Protein kinase inhibitor (versions), use thereof for treating oncological diseases and based pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

 

The text descriptions are given in facsimile form.

1. Chemical compound of General formula I

X1represents N; X2represents NX3represents NX4represents N, CH and where X1X2X3and X4are selected independently;
represents-H, GoLoG is h, -COOH, -CH3, -CH2CH3, -OH, -och3, -Och2CH3, -CN, -CH3HE;
represents H, halogen, -CH3, -CH2CH3, -OH, -och3, -Och2CH3, -CN, CH2HE, -NH2;
represents-H, -S(O)rR4, halogen, -CN, -COOH, -CONH2-SOON3-SOON2CH3;
cycle And represents a phenyl or 6-membered heteroaryl cycle, where heteroaryl contains 1-2 heteroatoms selected from N, optionally substituted by 1-4 groups R3;
the cycle represents a phenyl or 5 - or 6-membered heteroaryl cycle, where heteroaryl contains 1-2 heteroatoms selected from N, S, optionally substituted by 1-5 groups Rb;
Raand Rbare chosen independently and represent H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5where Y is selected independently represents a chemical bond, -O-, -S-, -NR5-;
L1represents NR3C(O) or C(O)NR3;
R3, R4and R5are chosen independently and represent H, C1-C6-alkyl group, NR4R5can represent a 5 - or 6-membered saturated or aromatic cycle;
ineach case, R 6is selected independently represents a C1-C6-alkyl, possibly substituted C1-C6the alkyl or 5-6 membered heterocyclyl, which may be substituted With1-C6-alkyl;
r is 0;
or its pharmaceutically acceptable salt, MES or hydrate.

2. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which,,X4=CH.

3. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which, -Cl, -COOH;

4. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which.

5. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which, -Cl.

6. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which preferably the cycle And is phenyl.

7. Chemical compound according to claim 1, characterized in that it is a compound of formula I, in which the cycle is phenyl.

8. Chemical compound of General formula II

where
Z of t is made by a CH;
X1represents; X2represents, X3representsX4represents CH and where X1X2X3and X4are selected independently;
represents-H;
represents-H, -F;
represents-H, -F;
cycle And represents a phenyl or 6-membered heteroaryl cycle, where heteroaryl contains 1-2 heteroatoms selected from N, optionally substituted by 1-4 groups R3;
the cycle represents a phenyl or 5 - or 6-membered heteroaryl cycle, where heteroaryl contains 1-2 heteroatoms selected from N, S, optionally substituted by 1-5 groups Rb,
Raand Rbare chosen independently and represent H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5where Y is selected independently represents a chemical bond, -NR5-;
L1represents NR3C(O) or C(O)NR3;
R4and R5are chosen independently and represent H, C1-With6-alkyl, a group NR4R5can represent a 6-membered saturated cycle;
in each case, R6selected independent is isimo and is a 1-C6-alkyl, possibly substituted C1-C6the alkyl or 5-6 membered heterocyclyl, which may be substituted With1-With6-alkyl;
r is 0;
m is 1;
R is 1,2, or its pharmaceutically acceptable salt, MES or hydrate.

9. Chemical compound, characterized in that it is a compound of formula II in which X1=X4and X2=X3Z=CH.

10. Chemical compound, characterized in that it is a compound of formula II in which.

11. Chemical compound, characterized in that it is a compound of formula II in which.

12. Chemical compound, characterized in that it is a compound of formula II in which.

13. Chemical compound according to any one of claims 1 to 12 for use as an inhibitor of protein kinases.

14. The use of chemical compounds according to any one of claims 1 to 12 to obtain a pharmaceutical composition for the treatment and/or prevention of diseases associated with abnormal activity of protein kinases.

15. The application 14, in which the disease associated with abnormal activity of protein kinases, is acute myelogenous leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, nemelkokletochnyi lung and gastrointestinal stromal tumors.

16. Pharmaceutical composition for treating and/or preventing diseases associated with abnormal activity of protein kinases, characterized in that it contains an effective amount of a chemical compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, solvent or excipient.



 

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2 cl, 20 tbl

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14 cl, 2 tbl, 67 ex

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19 cl, 62 tbl, 332 ex

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17 cl, 18 dwg, 81 ex

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SUBSTANCE: invention relates to a novel heterocyclic amide compound of formula I: or a pharmaceutically acceptable salt thereof. Described also is a pharmaceutical composition containing said compound, having protein kinase inhibitor, regulator or modulator properties, which is acceptable in treating or preventing a proliferative disease, an anti-proliferative disorder, inflammation, arthritis, neurologic or neurodegenerative disease, cardiovascular disease, hair loss, neural disease, ischemic disorder, viral disease or fungal disease.

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2 cl, 20 tbl

FIELD: medicine, pharmaceutics.

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,

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14 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

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EFFECT: novel 3-aza-bicyclo[3,3,0]octane derivatives as nonpeptide antagonists of human orexin receptors.

9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

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