Novel indole derivatives having iκb kinase β inhibiting activity

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

 

The text descriptions are given in facsimile form.

1. The compound of General formula (1) or its pharmaceutically acceptable salt

where R1represents a hydrogen atom, a lower alkyl group which may contain a Deputy, a phenyl group which may contain a Deputy, or a hydroxyl group;
when R1represents a substituted alkyl, Deputy represents one or more phenyl groups;
when the R 1represents a substituted phenyl group, Deputy represents one or more nitro groups;
R2represents a halogen atom, a lower alkyl group which may contain a Deputy, lower alkenylphenol group which may contain a Deputy, lower alkylamino group which may contain a Deputy, -X1-COR3, -X1-COOR3, -X1-CONRaRb, -X1-SR3, -X1-NRaRb, -X1-NHCO-R3, -X1-CN, -X1-N3or a group of the General formula (2)

when R2represents a substituted alkyl, substituted alkenyl or substituted quinil, Deputy represents one or more groups selected from halogen atom, hydroxy-group, the lower alkoxygroup, the carbonyl group and the lowest alkylsilane;
where X1represents a simple bond, lower alkylenes group which may contain a Deputy, lower alkynylamino group which may contain a Deputy, or lower alkynylamino group which may contain a Deputy;
when X1represents a substituted alkylene, substituted albaniles or substituted akinyan, Deputy represents one or more groups selected from a halogen atom and a hydroxy-group;
R3 represents a hydrogen atom, a lower alkyl group which may contain a Deputy, or lower alkenylphenol group which may contain a Deputy;
when R3represents a substituted alkyl or substituted alkenyl, Deputy represents one or more groups selected from a halogen atom, a C6-14-aryl and hydroxy-group;
Raand Rbmay be the same or different and each represents a hydrogen atom, a lower alkyl group which may contain a Deputy, lower alkenylphenol group which may contain a Deputy, the lower alkoxygroup, which may contain the Deputy, the lower alkylsulfonyl group which may contain a Deputy, or phenylsulfonyl group which may contain a Deputy;
when Raand Rbeach is a substituted alkyl, substituted alkenyl, replaced alkoxygroup, substituted alkylsulfonyl or substituted phenylsulfonyl, Deputy represents one or more groups selected from a halogen atom, phenyl, phenyl containing lower alkoxygroup as Deputy, 5-6-membered saturated or unsaturated monocyclic heterocyclic group containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen, and sulfur, g is proxygroup, low alkoxygroup, lower alkoxycarbonyl and cyano;
X2represents a simple bond, lower alkylenes group which may contain a Deputy, lower alkynylamino group which may contain a Deputy, lower alkynylamino group which may contain a Deputy, -X3-CO-, -X3-CONH-, -X3-S-, -X3-NH-, -X3-NHCO - or-X3-NHCONH-;
when X2represents a substituted alkylene, substituted albaniles or substituted akinyan, Deputy represents one or more groups selected from a halogen atom and a hydroxy-group;
X3represents a simple bond, lower alkylenes group which may contain a Deputy, lower alkynylamino group which may contain a Deputy, or lower alkynylamino group which may contain a Deputy;
when X3represents a substituted alkylene, substituted albaniles or substituted akinyan, Deputy represents one or more groups selected from a halogen atom and a hydroxy-group;
ring a represents a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring containing from 3 to 10 carbon atoms, or 5-10-membered saturated or unsaturated monocyclic or bicyclic con is inspirowane heterocyclic ring, containing 1-3 heteroatoms in the ring selected from nitrogen atoms, oxygen, sulfur and boron,
R4represents a halogen atom, a lower alkyl group which may contain a Deputy, -X4-OR5, -X4-OCOR5, -X4-COR5, -X4-COOR5, -X4-CONRcRd-X4-SR5, -X4-SOR5, -X4-SONRcRd, -X4-SO2R5, -X4-SO2NRcRd, -X4NRcRd, -X4-NHCOR5, -X4-NHCOOR5, -X4-NHSOR5, -X4-NHSO2R5, -X4-CN or-X4-NO2;
when R4represents a substituted alkyl, Deputy represents one or more halogen atoms;
X4represents a simple bond, lower alkylenes group which may contain a Deputy, or lower cycloalkenyl group which may contain a Deputy;
when X4represents a substituted alkylene or substituted cycloalkyl, Deputy represents one or more groups selected from a halogen atom and a hydroxy-group;
R5represents a hydrogen atom, a lower alkyl group which may contain a Deputy, lower cycloalkyl group which may contain a Deputy, or a phenyl group which may contain C is the election agent;
when R5represents a substituted alkyl, substituted cycloalkyl or substituted phenyl, Deputy represents one or more groups selected from a halogen atom, lower cycloalkyl and phenyl;
Rcand Rdmay be the same or different and each represents a hydrogen atom, a lower alkyl group which may contain a Deputy, lower cycloalkyl group which may contain a Deputy, a phenyl group which may contain a Deputy, or 5-10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic group containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur, which may contain a Deputy;
when Rcand Rdeach is a substituted alkyl, substituted cycloalkyl, substituted phenyl or substituted heterocyclic group, Deputy represents one or more groups selected from a halogen atom, lower alkyl, hydroxy-group, the lower alkoxygroup and NReRf;
Rcand Rdcan be connected to each other and form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur, which can in order to contain the Deputy;
when Rcand Rdconnected to each other with the formation of monocyclic saturated heterocyclic ring, Deputy represents one or more groups selected from lower alkyl and lower alkoxycarbonyl;
Reand Rfmay be the same or different and each represents a hydrogen atom or lower alkyl;
Reand Rfcan be connected to each other to form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
m is 0, 1, 2, 3, or 4, provided that R2may be the same or different when m is 2, 3 or 4; and
n is 0, 1, 2, 3, or 4, provided that R4may be the same or different when n is 2, 3 or 4.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
R1represents a hydrogen atom, a lower alkyl group, lower phenylalkyl group, phenyl group, nitrophenyl group or a hydroxyl group;
R2represents a halogen atom, a lower alkyl group, lower halogenating group, lower alkenylphenol group, lower halogenalkyls group, lower alkylamino group, lower halogenalkyls, -X1-COR3, -X1-COOR3, -X1-CONRaRb, -X1-SR3, -X1-NRaRb, -X1NHCO-R3, -X1CN, -X1-N3or a group of the General formula (2)

where X1represents a simple bond, lower alkylenes group, lower alkynylamino group or lower alkynylamino group;
R3represents a hydrogen atom, a lower alkyl group, lower halogenating group, lower6-14-arylalkyl group, a lower hydroxyalkyl group, a lower alkenylphenol group, lower halogenalkyls group, lower6-14-arylalkyl group or lower hydroxyalkyl group;
Raand Rbmay be the same or different and each represents a hydrogen atom, a lower alkyl group, lower phenylalkyl group, lower (5-6-membered saturated or unsaturated monocyclic heterocycle containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen, and sulfur) alkyl group, a lower hydroxyalkyl group, a lower alkoxyalkyl group, lower cyanoaniline group, lower alkenylphenol group, lower phenylalaninol group, lower (5-6-membered saturated or unsaturated monocyclic heterocycle containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen, and sulfur) Ala niloy group, lower hydroxyalkyl group, lower alkoxyalkyl group, lower cyanoacetylene group, a lower alkoxygroup, lower fenilalanina, lower (5-6-membered saturated or unsaturated monocyclic heterocycle containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen, and sulfur) alkoxygroup, lower hydroxyalkoxy, lower alkoxyalkyl, lower cyanoacetylurea, lower alkylsulfonyl group or phenylsulfonyl group;
X2represents a simple bond, lower alkylenes group, lower alkynylamino group, lower alkynylamino group, -X3-CO-, -X3-CONH-, -X3-S-, -X3-NH-, -X3-NHCO - or-X3-NHCONH-;
X3represents a simple bond, lower alkylenes group, lower alkynylamino group or lower alkynylamino group;
ring a represents a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring containing from 3 to 10 carbon atoms, or 5-10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic ring containing 1-3 heteroatoms in the ring selected from nitrogen atoms, oxygen, sulfur, and boron;
R4represents a halogen atom, a lower alkyl group, lower halogen is kilou group, -X4-OR5, -X4-OCOR5, -X4-R5, -X4-COOR5, -X4-NRcRd, -X4-SR5, -X4-SOR5, -X4-SONRcRd, -X4-SO2R5, -X4-SO2NRcRd, -X4-NRcRd, -X4-NHCOR5, -X4-NHCOOR5, -X4-NHSOR5, -X4-NHSO2R5, -X4-CN or-X4-NO2;
X4represents a simple bond, lower alkylenes group or lower cycloalkenyl group; and/or
R5represents a hydrogen atom, a lower alkyl group, lower halogenating group, lower cycloalkylcarbonyl group, lower phenylalkyl group, lower cycloalkyl group or phenyl group;
Rcand Rdmay be the same or different and each represents a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group, a lower alkoxyalkyl group, a lower alkyl group containing-NReRfas an alternate, lower cycloalkyl group, lower alkylcyclohexane group, phenyl group, lower alkylphenyl group, a 5-10 membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic group containing one or more heteroatoms in the ring selected from the atom is in nitrogen, oxygen, and sulfur, or lower alkyl (5 to 10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic group containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur);
Rcand Rdcan be connected to each other and form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
Reand Rfmay be the same or different and each represents a hydrogen atom or a lower alkyl group;
Reand Rfcan be connected to each other and form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
m is 0, 1, 2, 3, or 4, provided that R2may be the same or different when m is 2, 3 or 4; and
n can be 0, 1, 2, 3, or 4, provided that R4may be the same or different when n is 2, 3 or 4.

3. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
R1represents a hydrogen atom, a lower alkyl group, lower phenylalkyl group, nitrophenyl group or a hydroxyl group;
R2is the th halogen atom, lower alkyl group, lower halogenating group, lower alkenylphenol group, lower alkylamino group, -X1-COR3, -X1-COOR3, -X1-CONRaRb, -X1-SR3, -X1-NRaRb, -X1-NHCO-R3X1-CN, -X1-N3or a group of the General formula (2)

where X1represents a simple bond, lower alkylenes group, lower alkynylamino group or lower alkynylamino group;
R3represents a hydrogen atom, a lower alkyl group, lower halogenating group, lower6-14-arylalkyl group, a lower hydroxyalkyl group or a lower alkenylphenol group;
Raand Rbmay be the same or different and each represents a hydrogen atom or a lower alkyl group, lower phenylalkyl group, lower (5-6-membered saturated or unsaturated monocyclic heterocycle containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen, and sulfur) alkyl group, a lower hydroxyalkyl group, a lower cyanoaniline group or lower alkenylphenol group, a lower alkoxygroup or phenylsulfonyl group;
X2represents a simple bond, lower alkylenes group, lower alkynylamino group, lower alkynylamino group, -X 3-CO-, -X3-CONH-, -X3-S-, -X3-NH-, -X3-NHCO - or-X3-NHCONH-;
X3represents a simple bond, lower alkylenes group, lower alkynylamino group or lower alkynylamino group;
ring a represents a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring containing from 3 to 10 carbon atoms, or 5-10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic ring containing 1-3 heteroatoms in the ring selected from nitrogen atoms, oxygen, sulfur, and boron;
R4represents a halogen atom, a lower alkyl group, lower halogenating group, -X4-OR5, -X4-OCOR5, -X4-COR5, -X4-COOR5, -X4-CONRcRd, -X4-SO2R5, -X4-SO2NRcRd, -X4-NRcRd, -X4-NHCOR5, -X4-NHCOOR5, -X4-NHSO2R5, -X4-CN or-X4-NO2;
X4represents a simple bond, lower alkylenes group or lower cycloalkenyl group;
R5represents a hydrogen atom, a lower alkyl group, lower halogenating group, lower phenylalkyl group or phenyl group;
Rcand Rfcan be the same and or different and each represents a hydrogen atom, lower alkyl group, a lower hydroxyalkyl group, a lower alkoxyalkyl group, a lower alkyl group containing-NReRfas an alternate, lower cycloalkyl group, a 5-10 membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic group containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur, or lower alkyl (5 to 10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic group containing one or two heteroatoms in the ring selected from atomar nitrogen, oxygen and sulfur);
Rcand Rdcan be connected to each other and form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
Reand Rfmay be the same or different and each represents a hydrogen atom or a lower alkyl group;
Reand Rfcan be connected to each other and form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
m is 0, 1 or 2, provided that R2may be the same or different when m is equal is 2; and
n is 0, 1, 2, 3, or 4, provided that R4may be the same or different when n is 2, 3 or 4.

4. The compound or its pharmaceutically acceptable salt according to claim 1, where in the General formula (1)
R1represents a hydrogen atom, a lower alkyl group, lower phenylalkyl group, nitrophenyl group or a hydroxyl group;
R2represents a halogen atom, a lower alkyl group, lower halogenating group, lower alkenylphenol group, lower alkylamino group, -X1-COOR3, -X1-SR3, -X1-NRaRb, -X1-NHCO-R3or a group of the General formula (2)

where X1represents a simple bond, lower alkylenes group or lower alkynylamino group;
R3represents a hydrogen atom, a lower alkyl group or lower With6-14-arylalkyl group;
Raand Rbmay be the same or different and each represents a hydrogen atom or a lower alkyl group;
X2represents a simple bond, lower alkylenes group, lower alkynylamino group, -X3-NHCO - or-X3-NHCONH-;
X3represents a simple bond;
ring a represents a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon to lzo, containing from 3 to 10 carbon atoms, or 5-10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic ring containing 1-3 heteroatoms in the ring selected from nitrogen atoms, oxygen, sulfur, and boron;
R4represents a halogen atom, a lower alkyl group, X4-OR5, -X4-NRcRd, -X4-NHSO2R5, -X4-CN or-X4-NO2;
X4represents a simple bond or lower alkylenes group;
R5represents a hydrogen atom or a lower alkyl group;
Rcand Rdmay be the same or different and each represents a hydrogen atom, a lower alkyl group containing-NReRfas Deputy, or lower cycloalkyl group;
Rcand Rdcan be connected to each other to form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two heteroatoms in the ring selected from nitrogen atoms, oxygen and sulfur;
Reand Rfmay be the same or different and each represents a hydrogen atom or lower alkyl;
Reand Rfcan be connected to each other to form a 5-6-membered monocyclic saturated heterocyclic ring containing one or two courtesans the atom in the ring, selected from nitrogen atoms, oxygen and sulfur;
m is 0, 1 or 2, provided that R2may be the same or different when m is 2; and
n can be 0, 1 or 2, provided that R4may be the same or different when n is 2.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein ring a represents a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring containing from 3 to 10 carbon atoms.

6. The compound or its pharmaceutically acceptable salt according to claim 5, where the hydrocarbon ring selected from the group consisting of cyclopropane, cyclopentane, cyclohexane, cyclohexene, adamantane, benzene and naphthalene.

7. The compound or its pharmaceutically acceptable salt according to claim 5, where the hydrocarbon ring selected from the group consisting of cyclohexane and benzene.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein ring a represents a 5-to 10-membered saturated or unsaturated monocyclic or bicyclic condensed heterocyclic ring containing 1-3 heteroatoms in the ring selected from nitrogen atoms, oxygen, sulfur and boron.

9. The compound or its pharmaceutically acceptable salt of claim 8, where the heterocyclic ring are selected from the group consisting of pyrrolidine, is pirrolidone, of pyrrole, imidazole, pyrazole, indole, pyridine, pyrimidine, quinoline, furan, benzofuran, thiophene, benzothiophene, isoxazol, thiazole, research, thiomorpholine, dioxanonane and dithiolane.

10. The compound or its pharmaceutically acceptable salt of claim 8, where the heterocyclic ring are selected from the group consisting of pyrrolidine, pyrrole, indole, pyridine, quinoline, furan, thiophene and dithiolane.

11. The compound or its pharmaceutically acceptable salt, selected from
2 Aminocarbonyl-6-bromo-1-hydroxyindole-3-carboxamide,
2 Aminocarbonyl-5-methylindol-3-carboxamide,
6-Acetylamino-2-aminocarbonylmethyl-3-carboxamide,
2 Aminocarbonyl-6-benzoylamino-3-carboxamide,
2 Aminocarbonyl-6-(3-phenylurea)indole-3-carboxamide,
2 Aminocarbonyl-6-dimethylaminoethyl-3-carboxamide,
2 Aminocarbonyl-6-(pyrrolidin-1-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(pyrrol-1-yl)indole-3-carboxamide,
2-Aminocarbonylmethyl-3-carboxamide,
2 Aminocarbonyl-6-bromo-7-methylindol-3-carboxamide,
2 Aminocarbonyl-6-cryptomaterial-3-carboxamide,
2 Aminocarbonyl-6-methoxycarbonylmethyl-3-carboxamide,
2 Aminocarbonyl-6-bromoindole-3-carboxamide,
2 Aminocarbonyl-6-(4-forfinal)indole-3-carboxamide,
2 Aminocarbonyl-6-phenylindol-3-carboxamide,
2-Amin is carbylamine-6-(3-methoxyphenyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(thiophene-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(pyridin-3-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(2-forfinal)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-forfinal)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-cyanophenyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-nitrophenyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-methylsulfonylamino)indole-3-carboxamide,
2 Aminocarbonyl-6-(thiophene-3-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(furan-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(furan-3-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(2-chlorothiophene-3-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(quinoline-3-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-winrental-3-carboxamide,
2 Aminocarbonyl-6-[(E)-3-methoxy-1-propenyl]indole-3-carboxamide,
2 Aminocarbonyl-6-(indol-5-yl)indol-3-carboxamide,
2 Aminocarbonyl-6-[(E)-1-pentenyl]indole-3-carboxamide,
2 Aminocarbonyl-6-(4-dimethylaminophenyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(furan-3-yl)-7-methylindol-3-carboxamide,
2 Aminocarbonyl-6-(pyrrol-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-[3-(2-hydroxyethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-(pyridin-4-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(4-hydroxymethyl-3-methoxyphenyl)in the ol-3-carboxamide,
2 Aminocarbonyl-6-(2-chloropyridin-4-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-[(1R)-3-(1-hydroxyethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-[(1S)-3-(1-hydroxyethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-(4-aminomethylphenol)indole-3-carboxamide,
2 Aminocarbonyl-6-[4-(1-amino-ethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-[4-(1-amino-1-methylethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-phenylalaninol-3-carboxamide,
2 Aminocarbonyl-6-(3-hydroxy-1-PROPYNYL)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-dimethylamino-1-PROPYNYL)indole-3-carboxamide,
2 Aminocarbonyl-6-atenilol-3-carboxamide,
2 Aminocarbonyl-6-ethylindole-3-carboxamide,
2 Aminocarbonyl-6-cyclohexylphenol-3-carboxamide,
2 Aminocarbonyl-6-(4-hydroxybutyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-dimethylaminopropyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-methoxypropyl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-hydroxymethylene)indole-3-carboxamide,
2 Aminocarbonyl-6-(5-hydroxymethylene-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(3-isopropylaminomethyl)indole-3-carboxamide,
2 Aminocarbonyl-6-[3-(2-hydroxyethylaminomethyl)phenyl]indol-3-carboxamide,
2 Aminocarbonyl-6-(5-cyclopropylacetylene-2-yl)indole-3-carb is camid,
2 Aminocarbonyl-6-(5-methylaminomethyl-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-hydroxymethylene-3-carboxamide,
2 Aminocarbonyl-6-(1,3-ditiolan-2-yl)indole-3-carboxamide,
2 Aminocarbonyl-6-(pyrrolidin-1-ylcarbonyl)indole-3-carboxamide,
2 Aminocarbonyl-6-benzylaminocarbonyl-3-carboxamide,
2 Aminocarbonyl-6-(pyrrolidin-1-ylmethyl)indole-3-carboxamide and
2 Aminocarbonyl-6-ethylthiomethyl-3-carboxamide.

12. Pharmaceutical composition having inhibitory activity against IKKβ receptor, containing as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

13. The IKKβ inhibitor containing as an active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

14. Preventive or therapeutic agent for the prevention and treatment of diseases such as age-related degeneration yellow spots, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis, uveitis, glaucoma, rheumatoid arthritis, due to IKKβ, containing as active ingredient the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

15. Preventive or therapeutic agent according to 14, where a disease caused by IKKβ, presented yet an age dystrophy yellow spots.

16. Preventive or therapeutic agent according to 14, where the disease is associated with IKKβ is a diabetic retinopathy or diabetic macular edema.

17. Preventive or therapeutic agent according to 14, where a disease caused by IKKβ is a keratitis, conjunctivitis or uveitis.

18. Preventive or therapeutic agent according to 14, where a disease caused by IKKβ, is a glaucoma.

19. Preventive or therapeutic agent according to 14, where a disease caused by IKKβ, represents rheumatoid arthritis.

20. The method of IKKβ inhibition, comprising the administration to a patient in need pharmacologically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

21. The method of prevention or treatment of diseases such as age-related degeneration yellow spots, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis, uveitis, glaucoma, rheumatoid arthritis, due to IKKβ, including the introduction to a patient in need a therapeutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11.

22. The method of prevention or treatment according to item 21, where a disease caused by IKKβ, is an age remote is ofiu yellow spots.

23. The method of prevention or treatment according to item 21, where the disease caused IKKβ is a diabetic retinopathy or diabetic macular edema.

24. The method of prevention or treatment according to item 21, where the disease caused IKKβ is a keratitis, conjunctivitis or uveitis.

25. The method of prevention or treatment according to item 21, where a disease caused by IKKβ, is a glaucoma.

26. The method of prevention or treatment according to item 21, where the disease caused IKKβ is a rheumatoid arthritis.



 

Same patents:

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SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

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8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing bis-2,4-dialkyl-1,5,3-dithiazepan-3-yls of general formula (1): R=Me, Et, nPr, nBu, which involves reaction of a prepared mixture of ethane dithiol and aldehyde at 0°C (acetic or propionic or butyric or valeric) with hydrazine hydrate (60%) with molar ratio aldehyde: ethane dithiol: hydrazine=40:20:10 at temperature 0°C and atmospheric pressure for 2-4 hours.

EFFECT: method of producing novel compounds which can be used as antibacterial, antifungal and antiviral agents.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 and salts thereof, fungicidal compositions based on said compounds, a plant disease control method using compounds of formula , as well as intermediate compounds of formulae and . Values of radicals are given in the description.

EFFECT: high efficiency of the compounds.

14 cl, 20 dwg, 284 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3,3'-bi-1,5,3-dithiazepinane of formula (1) having fungicidal activity against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger and Paecilomyces variotii. The method involves reaction of a mixture of ethanedithiol and formaldehyde with hydrazine hydrate (60%) with molar ratio aldehyde: ethanedithiol: hydrazine = 40:20:10 at temperature 25°C and atmospheric pressure for 2-4 hours.

EFFECT: improved method.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3,4-thiadiazolines (I), thiadiazinones (II) and thiadiazepines (III), obtained based on thiohydrazides of oxamic acids, which can be used to inhibit pathogenic bacteria, and can particularly affect type III secretion system in pathogens, having general formula:

, , ,

where R denotes H; R1 denotes H, pyridinyl; phenyl, substituted with alkyl C1-C5, Hal, CF3; a group , where X denotes S, substituted with alkyl C1-C5, COOR4; R2, R3 denotes alkyl C1-C5, pyridinyl, phenyl, substituted Hal, OH, OR4, a R4 denotes unsubstituted alkyl C1-C4.

EFFECT: obtaining compounds which can be used to inhibit pathogenic bacteria.

2 cl, 2 dwg, 6 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,3-disubstituted indoles of general formula (I): , where the method involves the following steps: a) reaction of bromine diol (i): with dialkoxyborane in the presence of a ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2, Pd2(dba)3, Pd2(dba)3.CHCl3, [Pd(ally)Cl]2,- Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Pd/C and encapsulated Pd and a base to obtain a compound of general formula or, alternatively, reaction of compound (i) with a magnesium compound containing 3 alkyl groups, with subsequent treatment with a borate to obtain a compound of general formula ii given above; b) reaction of the product from step (a) with R2-Hal to obtain a compound of general formula I; where: R denotes (C1-C6)alkyl; R2 denotes: , , , , ,

, , , , ;

R3 denotes cyclopentyl: X denotes carboxymethyl; Hal denotes Br or I; or pharmaceutically acceptable salt thereof.

EFFECT: higher efficiency.

12 cl, 4 dwg, 2 tbl, 14 ex

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