

6. The compound of formula (Va)

in which
X1, X3and X4represent a hydrogen atom;
X2denotes a hydrogen atom, halogen or C1-C6-alkoxygroup and
Y represents C1-C6-Alki is inuu, C1-C6-alkyl fluoride, phenyl, pyridinyl or personilnya group;
this phenyl group, possibly substituted by one or more atoms or groups selected from halogen atoms, C1-C6-alkyl, C1-C6-CNS group.

7. The compound of formula (Vb)

in which X1and X3denote, each independently of one another, hydrogen or C1-C6-alkoxy;
X2denotes a hydrogen atom, halogen, C1-C6-alkyl or C1-C6-alkoxygroup,
X4denotes a hydrogen atom;
Y represents phenyl, pyridinyl or pyrimidinyl group;
this phenyl group, possibly substituted by one or more atoms or groups selected from halogen atoms, C1-C6-alkyl, C1-C6-CNS group.

8. Medicinal product for the prevention and treatment of pathologies involving receptors of peripheral benzodiazepine type, characterized in that it contains a compound of the formula (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

9. Pharmaceutical composition for the prevention and treatment of pathologies involving receptors of peripheral benzodiazepine type, characterized in that it contains the effect of the main amount of the compounds of formula (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, and at least one farmacevtichesky acceptable excipient.

10. The use of the compounds of formula (I) according to any one of claims 1 to 3 to obtain a medicinal product intended for the prevention or treatment of pathologies involving receptors of peripheral benzodiazepine type.

11. The use of the compounds of formula (I) in paragraph 10 for obtaining a medicinal product intended for the prevention or treatment of peripheral neuropathies, disorders of motor neurons, neurodegenerative diseases of the Central nervous system, anxiety, epilepsy, sleep disorders, acute or chronic renal insufficiency, glomerulonephritis, diabetic nephropathy, myocardial ischemia and heart failure, myocardial infarction, lower limb ischemia, coronary vasospasm, angina, pathologies associated with heart valves, inflammatory heart disease, side effects associated with cardiotoxic drugs or the effects of operations on the heart, atherosclerosis and thromboembolic complications, restenosis, of transplants, conditions associated with proliferation or incorrect migration of smooth muscle cells, tumors and cancer, skin stress, chronic inflammatory diseases, particularly rheumatoid arthritis and lung is especiallyh diseases.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention covers new compounds of formula I: or its pharmaceutically acceptable salt with antagonist activity to corticotrophin release factor (CRF). In formula (I) X means heteroaryl chosen of pyrazolyl and imidazolyl optionally substituted with (C1-C6)alkyl, haloid or phenyl; Y means -NRaRb where Ra means hydrogen, and Rb means phenyl optionally substituted with (C1-C6)alkyl or haloid; Z means (C1-C6)alkyl; and R1 means hydrogen, (C1-C6)alkyl or haloid.

EFFECT: compounds can find application in treatment, eg of neurodegenerative diseases, neuropsychiatric disorders and stresses.

19 cl, 1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: there are described new isoindole derivatives of general formula (1), wherein A1, A2 and A4 stands for CH, and A3 means N or C-OH; n is equal to 2; R1 represents O; R2-stands for H; and a pharmaceutical composition containing thereof.

EFFECT: new compounds are inhibitors of chaperone protein Hsp90 activity and can be used in chemotherapy of cancerous diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives of formula I: , where: Ra is H, C1-4alkyl; one of Ra, Rc, Rd and Re is C1-4alkyl; and the other three substitutes are H; or Rb, Rd, Re are all H; and R is a radical of formula (a): , where R1 is -(CH2)n-NR3R4, where each of R3 and R4 are independently H, C1-4alkyl; n is 0, 1, 2; R2 is H; halogen; or its pharmaceutically acceptable salt.

EFFECT: wider field of use of the compounds.

8 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

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