Method for preparing indolinone derivatives

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

 

The invention relates to a method for producing derivatives of indolinone and intermediates of this method.

Background of the invention

It was found that the number of derivatives of indolinone show pharmaceutical activity. Due to its ability to modulate the activity of protein kinases, they have been proposed to treat a number of conditions such as various types of cancer, mastocytosis, chronic rhinitis associated with allergies, diabetes, autoimmune disorder, restenosis, fibrosis, psoriasis, disease von Hippel-Lindau, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder (WO 01/45689, WO 01/60814, WO 99/48868, US-A-6316429, US-A-6316635, 6133305 and US-A-6248771).

Among the derivatives of indolinone interest were those that have amide group in the heterocyclic ring condensed with indolinone. These compounds modulate the activity of protein kinase and, thus, they can be used in the treatment of diseases associated with abnormal activity of protein kinase. The method of obtaining the amide derivatives disclosed in WO 01/60814. The corresponding pyrrole formuliruut and subsequent condensation with 2-indolinone to obtain the corresponding 5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole. If it is desired amide derivative of pyrrole, you who eraut pyrrole, having a carboxylic acid group. The carboxylic acid group is reacted with the desired amine in the presence of dimethylformamide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole. In example 129 disclosed methods of large-scale transition in which the amidation is carried out in the presence of dimethylformamide, hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) and triethylamine.

The aim of the present invention is an improved method of obtaining derivatives of indolinone that have amide group on the heterocyclic ring condensed with indolinone.

The invention

The present invention provides a method of obtaining indolinone General formula (VI)

where

R1, R2, R3, R4independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12alkoxy, C5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, With6-12aryloxy,6-12alkaryl,6-12alkalilike, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'r R", -SO3R', -SR', -NO2, -NR'r R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2 nCO2R' and-CONR'R";

each R5independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12alkoxy, C5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, With6-12aryloxy,6-12alkaryl,6-12alkalilike, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'r R", -SO3R', -SR', -NO2, -NR'r R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R' and-CONR'R";

R6selected from-NR8(CH2)mR9and-NR10R11provided that you don't have one to two groups of CH2can be replaced with HE or halogen;

R8represents hydrogen or C1-12alkyl;

R9selected from the group consisting of-NR10R11, -OH, -C(O)R12With6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, -N+(O-R10and-NHC(O)R13;

R10and R11independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12zainoulline,5-12cycloalkyl,6-12aryl, and C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R10and R11can comb nravatsa to form five - or six-membered heterocyclic group, optionally containing 1 to 3 atoms selected from N, O or S, in addition to the nitrogen atom, which is associated with R10and R11provided that the heterocyclic group formed by R10and R11may optionally be substituted by R';

R12selected from the group consisting of hydrogen, -HE1-12alkoxy and C6-12aryloxy;

R13selected from the group consisting of C1-12of alkyl, C1-12halogenoalkane and C6-12aralkyl;

R' and R" are independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12zainoulline,5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or the group-NR'r R" substituents R' and R" may be combined with the formation of five - or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O or S, in addition to the nitrogen atom, which is associated with R' and R";

the term "halogen" refers to substituents selected from the group consisting of F, Cl, Br and I;

J is selected from the group consisting of O, S and NH;

one of K, L and M represents S, and the group-C(O)R6associated with him, the other from a group of K, L and M are independently selected from the group consisting of CR5, CR52 , N, NR5, O and S;

n is 0, 1 or 2;

m is 1, 2, 3, or 4; and

p is 0, 1 or 2;

includes stage

(i) reaction of compounds of General formula (I)

The formula I

where R5, J, K, L, M, and p are as defined above,

Q is selected from the group consisting of

with a compound of General formula (II)

where

(a) one of X1and X2represents chlorine or bromine and the other is selected from the group consisting of hydroxy, -O-C1-4the alkyl and-O-phenyl; and R is selected from the group consisting of-C(O)-C1-4of alkyl, -C(O)-O-(C1-4)alkyl, -C(O)-O-phenyl, provided that the phenyl may be optionally substituted by 1 to 3 halogen atoms, -C(O)-O-CH2-phenyl, provided that the phenyl may be optionally substituted by 1 to 3 halogen atoms, or

(b) X1represents chlorine or bromine, X2is a halogen and R is selected from the group consisting of

or

(C) X1represents hydroxy, -O-C1-4alkyl and-O-phenyl,

X2represents a

and R represents a

with the formation of compounds of General formula (III)

where R* represents-O-R in case (a) phase (i) and-R in cases (b) and (c) stage (i);

(ii) the reaction of compounds of General formula (III) with a compound of General formula (IV)

where R1, R2, R3and R4defined above,

and an amine of General formula (V)

where R6defined above, with the formation of indolinone General formula (VI).

The dotted line in the system of heterocyclic rings mean that there are two double bonds, but their position is not particularly specified.

A further embodiment of the present invention relates to a method for obtaining compounds of General formula (III)

where R5, J, K, L, M, and p are defined above;

includes stage

(i) reaction of compounds of General formula (I)

where R5, J, K, L, M, and p are defined above;

with a compound of General formula (II)

(a) where one of X1and X2represents a chlorine or bromine; and the other is selected from the group consisting of hydroxy, -O-C1-4the alkyl and-O-phenyl; and R is selected from the group consisting of-C(O)-C1-4of alkyl, -C(O)-O-(C1-4)alkyl, -C(O)-O-phenyl, -C(O)-O-CH2-phenyl, where phenyl may be optionally substituted by 1 to 3 halogen atoms;

(b) where X1 represents chlorine or bromine, X2represents hydrogen and R is selected from the group consisting of

or

(C) where X1represents hydroxy, -O-C1-4alkyl and-O-phenyl, and X2represents a

and R represents a

with the formation of compounds of General formula (III)

where R* represents-O-R in case (a) phase (i) and-R in cases (b) and (C) stage (i).

(ii) reaction of compounds of General formula (III) with a compound of General formula (IV)

where R1, R2, R3and R4defined above,

and an amine of General formula (V)

where R6defined above, with the formation of indolinone General formula (VI).

The present invention also relates to a method of obtaining indolinone General formula (VI)

where

R1, R2, R3, R4, R5, R6, J, K, L, M, and p are defined above;

includes stage

the reaction of compounds of General formula (III)

where R5, J, K, L, M, and p are defined above;

where R* is selected from the group consisting of-O-C(O)-C1-4of alkyl, -O-C(O)-O-(sub> 1-4)alkyl, -O-C(O)-O-phenyl, provided that the phenyl may be optionally substituted by 1-3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may be optionally substituted by 1-3 halogen atoms,

with a compound of General formula (IV)

where R1, R2, R3and R4defined above;

and an amine of General formula (V)

where R6defined above, with the formation of indolinone General formula (VI).

In yet another variant implementation of the disclosed compounds of General formula (III):

where R5, J, K, L, M, and p are defined above and R* is selected from the group consisting of-O-C(O)-C1-4of alkyl, -O-C(O)-O-(C1-4)alkyl, -O-C(O)-O-phenyl, provided that the phenyl may be optionally substituted by 1-3 halogen atoms, -O-C(O)-O-CH2-phenyl, provided that the phenyl may be optionally substituted by 1-3 halogen atoms,

Preferably R* is a

Detailed description of the invention

The present invention provides a method of obtaining derivatives of indolinone General formula (VI). These compounds can modules the SQL activity of protein kinases, the compounds, their pharmaceutically acceptable salts and derivatives are useful for many medical applications. Preferred compounds having formula (VI), pharmaceutical compositions containing such compounds, and medical applicability of these compounds have been described, for example, in WO 01/45689, WO 01/60814, WO 99/48868, US-A-6316429, US-A-6316635, 6133305 and US-A-6248771, all of which are fully incorporated here by reference. Particularly preferred compounds are described in WO 01/45689 (for example, compounds 15 and 16) and in WO 01/60814 (for example, in the examples and in table 1).

Connection indolinone have the General formula (VI)

where R1, R2, R3, R4independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12alkoxy, C5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, With6-12aryloxy,6-12alkaryl,6-12alkalilike, halogen, trihalomethyl, hydroxy, -S(O)R', -SO2NR'r R", -SO3R', -SR', -NO2, -NR'r R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R' and-CONR'R". Preferably, R1represents hydrogen or C1-4alkyl; preferably, R1is salavtore. In a preferred embodiment, the implementation of R2selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4of alkyl, -OS1-4of alkyl, phenyl, -COOH, -CN, -C(O)CH3,-SO2NH2and-SO2N(CH3)2; preferably, R2selected from the group consisting of hydrogen, fluorine, chlorine, C1-4of alkyl, -O-C1-4of alkyl, -CN, -SO2NH2and-SO2N(CH3)2; and even more preferably, R2represents hydrogen, fluorine, chlorine and C1-4alkyl. Most preferably, R2represents fluorine.

In a preferred embodiment, the implementation of R3selected from the group consisting of hydrogen, C1-4of alkyl, phenyl, C1-4alkoxy, and-COOH; preferably, R3represents hydrogen or C1-4alkyl, most preferably, R3represents hydrogen.

Preferably, R4represented hydrogen.

Each R5independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12alkoxy, C5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, With6-12aryloxy,6-12alkaryl,6-12alkalilike, halogen, trihalogen is stated, hydroxy, -S(O)R', -SO2NR'r R", -SO3R', -SR', -NO2, -NR'r R", -OH, -CN, -C(O)R', -OC(O)R', -NHC(O)R', -(CH2)nCO2R' and-CONR'R". Preferably, R5represents hydrogen or C1-4alkyl.

R6selected from-NR8(CH2)mR9and-NR10R11provided that you don't have one to two groups of CH2can be replaced with HE or halogen. Preferably, R6represents-NR8(CH2)mR9. In a preferred embodiment, the implementation of the group SN2are unsubstituted or one of the groups CH2substituted-HE.

R8represents hydrogen or C1-12alkyl. Preferably, R8represents hydrogen or C1-4alkyl, and preferably, R8represents hydrogen.

R9selected from the group consisting of-NR10R11, -OH, -C(O)R12With6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, -N+(O-R10and-NHC(O)R13. In one embodiment, the implementation of R9represents preferably-NR10R11. In the second variant of realization of R9represents preferably5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O. Preferably, the heterocyclic group performance is to place a five-semicolony heterocyclic group, associated with the group (CH2)mthrough the nitrogen atom and optionally containing another heteroatom selected from N, O and S. Examples of heterocyclic groups include, but are not limited to

Preferably, the heterocyclic group represents

R10and R11independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12zainoulline,5-12cycloalkyl,6-12aryl, and C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R10and R11can be combined with the formation of five - or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O or S, in addition to the nitrogen atom, which is associated with R10and R11provided that the heterocyclic group formed by R10and R11may optionally be substituted by R'. Preferably, R10and R11represent hydrogen or C1-12alkyl. Preferably, R10and R11represent hydrogen.

R12selected from the group consisting of hydrogen, -HE1-12alkoxy and C6-12aryloxy. Preferably, R12represents a C1-4lcil.

R13selected from the group consisting of C1-12of alkyl, C1-12halogenoalkane, and C6-12aralkyl. Preferably, R13represents a C1-4alkyl.

R' and R" are independently selected from the group consisting of hydrogen, C1-12of alkyl, C1-12zainoulline,5-12cycloalkyl,6-12aryl, C5-12heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or the group-NR'r R" substituents R' and R" may be combined with the formation of five - or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O or S, in addition to the nitrogen atom, which is associated with R' and R". Preferably, R' and R" independently represent a1-4alkyl.

J is selected from the group consisting of O, S and NH, preferably, J represents NH;

one of K, L and M represents S, and the group-C(O)R6associated with him, the other from a group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S. Preferred heterocyclic groups

are

Especially preferred as the heterocyclic group I have is

where

n is 0, 1 or 2;

m is 1, 2, 3 or 4; preferably, m is 2 or 3.

p is 0, 1 or 2.

Shows the preferred connection, where X represents a halogen

and

In the first stage of the method of the present invention the compound of General formula (I)

where R5, R6, J, K, L, M, and p are defined above, is reacted with a compound of General formula (II)

(a) where one of X1and X2represents chlorine or bromine and the other is selected from the group consisting of hydroxy, -O-C1-4the alkyl and-O-phenyl; and R is selected from the group consisting of-C(O)-C1-4of alkyl, -C(O)-O-(C1-4)alkyl, -C(O)-O-phenyl, provided that the phenyl may be optionally substituted by 1 to 3 halogen atoms, -C(O)-O-CH2-phenyl, provided that the phenyl may be optionally substituted by 1 to 3 halogen atoms,

(b) where X1represents chlorine or bromine, X2represents hydrogen, and R is selected from the group consisting of

or

(C) where X1represents hydroxy, -O-C1-4alkyl and-O-phenyl, and X2represents a

and R represents a

with the formation of compounds of General formula (III)

where R* represents-O-R in case (a) phase (i) and-R in cases (b) and (c) of the first stage. In the first stage the preferred option (s).

Compounds of General formula (I) and (II) or are commercially available or can be obtained by methods well known in the field. For example, heterocycles having formyl group, can be obtained by slow addition of POCl3to dimethylformamide followed by the addition of the appropriate heterocycle, which is also dissolved in dimethylformamide. This reaction is further described and illustrated, for example, in WO 01/60814, which is incorporated here by reference.

The reaction is usually carried out in a polar aprotic solvent. Aprotic solvent is any solvent which under normal reaction conditions does not give the proton in the permeate. Polar solvents are those that have an uneven distribution of charge. In General, they include from 1 to 3 atoms selected from a heteroatom, such as N, S or O. Examples of polar aprotic process is Italy, which can be used in the invention are ethers, such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether; a nitrile solvent such as acetonitrile; and amide solvents such as dimethylformamide. Preferably, the reaction solvent is a simple ester, preferably, the solvent represents tetrahydrofuran. You can also use a mixture of solvents. Aprotic, polar solvent preferably has a boiling point of from 30°to 130°With, preferably, from 50°C to 80°C. Both components of the reaction mixture is introduced into the reaction vessel together with the solvent. Reagents can be added in any order, although it is preferable to add the compound I to a stirred suspension of compound II in a suitable solvent, at room temperature (18-25°). The preferred concentration of the reagent from 0.3 to 0.5 mol/l, although the person skilled in the art will understand that the reaction can be carried out at various concentrations. The reaction can be conducted at a temperature of from 0°to the temperature of reflux distilled solvent. However, it is preferable to conduct the reaction at a temperature of from 25°C to 80°With mechanical stirring. The course of the reaction can be monitored with a suitable analytical method such as HPLC. P is after completion of the reaction, the reaction mixture is cooled, and the intermediate compound III crystallizes. It is preferable to cool the reaction mixture to a temperature below room temperature, and the most preferred temperature 0°C. an Intermediate compound III can be isolated from the reaction mixture by methods known to experts in this field, such as centrifugation and filtration. The intermediate compound III is a crystalline solid that is non-hygroscopic and stable in air at room temperature.

Then the compound of General formula (III) reacts in the second stage with a compound of General formula (IV)

where R1, R2, R3and R4defined above,

and an amine of General formula (V)

where R6defined above, with the formation of indolinone General formula (VI).

The reaction can be conducted in solution using the same solvent that was used in the first stage of the reaction. The reaction can be performed sequentially by reaction of compound III with compound IV or compound V, and then adding another connection. However, it is preferable that compounds II, IV and V were introduced into the reaction vessel together with the solvent. Reagents can be added in any order, although it is preferable to add the group III to a stirred suspension of compound IV and the amine V in a suitable solvent, at room temperature (18-25°). The preferred concentration of the reagent from 0.3 to 0.5 mol/l, although the person skilled in the art will understand that the reaction can be carried out at various concentrations. The reaction can be conducted at a temperature of from 50°to the temperature of reflux distilled solvent. However, it is preferable to conduct the reaction at a temperature of from 50°C to 80°With mechanical stirring. The course of the reaction can be monitored with a suitable analytical method such as HPLC. After completion of the reaction, the reaction mixture is cooled, and the connection VI crystallizes. It is preferable to cool the reaction mixture to a temperature below room temperature, and the most preferred temperature 0°C. Compound VI can be isolated from the reaction mixture by methods known to experts in this field, such as centrifugation and filtration. Although the compound VI obtained as indicated above, has sufficient purity for medical use, if desired, compound VI can be further cleaned by methods known to experts in this field, such as recrystallization.

If desired, the indole compounds of General formula (VI) can be subjected to further reaction to produce their pharmaceutically acceptable salts or derivatives, in accordance with the usual SP is the event.

The present invention provides a method of obtaining derivatives of indolinone, which is more convenient than the methods of the prior art. In General, the intermediate compounds are easier to manipulate. In addition, facilitated the selection of the product.

The following examples serve to illustrate the invention and should not be construed as limiting. In the absence of other definitions, all percentages, parts and the quantities are massive.

EXAMPLES

Example 1

N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (14.0 g), N,N-diethylethylenediamine (15.0 g), 5-peroxisomal (9,86 g), triethylamine (27 ml) and acetonitrile (250 ml) were mixed and heated to 60°C. Black suspension was stirred for 18 h at 60° (requires mechanical stirrer). The obtained yellow suspension was cooled to room temperature, diluted with 100 ml of acetonitrile and filtered. The precipitate on the filter was washed for 3 H in 100 ml of acetonitrile and dried overnight at 50°With low vacuum. Received N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide (21,7 g) at exit 85%.

Example 2

5-[(Z)-(5-bromo-2-oxo-1,2-digitron-indol-3-ilidene)methyl]-N-[2-(dimethylamino)ethyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

In a flask with a capacity of 0.1 l equipped with a thermometer, reflux condenser, heating casing, inlet for nitrogen and a magnetic stirrer, was loaded 3.0 g 5-bromooxindole, 3.03 g of 4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde, 3,24 g of N,N-diethylethylenediamine, to 4.23 g of triethylamine and 30 ml of tetrahydrofuran. The mixture was heated to 60-65°C for 8 h, then was cooled to ambient temperature. 10 ml of tetrahydrofuran was added to facilitate stirring and the reaction mixture was filtered. After drying was obtained 3.7 g (57,7%) of the first batch of 5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[2-(dimethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The mother solution was cooled to -10°C for 6 h for more of 1.9 g (29.6 per cent).

1H NMR (DMSO): δ 8,08 (1H, s); of 7.75 (1H, s); 7,41 (1H, s); from 7.24 (1H, d); for 6.81 (1H, d); and 3.31 (4H, users); 2,46 (14N, users); 0,96 (6N, t).

Example 3

5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2R)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

In a flask with a capacity of 0.25 l, equipped with a thermometer, reflux condenser, magnetic stirrer and inlet for nitrogen was loaded to 4.92 g of 5-peroxidase, 7.0 g of 4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde, 15.5 g (R)-1-amino-3-(-morpholinyl)-2-propanol, 9,78 g of triethylamine and 88 ml of tetrahydrofuran (THF). The mixture was heated to 60°in the course of 16.5 h, the Reaction mixture was cooled to ambient temperature and filtered. The obtained solids three times successively suspended (3) in acetonitrile in the volume of 11 ml/g, was dried in vacuum to obtain yield 3.6 g (25,25%) 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2R)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.

1H NMR (DMSO): δ 10,86 (1H, users); of 7.75 (1H, d); of 7.70 (1H, s); 7,50 (1H, m); to 6.88 (2H, m); 4.72 in (1H, users); of 3.78 (1H, users); of 3.56 (4H, m); 3,32 (6N, m); 3.15 in (1H, m); 2,43 (8H, osirm).

Example 4

5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2S)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (6.8 g, 31,3 mmol), (2S)-1-amino-3-morpholine-4-improper-2-ol (10.0 g, 62.5 mmol), 5-chlorobenzol (5.3g, of 31.6 mmol) and THF (100 ml) were mixed and heated to 60°C. After stirring for 68 hours at 60°C was added triethylamine (14 ml) and was stirred for 5 h at 60°C. was Added 4.6 g (2S)-1-amino-3-morpholine-4-improper-2-ol and stirred for 20 h at 60°C. the Yellow suspension was cooled to room temperature and filtered. The filter cake was washed 2×50 ml THF and dried over night at 50°in ISCOM vacuum. Received 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2S)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide (5,48 g) at exit 38%.

Example 5

5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-retil)-1H-pyrrol-3-carboxamide

A mixture of 4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (4.1 kg), THF (70,8 kg) and water (4,7 l) was heated at 40-50°to dissolve the solids. The resulting solution was filtered and then person to distil up to 40-50 L. the Mixture is subsequently cooled to 25-30°C. was Added a solution of 1-(2-amino-ethyl)pyrrolidine (2.8 kg) in THF (2.1 liters). Also added a solution of 5-peroxidase (2.9 kg) in THF (18.8 kg). Then the mixture was heated at 45-50°C for 17 hours the Mixture was cooled, filtered, washed with THF (28 kg) and dried at 45-50°for receipt of 5.53 kg (73%) of 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-retil)-1H-pyrrole-3-carboxamide.

1H NMR (DMSO-d6): δ 2,48 (d, J=8 Hz, 6N); to 2.55 (m, 7H); 2,62 (t, J=8 Hz, 1H); 3,37 (m, 6N); 6,90 (m, 1H); 7,00 (m, 1H); EUR 7.57 (t, J=4 Hz, 1H); 7,80 (m, 2H).

Example 6

5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2R)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (7,0 who, and 32.3 mmol), (2R)-1-amino-3-morpholine-4-improper-2-ol (15.5 g, a 96.9 mmol), 5-chlorobenzol (5,48 g, a 32.6 mmol), triethylamine (14 ml) and THF (88 ml) were mixed and heated to 60°C. Formed red solution. After stirring for 16 h at 60°yellow suspension was cooled to room temperature and filtered. The filter cake was washed 2×50 ml THF and dried over night at 50°With low vacuum. Received 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2R)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide (4,36 g) at exit 29%.

Example 7

5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2S)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (7.0 g, and 32.3 mmol), (2S)-1-amino-3-morpholine-4-improper-2-ol (15.0 g, a 64.6 mmol), 5-peroxisomal (4,93 g, a 32.6 mmol), triethylamine (9,79 g, a 96.9 mmol) and THF (88 ml) were mixed and heated to 60°C. After stirring for 24 h at 60°the mixture was cooled to room temperature and filtered. The filter cake was washed with 80 ml of THF and dried over night at 50°With low vacuum. Got a brown solid (23,2 g). The solid is suspended in 350 ml of water for 5 h at room temperature and was filtered. The filter cake washing is whether 100 ml of water and dried at 50° With low vacuum during the night. Received 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-N-[(2S)-2-hydroxy-3-morpholine-4-ylpropyl]-2,4-dimethyl-1H-pyrrol-3-carboxamide (8,31 g) at exit 56%.

Example 8

5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-N-(2-morpholine-4-retil)-1H-pyrrol-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.0 g, 23,0 mmol), 4-(2-amino-ethyl)morpholine (4.5 g, 34.6 mmol), 5-peroxisomal (3,47 g, 23,0 mmol), and THF (80 ml) were mixed and heated to 65°C. After stirring for 24 h at 65°the mixture was cooled to room temperature and filtered. The filter cake was washed with 40 ml THF and dried over night at 50°With low vacuum. Received 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ilidene)methyl]-2,4-dimethyl-N-(2-morpholine-4-retil)-1H-pyrrol-3-carboxamide (8,28 g) at exit 87%.

Example 9

(3Z)-3-({3,5-dimethyl-4-[(4-morpholine-4-reparacin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-he

4-(1H-imidazol-1-ylcarbonyl)for 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (11.3 g, with 51.9 mmol), 4-morpholinopropan (15.0 g, 88,2 mmol), 5-peroxisomal (7,84 g, with 51.9 mmol) and THF (126 ml) were mixed and heated to 66°C. After stirring for 68 hours at 66°the mixture was cooled to room temperature and f is literaly. The precipitate on the filter was washed 4×20 ml THF and dried over night at 70°With low vacuum. Received 16,09 g (3Z)-3-({3,5-dimethyl-4-[(4-morpholine-4-reparacin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-itat exit 68%.

1. The method of receiving indolinone General formula (VI)

where R1, R2, R3, R4independently selected from the group consisting of hydrogen and halogen,

each R5independently represents C1-12alkyl;

R6selected from-NR8(CH2)mR9and-NR10R11provided that from one to two groups of CH2may be optionally substituted-HE;

R8represents hydrogen;

R9represents-NR10R11;

R10and R11represent1-12alkyl; or R10and R11together with the nitrogen atom to which they are attached, can join to form heterocyclic group selected from morpholinyl, pyrrolidinyl and piperidinyl, provided that the heterocyclic group formed by R10and R11may optionally be substituted by R', where R' represents morpholino;

J represents NH;

L represents S, and the group-C(O)R6associated with L;

K and M depict ablaut a CR 5;

m is 1, 2, 3, or 4; and

p is 2,

comprising the reaction of compounds of General formula (III)

where R* represents R,

with a compound of General formula (IV)

where R1, R2, R3and R4defined above,

and an amine of General formula (V)

where R6defined above, with the formation of indolinone General formula (VI).

2. The method according to claim 1, where R1represents hydrogen.

3. The method according to claim 1, where R2selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

4. The method according to claim 1, where R2represents fluorine.

5. The method according to claim 1, where R3represents hydrogen.

6. The method according to claim 1, where R4represents hydrogen.

7. The method according to claim 1, where R5represents a C1-4alkyl.

8. The method according to claim 1, where R6represents-NR8(CH2)mR9provided that from one to two groups of CH2may be optionally substituted-HE.

9. The method according to claim 1, where m is 2 or 3.

10. The method according to claim 1, where R10and R11represent1-4alkyl.

11. The method of claim 8, where m is 2 or 3.

12. The method of claim 8, where R10and R11represents a C1-4alkyl.

13. the procedure according to claim 1, where compounds of General formula (III), General formula (IV) and General formula (V) react in a polar, aprotic solvent.

14. The method according to item 13, where the polar, aprotic solvent is a simple ether.

15. The method according to item 13, where the compounds of General formula (III), General formula (IV) and General formula (V) react at a temperature in the range from +50°to a temperature at which delegacia reaction mixture.

16. The method according to claim 1, where the compounds of General formula (III), General formula (IV) and General formula (V) enter into the reaction taking place in a single reactor.

17. The method according to claim 1, where the compound of General formula (VI) selected from the group consisting of

and

where X is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

18. The method according to 17, where X represents fluorine.

19. The method according to claim 1, where the compound of General formula (VI) is further converted into pharmaceutically acceptable salt.

20. The method according to claim 1, where the compound of General formula (VI) selected from the group consisting of

and

Priority points and features:

15.02.2002 according to claims 1-16, 19 and 20 in terms of connections

and

17, except X is F;

18.09.2002 on 17, where X is F, PP and 20 parts of connections

;

;and



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

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

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R1 represents hydrogen atom (H); R2 represents a linear or branched (C1-C8)-alkyl possibly substituted with phenyl; or R1 and R2 in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R3 represents (C1-C4)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R1 and R2 have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted pyrazoles of general formula I , wherein X, Y, Z are nitrogen or R12C; R1 is, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano nitro, R9R10N, R9OC=O, R10R11NC=O or R10R11NSO2; R2 is hydrogen, halogen, alkoxy, alkyl, alkenyl, haloalkyl, cyano or R48R49N; R3, R4, R5, R6 are hydrogen or alkyl. Pharmaceutical composition and method for inhibiting of S. cathepsin also are disclosed.

EFFECT: agents useful in treatment of autoimmune diseases mediated by S. cathepsin.

43 cl, 312 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) wherein radicals R1, R2 and alk have values given in claim 1 of the invention claim. Compounds prepared by a method by claim 6 are important antagonists of 5-HT2A-receptors and can be sued in treatment psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea, nutritional disturbances, such as bulimia, nervous-psychic anorexia, premenstrual syndrome and/or for the positive effect on obsessive-compulsive disorder.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 12 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

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

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperazine oxime of the general formula (I): wherein X means phenyl or pyridyl substituted with 1 or 2 substitutes; Y means 2- or 3-indolyl, phenyl, 7-azaindole-3-yl, 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl that can be substituted; n = 0-3; m = 0-2; R1 means -NH2, morpholino-, thiomorpholino-group, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl. Compounds possess antagonistic activity with respect to neurokinine receptors and can be used in treatment of anxiety states. Also, invention describes a pharmaceutical composition based on compounds of the formula (I), method for its preparing and using.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

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