Amide derivatives

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

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

where m represents 0, 1 or 2;
R1represents halogeno, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkylthio, (1-6C)alkylsulfonyl, (1-6C)alkylsulfonyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)allylcarbamate-(1-6C)alkoxy, di[(1-6C)alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclic and heterocyclyl-(1-6C)alkoxy,
and where any heteroaryl or heterocyclyl group Deputy representing R1, who possibly may have 1 or 2 substituent, selected from hydroxy, halogeno, (1-6C)alkyl, (2-6C)quinil, (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 methylsulfonyl, and where any of the above defined substituents representing R1that contains a group of CH2attached to 2 carbon atoms, or a group CH3,
attached to the carbon atom or nitrogen, may possibly be in each specified group of CH2or CH3one or two substituent selected from halogeno, hydroxy, amino, trifloromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkylamino, 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-[(1-6C)alkyl]carbamoyl, (1-6C)alkylsulfonyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclic,
and where any heterocyclyl group Deputy representing
a R1possibly can have 1 oxazolidine;
R2represents trifluoromethyl or (1-6C)alkyl;
R3represents hydrogen or (1-6C)alkyl; and
R4represents a (3-6C)cycloalkyl, and R4may possibly be substituted by one or more than one Deputy, selected the output from (1-6C)alkyl; and
where heteroaryl represents an aromatic 5 - or 6-membered monocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen and sulfur;
heterocyclyl represents a saturated 3-10 membered monocyclic or bicyclic ring, each containing one or two heteroatoms selected from oxygen, nitrogen and sulfur;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents halogeno, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkylthio, (1-6C)alkylsulfonyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, di [(1-6C)alkyl]amino-(1-6C)alkyl,
heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclic and heterocyclyl-(1-6C)alkoxy, and where any heteroaryl or heterocyclyl group Deputy representing R1possibly may have 1 or 2 substituent selected from hydroxy, halogeno, (1-6C)alkyl, (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,
and where any of the above defined substituents representing R1that contains a group of CH2attached to 2 carbon atoms, or a group CH3,
attached to the carbon atom or nitrogen, it is possible to mod the em have at each specified group of CH 2or CH3one or two substituent selected from halogeno, hydroxy, trifloromethyl, oxo, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclic,
and where any heterocyclyl group Deputy representing R1possibly can have 1 oxazolidine; or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where R1represents halogeno, hydroxy, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkylthio, (1-6C)alkylsulfonyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, di[(1-6C)alkyl]amino-(1-6C)alkyl, heterocyclyl, heterocyclic and heterocyclyl-(1-6C)alkoxy,
and where any heteroaryl or heterocyclyl group Deputy representing R1possibly may have 1 or 2 substituent selected from hydroxy, halogeno, (1-6C)alkyl, (3-6C)cycloalkyl-(1-6C)alkyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,
and where any of the above defined substituents representing R1that contains a group of CH2attached to 2 carbon atoms, or a group CH3,
attached to the carbon atom or AZ is the may possibly be in each specified group of CH2or CH3one or two substituent selected from halogeno, hydroxy, trifloromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, di-[(1-6C)alkyl]amino, (1-6C)alkoxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl, heteroaryl-(1-6C)alkyl, heterocyclic;
or its pharmaceutically acceptable salt.

4. The compound according to claim 1, where m represents 1 or 2; or its pharmaceutically acceptable salt.

5. The compound according to claim 1, where R2represents (1-6C)alkyl; or its pharmaceutically acceptable salt.

6. The compound according to claim 1, where R2represents methyl; or its pharmaceutically acceptable salt.

7. The compound according to claim 1, where R3represents hydrogen; or its pharmaceutically acceptable salt.

8. The compound according to claim 1, where R4is cyclopropyl or cyclobutyl, and R4may possibly be substituted by one or more than one Deputy, selected from (1-6C)alkyl; or its pharmaceutically acceptable salt.

9. The compound according to claim 1, where R4is cyclopropyl and may possibly be substituted by one or more than one Deputy, selected from methyl and ethyl; or its pharmaceutically acceptable salt.

10. The compound according to claim 1, where R4is cyclopropyl or cyclobutyl; or the pharmaceutically priemysel.

11. The compound according to claim 1, where m represents 1;
R1represents halogeno, hydroxy, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkylthio, (1-6C)alkylsulfonyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy,di-[(1-6C)alkyl]amino-(2-6C)alkoxy, di[(1-6C)alkyl]amino-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclic and heterocyclyl-(1-6C)alkoxy,
and where any heteroaryl or heterocyclyl group Deputy representing R1possibly may have 1 or 2 substituent selected from hydroxy, halogeno, (1-6C)alkyl, (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,
and where any of the above defined substituents representing R1that contains a group of CH2attached to 2 carbon atoms, or a group CH3,
attached to the carbon atom or nitrogen, may possibly be in each specified group CH2or CH3one or two substituent selected from halogeno, hydroxy,
trifloromethyl, oxo, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclic,
and where any of heterocyclyl group Deputy representing R1possibly can have 1 oxazolidine;
R2represents trifluoromethyl or methyl;
R represents hydrogen;
R4is cyclopropyl or cyclobutyl and may possibly be substituted by one or more than one Deputy, selected from methyl and ethyl;
or its pharmaceutically acceptable salt.

12. The compound according to claim 1, where m represents 1;
R1is a fluorescent, chloro, bromo, iodine, hydroxy, methoxy, ethoxy, propoxy, methylthio, ethylthio, methylsulphonyl, ethylsulfanyl, 2-aminoethoxy, 2-amino-1-methylethoxy, 3 aminopropoxy, 2-amino-2-methylpropoxy, 2-methylaminoethanol, 2-methylamino-1 methylethoxy, 3 Ethylenedioxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dimethylaminopropoxy, 2-dimethylamino-2-methylethoxy, 3 dimethylaminopropoxy, dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, heterocyclyl, heterocyclic, heterocyclisation and 2 heterocyclizations,
and where any heteroaryl or heterocyclyl group Deputy representing R1possibly may have 1 or 2 substituent selected from hydroxy, fluorescent, chloro, bromo, iodine, methyl, ethyl, propyl, isopropyl, cyclobutylmethyl, cyclopropylmethyl, acetyl, formatie, chlormethyl, methyl bromide, deform is stated, dichloromethyl, dibromomethyl, 2-veratile, 2-chloroethyl, 2-bromacil, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl,
and where any of the above defined substituents representing R1that contains a group of CH2attached to 2 carbon atoms, or a group CH3attached to the carbon atom or nitrogen, may possibly be in each specified group CH2or CH3one or two substituent selected from the fluorescent, chloro, bromo, iodine, hydroxy, trifloromethyl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, dimethylamino, diethylamino, N-ethyl-N-methylamino, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, heteroaromatic, heteroaromatic, heterocyclic,
R2represents methyl;
R3represents hydrogen;
R4is cyclopropyl or cyclobutyl and may possibly be replaced by stands;
or its pharmaceutically acceptable salt.

13. Soedinenie to claim 1, chosen from:
N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclobutyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[4-oxo-6-(piperidine-4-yloxy)hinzelin-3(4H)-yl]benzamide,
N-cyclopropyl-3-[6-{[1-(cyclopropylmethyl)piperidine-4-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide,
N-cyclopropyl-3-[6-(1,4-diazepan-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide,
N-cyclopropyl-4-methyl-3-(4-oxo-6-piperazine-1-imaginaton-3(4H)-yl)benzamide,
N-cyclopropyl-4-methyl-3-[6-(4-methyl-1,4-diazepan-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-(4-ethylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-(4-isopropylpiperazine-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-[(3S)-3-methylpiperazin-1-yl]-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-[(3R)-3-methylpiperazin-1-yl]-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-[4-(2-hydroxyethyl)piperazine-1-yl]-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[4-oxo-6-(4-propylpiperazine-1-yl)hinzelin-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[4-oxo-6-(4-propyl-1,4-diazepan-1-yl)hinzelin-3(4H)-yl]benzamide,
N-cyclopropyl-4-trifluoromethyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-(4-[tert-butylate the yl]piperazine-1-yl)-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-[(3S)-3,4-dimethylpiperidin-1-yl)]-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopropyl-4-methyl-3-[6-[(3R)-3,4-dimethylpiperidin-1-yl]-4-oxoindole-3(4H)-yl]benzamide,
N-cyclopentyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[(3-hydroxy-2,2-dimethylpropyl)amino]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[2-methyl-6-(4-methyl-1,4-diazepan-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[4-(cyclopropylmethyl)-1,4-diazepan-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-(4-ethyl-1,4-diazepan-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
3-[6-[4-(2-amino-2-oxoethyl)-1,4-diazepan-1-yl]-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
[4-(3-{5-[(cyclopropylamino)carbonyl]-2-were}-4-oxo-3,4-dihydroquinazolin-6-yl)piperazine-1-yl]acetic acid;
N-cyclopropyl-3-[6-[4-(cyclopropylmethyl)piperazine-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[4-(2-ethoxyethyl)piperazine-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]-2-methyl-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-(7-fluoro-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-3-[6-(2,3-dihydroxy-2-methylpropoxy)-4-about shinasai-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-(6-isobutoxy-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-3-[6-(2-hydroxy-2-methyl-3-pyrrolidin-1 ipropose)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-(6-morpholine-4-yl-4-oxoindole-3(4H)-yl)benzamide;
N-cyclopropyl-4-methyl-3-(4-oxo-6-thiomorpholine-4-imaginaton-3(4H)-yl)benzamide;
N-cyclopropyl-3-[6-(4-hydroxypiperidine-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-(3-hydroxyazetidine-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-(4-methyl-4-oxidability-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[4-(methylsulphonyl)piperazine-1-yl]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[(3R,5S) - for 3,5-dimethylpiperazine-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-(4-methylpiperidin-l-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-(4-oxo-6-piperidine-1-imaginaton-3(4H)-yl)benzamide;
4-methyl-N-(1-methylcyclopropyl)-3-[6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
3-[6-[4-(cyanomethyl)piperazine-1-yl]-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(4-prop-2-in-1-reparation-1-yl)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-(4-oxoindole-3(4H)-yl)benzamide;
3-[6-(4-acetylpiperidine-1-yl)-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methyl who ansamed;
3-[6-(4-cyclobutylmethyl-1-yl)-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-3-(6-iodine-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-[(1-methylpiperidin-4-yl)oxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-(6-methoxy-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclobutyl-3-[6-(4-isopropylpiperazine-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(1-ethylpiperazin-4-yl)oxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[7-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[(1-isopropylpiperazine-4-yl)oxy]-4-exogenesis-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[4-(1,3-thiazol-4-ylmethyl)piperazine-1-yl]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-{4-[(5-methylisoxazol-3-yl)methyl]piperazine-1-yl}-4-oxoindole-3(4H)-yl]benzamide;
tert-butyl 3-[(3-{5-[(cyclopropylamino)carbonyl]-2-were}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(pyrrolidin-3-yloxy)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(pyridine-2-ylethoxy)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[4-(2-foradil)piperazine-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
M-cyclopropyl-3-[6-[4-(2,2-dottorati)piperazine-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-C is chlorophyl-4-methyl-3-[4-oxo-6-{4-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]piperazine-1-yl}hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[(1-methylpyrrolidine-3-yl)oxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[(1-ethylpyrrolidin-3-yl)oxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[1-(2-foradil)piperidine-4-yl]oxy}-4-oxoindole-3(4H)-yl}-4-methylbenzamide;
N-cyclopropyl-3-[6-{[1-(2-methoxyethyl)piperidine-4-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[2-(dimethylamino)ethoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(1-cyclopropylidene-4-yl)oxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[7-fluoro-6-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(3R)-4-isopropyl-3-methylpiperazin-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(3R)-4-(cyclopropylmethyl)-3-methylpiperazin-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(2-pyrrolidin-1 ylethoxy)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-(2-morpholine-4-ylethoxy)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(2-piperidine-l-ylethoxy)hinzelin-3(4H)-yl]benzamide;
3-[6-(2-azetidin-1 ylethoxy)-4-oxoindole-3(4H)yl]-N-cyclopropyl-4-methylbenzamide;
tert-butyl-5-(3-{5-[(cyclopropylamino)carbonyl]-2-were}-4-oxo-3,4-dihydroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;
N-cyclopropyl-3-[6-[3-(dimethylamino)propoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[(1-isopropylpyrimidine-3-yl)oxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-
4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-(6-hydroxy-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(1,2,3,6-tetrahydropyridine-4-yl)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[2-(4-isopropylpiperazine-1-yl)ethoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[2-(4,4-deformability-1-yl)ethoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{2-[(3R)-3-ftorpirimidinu-l-yl]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[2-(1,4-oxazepan-4-yl)ethoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-{2-[methyl(pyridin-2-ylmethyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[4-(2,2,2-Cryptor-1-methylethyl)piperazine-1-yl]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{2-[(2-methoxyethyl)(methyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-is ecoprofile-4-methyl-3-[6-{[(3S)-1-methylpyrrolidine-3-yl]oxy}-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[(3S)-1-ethylpyrrolidin-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[(3S)-1-isopropylpyrimidine-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[(3S)-pyrrolidin-3-yloxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(3-piperidine-1-ylpropionic)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[2-(1H-pyrrol-1-yl)ethoxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(3-pyrrolidin-1 ipropose)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[2-(dimethylamino)-2-methylpropoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[3-(1H-pyrrol-1-yl)propoxy]hinzelin-3(4H)-yl]benzamide;
3-[6-(2-aminoethoxy)-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-{[(3R)-1-methylpyrrolidine-3-yl]oxy}-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[(3R)-1-ethylpyrrolidin-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[(3R)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{[(3R)-1-isopropylpyrimidine-3-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[2-(dimethylamino)-2-oksidoksi]-4-exohi azolin-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-{2-[(methylsulphonyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]benzamide;
3-[6-[2-(acetylamino)ethoxy]-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-3-(7-methoxy-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-[3-(4-methylpiperazin-1-yl)propoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[(1-methylpiperidin-3-yl)methoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[2-(1H-imidazol-1-yl)ethoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[2-(2-Oxymetazoline-1-yl)ethoxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[(1-methylpiperidin-2-yl)methoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-[(1-methyl-1H-imidazol-2-yl)methoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[2-(dimethylamino)ethyl]thio}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(2-thiomorpholine-4-ylethoxy)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-[2-(4-hydroxypiperidine-1-yl)ethoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
3-[6-{2-[(cyclobutylmethyl)(methyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-(2-{methyl[2-(methylsulphonyl)ethyl]amino}ethoxy)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-(2-{methyl[(1-methyl-1H-pyrazole-4-yl)methylamino}ethoxy)-4-oxoindole-3(4H)-yl]benzamide;
methyl-(2E)-3-(3-{5-[(cyclopropylamino)carbonyl]-2-were}-4-oxo-3,4-dihydroquinazolin-6-yl)acrylate;
N-cyclopropyl-3-[6-[3-(dimethylamino)prop-1-Jn-1-yl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[3-(dimethylamino)propyl]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-(1-methylpiperidin-4-yl)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[7-[3-(dimethylamino)propoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[7-(2-morpholine-4-ylethoxy)-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[1-(2-hydroxy-2-methylpropyl " piperidine-4-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-({1-[(2S)-2-hydroxypropyl]piperidine-4-yl}oxy)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-({1-[(2R)-2-hydroxypropyl]piperidine-4-yl}oxy)-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylethoxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-{[(2S)-1-methylpyrrolidine-2-yl]methoxy}-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[1-(2-hydroxyethyl)piperidine-4-yl]oxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{2-[(25)-2-(hydroxymethyl)pyrrolidin-1-yl]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cycle is propyl-3-[6-{2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{2-[isopropyl(methyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{2-[isopropyl(2-methoxyethyl)amino]ethoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
3-[6-[2-(tert-butylamino)ethoxy]-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
N-cyclopropyl-3-[6-[3-(dimethylamino)-2-methylpropoxy]-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[6-[(4-methylmorpholin-2-yl)methoxy]-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[8-(4-methylpiperazin-1-yl)-4-oxoindole-3(4H)-yl]benzamide;
3-[6-[2-(dimethylamino)ethoxy]-4-oxoindole-3(4H)-yl]-4-methyl-N-(1-methylcyclopropyl)benzamide;
4-methyl-N-(1-methylcyclopropyl)-3-[4-oxo-6-(2-piperidine-1-ylethoxy)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-(8-methoxy-4-oxoindole-3(4H)-yl)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2R)-pyrrolidin-2-ylethoxy]hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-4-methyl-3-[6-{[(2R)-1-methylpyrrolidine-2-yl]methoxy}-4-oxoindole-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{[(2S)-1-glycolylneuraminic-2-yl]methoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-[4-oxo-6-(3-thiomorpholine-4-ylpropionic)hinzelin-3(4H)-yl]benzamide;
N-cyclopropyl-3-[6-{3-[(3R)-3-hydroxypyrrolidine-1-yl]propoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-[3-(4-hydroxypiperidine-1-yl)propoxy]-4-about shinasai-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{3-[(2-methoxyethyl)(methyl)amino]propoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide;
N-cyclopropyl-3-[6-{3-[(3-furylmethyl)(methyl)amino]propoxy}-4-oxoindole-3(4H)-yl]-4-methylbenzamide; and
3-[6-{3-[(cyclobutylmethyl)(methyl)amino]propoxy}-4-oxoindole-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide;
or its pharmaceutically acceptable salt.

14. The method of obtaining the compounds of formula I according to claim 1 or its pharmaceutically acceptable salts, including:
the interaction of N-phenyl-2-aminobenzamide formula II

with a carboxylic acid of formula III or its reactive derivative

where R1-R4and m are as defined in claim 1, and where any functional group is protected if necessary, and:
(1) removing any protective groups; and
(2) it is possible that the formation of pharmaceutically acceptable salts.

15. The method of obtaining the compounds of formula I according to claim 1 or its pharmaceutically acceptable salts, including:
the interaction of the carboxylic acid of the formula X or its reactive derivative, as defined above,

with an amine of formula VI,

for the formation of amide linkages, where R1-R4and m are as defined in claim 1, any functional group is protected if necessary is about, and:
(1) removing any protective groups; and
(2) it is possible that the formation of pharmaceutically acceptable salts.

16. Pharmaceutical composition having the properties of inhibitors of cytokines, containing an effective amount of a compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

17. The compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt having the properties of inhibitors of cytokines.

18. The compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt having inhibitory activity against the kinase 38α.

19. A method of inhibiting TNF (tumor necrosis factor), including the introduction of an effective amount of the compounds of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt.

20. Method of inhibiting kinase 38α, including the introduction of an effective amount of the compounds of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt.

21. The compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for use in the treatment of diseases or conditions mediated by cytokines.

22. The compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt for the manufacture the Oia medicinal product for use in the inhibition of TNF-alpha.

23. The compound of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for use in the inhibition of kinase 38α.

24. The use of the compounds of formula I according to any one of claims 1 to 13 or its pharmaceutically acceptable salts in the manufacture of medicaments for use in treating diseases mediated by cytokines.



 

Same patents:

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: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 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: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

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

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

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to derivatives of 5- or 6-substituted benzimidazoles, being inhibitory active as regards replication of respiratory syncytial viruses and having formula (I), wherein Q is R6a, piperidinyl, substituted with R6; G is methylene; R1 is piridyl, substituted with 2 substitutes, chosen from hydroxy, C1-6alkyl; one of R2a and R2b is cyano-C2-6alkenyl, Ar3C1-6alkyl, Het-C1-6alkyl, N(R8aR8b)C1-6alkyl, Ar3C2-6alkenyl, Ar3-amino-C1-6alkyl, Het-amino-C1-6alkyl, Het-C1-6alkyl-amino-C1-6alkyl, Ar3tioC1-6alkyl, Ar3amino-carbonyl, Het-amino-carbonyl, Ar3(CH2)ncarbonyl-amino, Het-(CH2)ncarbonyl-amino; and the other of R2a and R2b represents hydrogen; R3 represents hydrogen or C1-6alkyl; in the case when R2a represents hydrogen, R3 represents hydrogen; in the case when R2b represents hydrogen, R3 represents hydrogen or C1-6alkyl; R5 represents hydrogen; R6 represents C1-6alkyl, optionally substituted with one or two substitutes, each of which is independently chosen from group consisting of NR7aR7b, Ar2, hydroxy, amino-carbonyl, amino-sulphonyl; R6a is C1-6alkyl, substituted with one or two substitutes, each of which is independently chosen from group consisting of Ar2, hydroxy or heterocyclic, chosen from a group consisting of piperidinyl, piperazinyl; R7a represents hydrogen; R7b represents hydrogen; R8a represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy C1-6alkyl, cyanoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl, amino-carbonyl C1-6alkyl, carboxylC1-6alkyl; R8b represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl; each independently represents 1; Ar1 represents phenyl; Ar2 represents phenyl or phenyl substituted with one C1-6alkyl-oxy; Ar3 represents phenyl, naphtalenyl, 1,2,3,4-tetra-hydro- naphtalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4- tetra-hydro- naphtalenyl or indanyl can be optionally and each individually substituted with one or more, for example, 2 or 3 substitutes chosen from group consisting of halogen, hydroxy-, mercapto- cyano-, C1-6alkyl, C2-6alkinyl, Ar3 , hydroxy-C1-6alkyl, CF3, cyano-C1-6alkyl, amino-carbonyl, C1-6alkyl-oxy, C1-6alkyltio, Ar1-oxy, Ar1-amino, amino-sulphonyl, amino-carbonylC1-6alkyl, C1-4alkyl-carbonyl, C1-4alkyl-carbonyl-amino and C1-4alko-oxy-carbonyl; Het represents heterocycle chosen from phuranyl, imidazolyl, morpholinyl, piridyl, quinolene, iso-quinolene, each of said heterocycles can be optionally substituted with hydroxyl-Sibalkyl, as well as to acid additional salt thereof and stereo-chemical isomeric forms. In addition, the invention relates to pharmaceutical composition on the basis of compound of formula I and to application of compound of formula I and for production of medicinal preparation.

EFFECT: new derivatives of benzimidazole having useful biological properties.

22 cl, 6 tbl, 18 ex

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