Compounds and compositions of 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine as kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

 

The text descriptions are given in facsimile form.

1. The compound of formula (1)

or its isomer or its pharmaceutically acceptable salt;
where R1denotes halogenated containing 1-6 at the MOU fluorine;
R2represents C1-C6alkyl or halogen;
R3represents-L-NR4R5, -X-NR-C(O)R8or-X-NR-C(O)NR4R5,
where L represents-S-C(O)- (CR2)j, -O(CR2)1-4or;
and X denotes (CR2)jor [C(R)(CR2'OR)];
R4and R5independently represent H, C1-C6alkyl, C1-C6alkyl substituted by halogen, C1-C6alkyl, substituted hydroxy-group, or (CR2)k-R6;
R6denotes unsubstituted With3-C7cycloalkyl,3-C7cycloalkyl, substituted hydroxy-group, unsubstituted 5-to 10-membered heteroaryl containing 1-2 heteroatoms N, 5-10-membered heteroaryl containing 1-2 heteroatoms N, substituted with 1-2 groups independently selected from C1-C6of alkyl and halogen, unsubstituted 5-7-membered heterocyclic ring containing 1-2 heteroatoms N, or a 5-7 membered heterocyclic ring containing 1-2 heteroatoms N, substituted with 1-2 groups independently selected from C1-C6of alkyl, C1-C6the alkyl substituted by a hydroxy-group, With3-C7cycloalkyl and =O;
R8independently represents (CR2)k-R6or C1-C6alkyl or C1-C6alkyl substituted by halogen;
R7denotes H;
alternate the VNO, R4and R5together with the N atom in each NR4R5form a 4-7-membered heterocyclic ring containing 1-2 heteroatoms independently selected from N and O, substituted by 0 to 3 groups of R11;
R11means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7or (CR2)kS(O)1-2R8;
each R denotes H or C1-C6alkyl;
each k is 0-6; and
j and m are independently equal to 0 to 4;
provided that R1doesn't mean cryptometer, if R3denotes C(O)NH2C(O)NR12R13where R12and R13together form piperazinil.

2. The compound according to claim 1, where R1means OCHF2or OCF3.

3. The compound according to claim 2, where R1means OCHF2.

4. The compound according to any one of claims 1 to 3, where R2if present, denotes a methyl or fluorine.

5. The compound according to any one of claims 1 to 4, where R3selected from the group including:
,,,,,
,,,,,
, ,,,,
,,,,,
,,,,,
,,,,
,,,,,,
,,,,,
,,,,,
,,,,,
,,,,,,
,, ,,,
,,,,,
,,,,,,
,,,,,
,,,,,
,,,,,
,,,,,,
,,,,,
,,,,,
, ,,,,
,,,,,,
,,,,,,,
,,,,,
,,,,,,,
,,,,,
,,,,
,,,,
,,and.

6. The compound according to any one of the claim 1 to 4, where R3selected from the group including:
,,,,,
,,,,
,,,,
,,,,
,,,,
,,,,
and;
where RAdenotes-NH2.

7. The compound according to claim 1, where the specified compound is a compound of the formula (2A) or (2B)


where R4and R5together with the N atom form a 5-6-membered heterocyclic ring containing 1-2 heteroatoms independently selected from N and O; where the specified heterocyclic ring is substituted by 0-2 groups R11;
R11means R8, (CR2)k-OR7, CO2R7, (CR2) k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7or (CR2)kS(O)1-2R8;
R8independently represents (CR2)k-R6or C1-C6alkyl or C1-C6alkyl substituted by halogen;
R7denotes H;
R6denotes unsubstituted With3-C7cycloalkyl,3-C7cycloalkyl, substituted hydroxy-group, unsubstituted 5-6-membered heteroaryl containing 1-2 heteroatoms N, a 5-6-membered heteroaryl containing 1-2 heteroatoms N, substituted with 1-2 groups independently selected from C1-C6of alkyl and halogen, unsubstituted 5-7-membered heterocyclic ring containing 1-2 heteroatoms N, or a 5-7 membered heterocyclic ring containing 1-2 heteroatoms N, substituted with 1-2 groups independently selected from C1-C6of alkyl, C1-C6the alkyl substituted by a hydroxy-group, With3-C7cycloalkyl and =O;
R denotes H or C1-C6alkyl; and
k is 0-2.

8. The connection according to claim 7, where R4and R5together with the N atom form an unsubstituted or substituted piperidinyl, piperazinil or morpholinyl, where substituted piperidinyl, piperazinil or morpholinyl are substituted by 1-2 groups independently selected from-C(O)HE, -C(O)CH3, -OH, -CF3, -C(O)NH2, -CH2CH2OH, -S(O)2With the 3, cyclopropyl and bromide.

9. The connection according to claim 7 or 8, where L represents-S-C(O)- (CR2)1-4or-O(CR2)1-4; X is (CR2)0-1or [C(R)(CR2'OR)]; and R denotes N.

10. The connection according to claim 9, where L denotes the (CR2)1-2.

11. The compound according to claim 1, where the specified connection selected from the group including
N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(triptoreline)phenyl)-pyrimidine-2-amine,
N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-(deformedarse)phenyl)-pyrimidine-2-amine,
1-(2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenoxy)ethyl)-piperidine-4-carboxylic acid,
1-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)benzyl)-piperidine-4-carboxylic acid,
1-(4-(5-(4-(triptoreline)phenyl)pyrimidine-2-ylamino)benzyl)-piperidine-4-carboxylic acid,
1-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenethyl)piperidine-4-carboxylic acid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-1-methylpiperidin-2-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-3-azabicyclo[3.1.0]hexane-2-carboxamide,
(1S,2R,5R)-N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-3-azabicyclo[3.1.0]hexane-2-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-piperidine-2-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-5-ocsober ridin-2-carboxamid,
(R)-N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-methyl-phenyl)-5-oxopyrrolidin-2-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-6-oxopiperidin-3-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-6-herperidin-3-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-1H-imidazol-5-carboxamid,
N-(2-methyl-5-(5-(4-(triptoreline)phenyl)pyrimidine-2-iluminator)-5-oxopyrrolidin-2-carboxamid,
(S)-N-(2-methyl-5-(5-(4-(triptoreline)phenyl)pyrimidine-2-ylamino)-phenyl)-5-oxopyrrolidin-2-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-1-cyclopropyl-5-oxopyrrolidin-3-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-1-ethyl-6-oxopiperidin-3-carboxamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-N-(2-foradil)-3-hydroxypropanoic,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidine-1-yl)propane-1-he,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidine-1-yl)propane-1-he,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidine-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxypropyl)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)Piri is one-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-(4-hydroxycyclohexyl)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,4R)-4-hydroxycyclohexyl)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,4R)-4-hydroxycyclohexyl)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,4R)-4-hydroxycyclohexyl)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,4S)-4-hydroxycyclohexyl)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,4S)-4-hydroxycyclohexyl)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,4S)-4-hydroxycyclohexyl)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(3-hydroxypiperidine-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)f the Nile)-3-hydroxy-1-((S)-3-hydroxypiperidine-1-yl)propane-1-he,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidine-1-yl)propane-1-he,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidine-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidine-1-yl)propane-1-he,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidine-1-yl)propane-1-he,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidine-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxycyclopent)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopent)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopent)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopent)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopent)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopent)propanamide,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopent)propanamide,
(R)-2-(4-(5-(4-(difftime is hydroxy)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopent)propanamide,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopent)propanamide,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-1-(4-hydroxypiperidine-1-yl)prop-2-EN-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-1-(4-hydroxypiperidine-1-yl)Etalon,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propane-1-he,
(R)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propane-1-he,
(S)-2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-3-hydroxy-1-(3-(trifluoromethyl)piperazine-1-yl)propane-1-he,
2-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-he,
N1-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-piperidine-1,4-dicarboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-methylpiperazin-1-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-methanesulfonylaminoethyl-1-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-acetylpiperidine-1-carboxamid,
1-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-3-(1,3-dimethyl-1H-pyrazole-5-yl)urea,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-morpholine-4-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-(2-hydroxyethyl)piperazine-1-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4,7-diazaspiro[2.5]octane-7-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-methyl-4,7-diazaspiro[2.5]octane-7-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-(2-hydroxyethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-3-(trifluoromethyl)piperazine-1-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-methyl-3-oxopiperidin-1-carboxamid,
N-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-were)-4-(2-hydroxyethyl)-3-oxopiperidin-1-carboxamid,
1-(2-(3-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenoxy)ethyl)-piperidine-4-carboxylic acid,
1-(3-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenethyl)piperidine-4-carboxylic acid,
1-(3-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)benzyl)-piperidine-4-carboxylic acid,
1-(2-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-pertenece)ethyl)piperidine-4-carboxylic acid,
1-(5-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)-2-methylphenyl)piperidine-4-carbon is the second acid,
4-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)benzoyl)-1-methylpiperazin-2-it,
4-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazine-2-it,
4-(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)benzoyl)-piperazine-2-it, and
(4-(5-(4-(deformedarse)phenyl)pyrimidine-2-ylamino)phenyl)-(3-(trifluoromethyl)piperazine-1-yl)methanon.

12. Pharmaceutical composition having inhibitory activity against c-kit, PDGFRα, PDGFRβ kinase or combinations thereof, comprising the compound according to any one of claims 1 to 11 in an effective amount and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes poly(ADP-riboso)polymerase inhibitors of formula (Ik) its pharmaceutically acceptable salt wherein R101, R104 and R105 represent H; R102 represents R11 wherein R11 is specified from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl with R102 being substituted by one or two (O) substitutes; R103 represents fluorine, besides, a pharmaceutical composition on the basis of said compounds showing poly(ADP-riboso)polymerase (PARP) inhibitory activity, a method of treating cancer and a method of reducing tumour volume in a mammal.

EFFECT: there are produced and described new compounds which show poly(ADP-riboso)polymerase (PARP) inhibitory activity.

9 cl, 491 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: described are novel 7-member heterocyclic compounds of general formula (values of radicals are given in the claim) or salts thereof or solvates thereof having chymase inhibiting activity and suitable for preventing or treating different diseases in which chymase is involved, a method of producing said compounds, intermediate compounds and a pharmaceutical composition for preventing or treating diseases in which chymase is involved, including compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.

EFFECT: improved properties of the compound.

23 cl, 12 tbl, 308 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes poly(ADP-riboso)polymerase inhibitors of formula (Ik) its pharmaceutically acceptable salt wherein R101, R104 and R105 represent H; R102 represents R11 wherein R11 is specified from pyrrolidinyl, oxazolyl, imidazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl and azepanyl with R102 being substituted by one or two (O) substitutes; R103 represents fluorine, besides, a pharmaceutical composition on the basis of said compounds showing poly(ADP-riboso)polymerase (PARP) inhibitory activity, a method of treating cancer and a method of reducing tumour volume in a mammal.

EFFECT: there are produced and described new compounds which show poly(ADP-riboso)polymerase (PARP) inhibitory activity.

9 cl, 491 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (II)

or to its pharmaceutically acceptable salt wherein the ring A represents a group presented by formula 2 R1 represents hydrogen or C1-6alkyl; R2 represents -SR5, halogen, halogenated C1-6alkyl, etc., R3 represents a group presented by formula: -CH=CH-C(RaRb)-Rc-Rd, or a group presented by formula: -(CReRf)m-C(RaRb)-Rc-Rd wherein radicals and symbols have the values presented in the patent claim, R4 represents -OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)POH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12; R5 represents C1-6alkyl; R6 represents -CONR7R8; each of R7 and R8 independently represents hydrogen or etc., R10 and R11 independently represents hydrogen; R12 represents C1-6alkyl; each of m and p independently represents an integer 1 to 3. This compound is applicable as a type 1 11β-hydroxysteroiddehydrogenase inhibitor.

EFFECT: invention also refers to single compounds, pharmaceutical compositions on the basis of the declared compounds, to a method for preventing and treating diabetes and the use of the compound of formula (II).

21 cl, 289 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing piperazinophenols, involving reaction of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperazine or N,N1-bis-(piperazinoethyl)ethylenediamine with a Mannich base in an aqueous medium at temperature 90-110°C in molar ratio of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperzine:Mannich base equal to 1:0,8-2, N,N1-bis-(piperazinoethyl)ethylenediamine:Mannich base equal to 1:2 or 1:4 until release of dimethylamine stops; as well as aminomethylation of piperazine or N-(β-aminoethyl) piperazine with diphenylol propane (DPP) in the presence of formaldehyde (FA) in an aqueous medium with molar ratio piperazine: FA: DPP equal to 1:1:1 or 1:2:2 at temperature 50-90°C for 4-10 hours. Reactants react in the presence of a surfactant in amount of 2-6% of the weight of the starting piperazine, and the surfactant used is neonol, OP-7, OP-10.

EFFECT: ensuring fire safety of the process, high output of the end product which can be used as antioxidant phenol stabilisers.

1 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula 1c

, where A, B, R1, R2 and n have values given in the description, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions based on compounds of formula 1c, which are used as modulators of ATP-binding cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"). The present invention also relates to a method of modulating ABC-transporter activity and methods of treating ABC-transporter mediated diseases using compounds of formula 1c.

EFFECT: improved method.

32 cl, 3 tbl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 1,2,4-triazole derivatives of formula I:

, where R1, R2 and R3 independently denote hydrogen or halogen; R4 denotes C1-C6 alkyl; R5 and R6 independently denote C1-C6 alkyl or, together with a nitrogen atom to which they are bonded, form a 5-7-member heterocyclyl group, in which the 6-member heterocyclyl can further contain one oxygen or nitrogen atom and can be substituted with acetyl, C1-C6 alkyl or phyenyl; X-S-, -SO-, -SO2- or O; and n is a whole number selected from 1-8; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, when producing a drug for treating or preventing sigma-1 receptor-mediated diseases or conditions, methods of producing said compounds, intermediate compounds and pharmaceutical compositions which contain compounds of formula 1.

EFFECT: improved compounds.

19 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to specific derivatives of bicyclic amides disclosed in the claim, as well as a pharmaceutical composition.

EFFECT: compounds having protein kinase inhibiting activity, meant for use in treating protein kinase-dependant diseases, preferably proliferative diseases such as tumorous diseases.

13 cl, 115 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

Up!