CA2617692A1 - Combinations containing ikk-.beta. inhibitors - Google Patents
Combinations containing ikk-.beta. inhibitors Download PDFInfo
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- CA2617692A1 CA2617692A1 CA002617692A CA2617692A CA2617692A1 CA 2617692 A1 CA2617692 A1 CA 2617692A1 CA 002617692 A CA002617692 A CA 002617692A CA 2617692 A CA2617692 A CA 2617692A CA 2617692 A1 CA2617692 A1 CA 2617692A1
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- piperidinyl
- hydroxyphenyl
- amino
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
The invention relates to the use of IKK-beta inhibitors for producing tumor-treating drugs and to IKK-beta inhibitor-containing drugs.
Description
BHC 05 1 046-Foreign countries Combinations with IKK-R inhibitors The application relates to medicaments comprising a combination of IKK-(3 inhibitors with other pharmaceuticals which can be employed for the treatment of inflammatory skin diseases and for the treatment of skin tumours.
The treatment of inflammatory skin diseases and of tumours of the skin represents a great, unsatisfactorily solved medical problem.
The object of the invention was thus the development of an innovative und efficacious therapeutic against inflammatory skin diseases and tumours of the skin, which has a favourable side-effect profile.
It has now surprisingly been found that a combination of IKK-(3 inhibitors with other pharmaceuticals which can be employed for the treatment of inflammatory skin diseases and for the treatment of skin tumours produce decidedly good treatment results.
The application therefore relates to combinations of inhibitors of IK]K-(3 with other pharmaceuticals which can be employed for the treatment of inflammatory skin diseases and for the treatment of skin tumours.
Suitable IKK-beta inhibitors are preferably the compounds described in WO-0224679, W002044153 and WO-03076447. Essentially, the IKK-beta inhibitors are compounds of the formula (I) and their salts in which R' represents a group of the formula BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 or d-4m C\I .- ' Itl Rll where * represents the site of linkage to the pyridine ring, Rrepresents hydrogen, Ci_1z-alkoxy or-0-(CHz)r,-R'ii in which n represents I to 6 and R' 11 represents phenyl, C3_8-cycloalkyl, RZ represents hydrogen, R3 represents 1,2,3,6-tetrahydropyridine, in which R31 represents hydrogen, and R32 and R33, together with the adjacent carbon, form a 5- to 8-membered saturated ring which contains NH. This ring can be substituted by phenyl-C1_6-alkyl, C1_6-alkoxy-substituted phenyl-Ci_6-alkyl, CI_6-a-kyl, amino, carboxyl, C1_6-alkylamino, CI_6-alkoxycarbonyl, di(C1_6-alkyl)amino, benzylamino, C1_6-alkylsulphonyl, piperidine-CI_6-alkylcarbonyl or optionally fused benzene;
or -NR3aR3s ~
in which R34 represents hydrogen and R35 represents -(CH2)n,-NR351R352 (m represents 1 to 6) BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 in which R351 represents hydrogen or C1_6-alkyl and R 352 represents hydrogen, CI_6-alkyl, CI_6-alkanoyl, CI_6-alkyl-substituted phenyl, benzoyl, C1_6-alkanoyl, phenylaminocarbonyl or phenylsulphonyl and R4 represents cyano, C1_6-alkyl, which can optionally be substituted by hydroxyl or C1_6-alkoxy or -(CH2)pNHCOR41, -(CHz)pNHC(=S)Rai in which p represents 1 to 6 and R41 represents C1_6-alkoxy, amino, phenylamino, C1_6-alkyl, C1_6-alkylamino, di(C1_6-alkyl)amino or C3_1 -cycloalkylamino, R5 represents amino or R4 and R5 can together be -R40-CO-NH, R40-SOZ-NH-, R40-C(=S)-NH- or R 40-CH2-NH-, in which R40 represents -CHR401 -O-, -CH2-NRa01 -CO-NR401-~
in which R401 represents hydrogen, C1_6-alkanoyl, Cl_6-alkoxycarbonyl, C1_6-alkyl, phenyl, C1_6-alkylsulphonyl, C3_8-cycloalkylaminocarbonyl, C1_6-alkylaminrnocarbonyl, carbamoyl, di(Ci_6-alkyl)aminocarbonyl, or represents -CHZ-CHR402-, -CI-I=CR402_ in which R402 represents hydrogen, halogen, nitro, amino, cyano, benzoylamino, phenylsulphonyl, carbamoyl, hydroxycarbonyl, C7_6-alkoxycarbonyl, C1_1z-alkylaminocarbonyl, halogen-substituted C1_6-alkylaminocarbonyl, CI_6-alkanoylamino, C1_6-alkylamino, di(C1_6-alkyl)aminocarbonyl, di(C1_6-alkyl)amino-C1_6-alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C1_6-alkoxy-C1_6-alkylaminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, phenyl-C1_6-alkylamino-carbonyl, C3_8-cycloalkylaminocarbonyl, hydroxycarbonyl-CI_6-alkylaminocarbonyl, C3_S-cycloalkyl-C1_6-alkylaminocarbonyl, hydroxy-C1_6-alkylaminocarbonyl, carboxyetllylaminocarbonyl, methylsulphonylaminocarbonyl, BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 or -CR41=N-NH-, in which R41 represents hydroxyl, amino, CI_6-alkanoylamino or -CR42=N-C=N, in which R42 represents amino and their salts, solvates and the solvates of the salts.
The following compounds and their salts, solvates and solvates of the salts are preferred:
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydro)cy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2- [6-amino-5-[2-(hydroxymethyl)-4-(piperidinyl)-2-pyridinyl]-3 -(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d] [1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1, 8-naphthyridin-2(1 H)-one;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1, 8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l , 8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1 H)-one;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl] -2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1, 8-naphthyridine-3 -carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
The treatment of inflammatory skin diseases and of tumours of the skin represents a great, unsatisfactorily solved medical problem.
The object of the invention was thus the development of an innovative und efficacious therapeutic against inflammatory skin diseases and tumours of the skin, which has a favourable side-effect profile.
It has now surprisingly been found that a combination of IKK-(3 inhibitors with other pharmaceuticals which can be employed for the treatment of inflammatory skin diseases and for the treatment of skin tumours produce decidedly good treatment results.
The application therefore relates to combinations of inhibitors of IK]K-(3 with other pharmaceuticals which can be employed for the treatment of inflammatory skin diseases and for the treatment of skin tumours.
Suitable IKK-beta inhibitors are preferably the compounds described in WO-0224679, W002044153 and WO-03076447. Essentially, the IKK-beta inhibitors are compounds of the formula (I) and their salts in which R' represents a group of the formula BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 or d-4m C\I .- ' Itl Rll where * represents the site of linkage to the pyridine ring, Rrepresents hydrogen, Ci_1z-alkoxy or-0-(CHz)r,-R'ii in which n represents I to 6 and R' 11 represents phenyl, C3_8-cycloalkyl, RZ represents hydrogen, R3 represents 1,2,3,6-tetrahydropyridine, in which R31 represents hydrogen, and R32 and R33, together with the adjacent carbon, form a 5- to 8-membered saturated ring which contains NH. This ring can be substituted by phenyl-C1_6-alkyl, C1_6-alkoxy-substituted phenyl-Ci_6-alkyl, CI_6-a-kyl, amino, carboxyl, C1_6-alkylamino, CI_6-alkoxycarbonyl, di(C1_6-alkyl)amino, benzylamino, C1_6-alkylsulphonyl, piperidine-CI_6-alkylcarbonyl or optionally fused benzene;
or -NR3aR3s ~
in which R34 represents hydrogen and R35 represents -(CH2)n,-NR351R352 (m represents 1 to 6) BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 in which R351 represents hydrogen or C1_6-alkyl and R 352 represents hydrogen, CI_6-alkyl, CI_6-alkanoyl, CI_6-alkyl-substituted phenyl, benzoyl, C1_6-alkanoyl, phenylaminocarbonyl or phenylsulphonyl and R4 represents cyano, C1_6-alkyl, which can optionally be substituted by hydroxyl or C1_6-alkoxy or -(CH2)pNHCOR41, -(CHz)pNHC(=S)Rai in which p represents 1 to 6 and R41 represents C1_6-alkoxy, amino, phenylamino, C1_6-alkyl, C1_6-alkylamino, di(C1_6-alkyl)amino or C3_1 -cycloalkylamino, R5 represents amino or R4 and R5 can together be -R40-CO-NH, R40-SOZ-NH-, R40-C(=S)-NH- or R 40-CH2-NH-, in which R40 represents -CHR401 -O-, -CH2-NRa01 -CO-NR401-~
in which R401 represents hydrogen, C1_6-alkanoyl, Cl_6-alkoxycarbonyl, C1_6-alkyl, phenyl, C1_6-alkylsulphonyl, C3_8-cycloalkylaminocarbonyl, C1_6-alkylaminrnocarbonyl, carbamoyl, di(Ci_6-alkyl)aminocarbonyl, or represents -CHZ-CHR402-, -CI-I=CR402_ in which R402 represents hydrogen, halogen, nitro, amino, cyano, benzoylamino, phenylsulphonyl, carbamoyl, hydroxycarbonyl, C7_6-alkoxycarbonyl, C1_1z-alkylaminocarbonyl, halogen-substituted C1_6-alkylaminocarbonyl, CI_6-alkanoylamino, C1_6-alkylamino, di(C1_6-alkyl)aminocarbonyl, di(C1_6-alkyl)amino-C1_6-alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C1_6-alkoxy-C1_6-alkylaminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, phenyl-C1_6-alkylamino-carbonyl, C3_8-cycloalkylaminocarbonyl, hydroxycarbonyl-CI_6-alkylaminocarbonyl, C3_S-cycloalkyl-C1_6-alkylaminocarbonyl, hydroxy-C1_6-alkylaminocarbonyl, carboxyetllylaminocarbonyl, methylsulphonylaminocarbonyl, BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 or -CR41=N-NH-, in which R41 represents hydroxyl, amino, CI_6-alkanoylamino or -CR42=N-C=N, in which R42 represents amino and their salts, solvates and the solvates of the salts.
The following compounds and their salts, solvates and solvates of the salts are preferred:
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydro)cy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2- [6-amino-5-[2-(hydroxymethyl)-4-(piperidinyl)-2-pyridinyl]-3 -(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d] [1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1, 8-naphthyridin-2(1 H)-one;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1, 8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l , 8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1 H)-one;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl] -2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1, 8-naphthyridine-3 -carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6'-amino-5'-(hydroxymethyl)-4'-(3-piperidinyl)-2,2'-bipyridin-3-ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1, 8-naphthyridin-2(1 H)-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3 -piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d] [1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1 H)-one;
2-amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido [2,3-d]
[ 1,3 ]-oxazin-2-one;
ethyl7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1H)-one;
2- [6-amino-5 -(hydroxymethyl)-4-(3 -piperidinyl)-2-pyridinyl] -3 -(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3 -(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1 H)-BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 one;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxyl ate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6 '-amino-5 '-(hydroxymethyl)-4 '-(3 -piperi dinyl)-2, 2'-b ipyridin-3 -ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1 H)-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluoro-5-(3-piperidinyl)-1, 8-naphthyridin-2(1 H)-one;
7-(2-hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
3 -(cycl opropylmethoxy)-2- [5 -(3 -piperidinyl)- 1,4-dihydro-2H-pyrido [2,3 -d] [1,3]oxazin-7-yl]phenol;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(neopentyloxy)phenol;
2-[6'-amino-5 '-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4'-bipyridin-2'-yl]phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1, 8-naphthyridin-2(1 H)-one;
N- { [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl } acetamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1 H)-one;
2-amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
2-amino-4- [(2-aminoethyl)amino]-6- [2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinenitrile;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 N-{ [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl} -N'-propylurea;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3 -piperidinyl)-3,4-dihydropyrido [2,3-d]pyrimidin-2(1 H)-one;
ethyl 2-[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl-carbamate;
2-amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3 -c arboxamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
ethyl 7-[2-(cyclopropylmethoxy)-6-]rydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d] pyrimidine-3 (2H)-carboxylate;
N- { [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl} urea;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinenitrile;
N-cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido [2,3 -d]pyrimidine-3 (2H)-carboxamide;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)r-icotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3 -piperidinyl)-1,4-dihydropyrido [2,3 -d]pyrimidine-3(2H)-carboxamide;
isopropyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]-methylcarbamate;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 -g-isopropyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydro-pyrido [2,3-d]pyrimidine-3 (2H)-carboxylate;
isobutyl 7-[2-(cyclopropylmetho)cy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxylate;
neopentyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxylate;
neopentyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile and 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxamide.
Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included here are salts which are not suitable themselves for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.
Physiologically acceptable salts of the compounds of the formula (I) include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, oxalic acid, p-bromophenylsulphonic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the formula (I) also include salts of customary bases, such as, by way of example and preferably, alkali metal salts (e.g.
sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having I to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoetlaanol, procaine, dibenzylamine, N-methyhmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 The compounds or salts of this invention, depending on their substituents, can be converted to low alkyl or other esters and/or their hydrates or other solvates. These esters, hydrates and solvates are included in the scope of the invention.
Solvates in the context of the invention are designated as those forms of the compounds according to the invention which in the solid or liquid state form a complex by coorclination with solvent molecules.
Hydrates are a special form of the solvates, in which the coordination takes place with water.
In the context of the present invention, the substituents, if not specified otherwise, have the following meaning:
Alkyl per se and "alk" and "alkyl" in alkoxy and alkylcarbonyloy rep:resent a linear or branched alkyl radical having 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
Alkoxy represents, by way of exainple and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
Al , lcarbonyloxy represents, by way of example and preferably, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.
Cycloalkyl represents a mono- or bicyclic cycloalkyl group generally having 3 to 7, preferably 5 or 6, carbon atoms; by way of example and preferably for cycloalkyl may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Heteroaryl represents an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, 0 and N, by way of example and preferably thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazoly], triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
If radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals, if not specified otherwise, can be mono- or polysubstituted in an identical or different manner. Substitution by up to three identical or different substituents is preferred.
Substitution by one substituent is very particularly preferred.
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 The preparation of the compounds of the formula (I) is known and is described in the literature.
Pharmaceuticals which can be employed for the treatment of inflammatory skin diseases are, in particular, medicaments for the treatment of dermatitis, contact dermatitis, contact allergy, psoriasis and atopic dermatitis.
Pharmaceuticals which can be employed for the treatment of skin tumours are, in particular, medicaments for the treatment of, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages such as, for example, actinic keratoses and Bowen's disease.
Combinations of IKK-beta inhibitors with the following pharmaceuticals are preferred:
corticosteroids, retinoids (e.g. acitretin), cyclosporin, methotrexate or fumaric acid, efalizumab, etanercept, onercept, adalimumab, infliximab, pimecrolimus or tacrolimus, efomycins and elaiophyllins, dacarbazine, doxorubicin, interferons (e.g. interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2), therapeutic melanoma vaccines (e.g. prepared or synthetic antigens or transfected cells), temozolomide.
Combined administration of IKK-beta inhibitors or the medicament combinations according to the invention with radiotherapies, irradiation therapy with visible light, ionizing radiation, UV radiation, photodynamic therapy likewise shows a surprisingly good therapeutic result.
In particular, it has been found that the medicament combinations according to the invention can be employed for the treatment of contact dermatitis, contact allergy, psoriasis, dermatitis, atopic dermatitis, discoid lupus erythematosus and/or of eczemas and for the treatment of skin tumours such as, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages, such as, in particular, actinic keratoses and Bowen's disease.
Treatment preferably takes place systemically and/or topically. In the case of systemic treatment, the administration of the active substance can be carried out orally using tablets, juices, emulsions, capsules, or other pharmaceutical preparations. Systemic treatment can also be carried out parenterally (intravenously, subcutaneously). Topical treatment is carried out by applying the active substance in suitable formulations to the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated. The formulations used can be ointments, creams, powders, emulsions or solutions. Moreover, BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 _11-patches or dressings impregnated with active substance can be used. Systemic and/or topical treatment can be carried out according to various time schemes (single treatment up to several times daily over a fixed time period).
Topical treatment of inflammations of the eye is preferred (keratitis, uveitis, retinitis) and of the ear and the treatment of tumours of the eye and metastases of other tumours on the eye and of tumours of the ear (and metastases of other tumours on the ear) and of tumours of the external genitalia (and metastases of other tumours on the external genitalia). This includes tumours which are caused by virus infections (e.g. genital warts caused by infection with different types of the human papillomavirus, Kaposi's sarcoma of the skin and mucous membrane, epidermodysplasia verucciformis or other neoplastic changes) and the topical treatment of tumours of the urogenital system, for example, by instillation of a solution or of a suspension of the medicament combination according to the invention or other suitable pharmaceutical preparations of the medicament combination according to the invention (e.g. emulsions, gels).
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3 -piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d] [1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1 H)-one;
2-amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido [2,3-d]
[ 1,3 ]-oxazin-2-one;
ethyl7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-l,8-naphthyridin-2(1H)-one;
2- [6-amino-5 -(hydroxymethyl)-4-(3 -piperidinyl)-2-pyridinyl] -3 -(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3 -(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1 H)-BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 one;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxyl ate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6 '-amino-5 '-(hydroxymethyl)-4 '-(3 -piperi dinyl)-2, 2'-b ipyridin-3 -ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1 H)-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluoro-5-(3-piperidinyl)-1, 8-naphthyridin-2(1 H)-one;
7-(2-hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
3 -(cycl opropylmethoxy)-2- [5 -(3 -piperidinyl)- 1,4-dihydro-2H-pyrido [2,3 -d] [1,3]oxazin-7-yl]phenol;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(neopentyloxy)phenol;
2-[6'-amino-5 '-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4'-bipyridin-2'-yl]phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1, 8-naphthyridin-2(1 H)-one;
N- { [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl } acetamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1 H)-one;
2-amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
2-amino-4- [(2-aminoethyl)amino]-6- [2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinenitrile;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 N-{ [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl} -N'-propylurea;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3 -piperidinyl)-3,4-dihydropyrido [2,3-d]pyrimidin-2(1 H)-one;
ethyl 2-[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl-carbamate;
2-amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3 -c arboxamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
ethyl 7-[2-(cyclopropylmethoxy)-6-]rydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d] pyrimidine-3 (2H)-carboxylate;
N- { [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl} urea;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinenitrile;
N-cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido [2,3 -d]pyrimidine-3 (2H)-carboxamide;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)r-icotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3 -piperidinyl)-1,4-dihydropyrido [2,3 -d]pyrimidine-3(2H)-carboxamide;
isopropyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]-methylcarbamate;
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 -g-isopropyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydro-pyrido [2,3-d]pyrimidine-3 (2H)-carboxylate;
isobutyl 7-[2-(cyclopropylmetho)cy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxylate;
neopentyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxylate;
neopentyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile and 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3 (2H)-carboxamide.
Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included here are salts which are not suitable themselves for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.
Physiologically acceptable salts of the compounds of the formula (I) include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, oxalic acid, p-bromophenylsulphonic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the formula (I) also include salts of customary bases, such as, by way of example and preferably, alkali metal salts (e.g.
sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having I to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoetlaanol, procaine, dibenzylamine, N-methyhmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 The compounds or salts of this invention, depending on their substituents, can be converted to low alkyl or other esters and/or their hydrates or other solvates. These esters, hydrates and solvates are included in the scope of the invention.
Solvates in the context of the invention are designated as those forms of the compounds according to the invention which in the solid or liquid state form a complex by coorclination with solvent molecules.
Hydrates are a special form of the solvates, in which the coordination takes place with water.
In the context of the present invention, the substituents, if not specified otherwise, have the following meaning:
Alkyl per se and "alk" and "alkyl" in alkoxy and alkylcarbonyloy rep:resent a linear or branched alkyl radical having 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
Alkoxy represents, by way of exainple and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
Al , lcarbonyloxy represents, by way of example and preferably, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.
Cycloalkyl represents a mono- or bicyclic cycloalkyl group generally having 3 to 7, preferably 5 or 6, carbon atoms; by way of example and preferably for cycloalkyl may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Heteroaryl represents an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, 0 and N, by way of example and preferably thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazoly], triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
If radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals, if not specified otherwise, can be mono- or polysubstituted in an identical or different manner. Substitution by up to three identical or different substituents is preferred.
Substitution by one substituent is very particularly preferred.
BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 The preparation of the compounds of the formula (I) is known and is described in the literature.
Pharmaceuticals which can be employed for the treatment of inflammatory skin diseases are, in particular, medicaments for the treatment of dermatitis, contact dermatitis, contact allergy, psoriasis and atopic dermatitis.
Pharmaceuticals which can be employed for the treatment of skin tumours are, in particular, medicaments for the treatment of, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages such as, for example, actinic keratoses and Bowen's disease.
Combinations of IKK-beta inhibitors with the following pharmaceuticals are preferred:
corticosteroids, retinoids (e.g. acitretin), cyclosporin, methotrexate or fumaric acid, efalizumab, etanercept, onercept, adalimumab, infliximab, pimecrolimus or tacrolimus, efomycins and elaiophyllins, dacarbazine, doxorubicin, interferons (e.g. interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2), therapeutic melanoma vaccines (e.g. prepared or synthetic antigens or transfected cells), temozolomide.
Combined administration of IKK-beta inhibitors or the medicament combinations according to the invention with radiotherapies, irradiation therapy with visible light, ionizing radiation, UV radiation, photodynamic therapy likewise shows a surprisingly good therapeutic result.
In particular, it has been found that the medicament combinations according to the invention can be employed for the treatment of contact dermatitis, contact allergy, psoriasis, dermatitis, atopic dermatitis, discoid lupus erythematosus and/or of eczemas and for the treatment of skin tumours such as, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages, such as, in particular, actinic keratoses and Bowen's disease.
Treatment preferably takes place systemically and/or topically. In the case of systemic treatment, the administration of the active substance can be carried out orally using tablets, juices, emulsions, capsules, or other pharmaceutical preparations. Systemic treatment can also be carried out parenterally (intravenously, subcutaneously). Topical treatment is carried out by applying the active substance in suitable formulations to the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated. The formulations used can be ointments, creams, powders, emulsions or solutions. Moreover, BHC 05 1 046-Foreign countries CA 02617692 2008-02-01 _11-patches or dressings impregnated with active substance can be used. Systemic and/or topical treatment can be carried out according to various time schemes (single treatment up to several times daily over a fixed time period).
Topical treatment of inflammations of the eye is preferred (keratitis, uveitis, retinitis) and of the ear and the treatment of tumours of the eye and metastases of other tumours on the eye and of tumours of the ear (and metastases of other tumours on the ear) and of tumours of the external genitalia (and metastases of other tumours on the external genitalia). This includes tumours which are caused by virus infections (e.g. genital warts caused by infection with different types of the human papillomavirus, Kaposi's sarcoma of the skin and mucous membrane, epidermodysplasia verucciformis or other neoplastic changes) and the topical treatment of tumours of the urogenital system, for example, by instillation of a solution or of a suspension of the medicament combination according to the invention or other suitable pharmaceutical preparations of the medicament combination according to the invention (e.g. emulsions, gels).
Claims (8)
1. Medicament combination comprising at least one IKK-beta inhibitor and at least one pharmaceutical which can be employed for the treatment of inflammatory skin diseases or of skin tumours.
2. Medicament combination according to Claim 1, comprising as the IKK-beta inhibitor a compound of the formula (I) and its salts in which R1 represents a group of the formula where * represents the site of linkage to the pyridine ring, R11 represents hydrogen, C1-12-alkoxy or -O-(CH2)n-R111, in which n represents 1 to 6 and R111 represents phenyl, C3-8-cycloalkyl, R2 represents hydrogen, R3 represents 1,2,3,6-tetrahydropyridine, -CR31R32R33, in which R31 represents hydrogen, and R32 and R33, together with the adjacent carbon, form a 5- to 8-membered saturated ring which contains NH. This ring can be substituted by phenyl-C1-6-alkyl, C1-6-alkoxy-substituted phenyl-C1-6-alkyl, C1-6-alkyl, amino, carboxyl, C1-6-alkylamino, C1-6-alkoxycarbonyl, di(C1-6-alkyl)amino, benzylamino, C1-6-alkylsulphonyl, piperidine-C1-6-alkylcarbonyl or optionally fused benzene;
or -NR34R35, in which R34 represents hydrogen and R35 represents -(CH2)m-NR351R352 (m represents 1 to 6) in which R351 represents hydrogen or C1-6-alkyl and R352 represents hydrogen, C1-6-alkyl, C1-6-alkanoyl, C1-6-alkyl-substituted phenyl, benzoyl, C1-6-alkanoyl, phenylaminocarbonyl or phenylsulphonyl and R4 represents cyano, C1-6-alkyl, which can optionally be substituted by hydroxyl or C1-6-alkoxy or -(CH2)p NHCOR41, -(CH2)p NHC(=S)R41 in which p represents 1 to 6 and R41 represents C1-6-alkoxy, amino, phenylamino, C1-6-alkyl, C1-6-alkylamino, di(C1-6-alkyl)amino or C3-10-cycloalkylamino, R5 represents amino or R4 and R5 can together be -R40-CO-NH, R40-SO2-NH-, R40-C(=S)-NH- or R40-CH2-NH-, in which R40 represents -CHR401-O-, -CH2-NR401-, -CO-NR401-, in which R401 represents hydrogen, C1-6-alkanoyl, C1-6-alkoxycarbonyl, C1-6-alkyl, phenyl, C1-6-alkylsulphonyl, C3-8-cycloalkylaminocarbonyl, C1-6-alkylaminocarbonyl, carbamoyl, di(C1-6-alkyl)aminocarbonyl, or represents -CH2-CHR402-, -CH=CR402-, in which R402 represents hydrogen, halogen, nitro, amino, cyano, benzoylamino, phenylsulphonyl, carbamoyl, hydroxycarbonyl, C1-6-alkoxycarbonyl, C1-12-alkylaminocarbonyl, halogen-substituted C1-6-alkylaminocarbonyl, C1-6-alkanoylamino, C1-6-alkylamino, di(C1-6-alkyl)aminocarbonyl, di(C1-6-alkyl)amino-C1-6-alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C1-6-alkoxy-C1-6-alkylaminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, phenyl-C1-6-alkylaminocarbonyl, C3-8-cycloalkylaminocarbonyl, hydroxycarbonyl-C1-6-alkylaminocarbonyl, C3-8-cycloalkyl-C1-6-alkylaminocarbonyl, hydroxy-C1-6-alkylaminocarbonyl, carboxyethylaminocarbonyl, methylsulphonylaminocarbonyl, or -CR41=N-NH-, in which R41 represents hydroxyl, amino, C1-6-alkanoylamino or -CR42=N-C=N, in which R42 represents amino and their salts, solvates and the solvates of the salts.
or -NR34R35, in which R34 represents hydrogen and R35 represents -(CH2)m-NR351R352 (m represents 1 to 6) in which R351 represents hydrogen or C1-6-alkyl and R352 represents hydrogen, C1-6-alkyl, C1-6-alkanoyl, C1-6-alkyl-substituted phenyl, benzoyl, C1-6-alkanoyl, phenylaminocarbonyl or phenylsulphonyl and R4 represents cyano, C1-6-alkyl, which can optionally be substituted by hydroxyl or C1-6-alkoxy or -(CH2)p NHCOR41, -(CH2)p NHC(=S)R41 in which p represents 1 to 6 and R41 represents C1-6-alkoxy, amino, phenylamino, C1-6-alkyl, C1-6-alkylamino, di(C1-6-alkyl)amino or C3-10-cycloalkylamino, R5 represents amino or R4 and R5 can together be -R40-CO-NH, R40-SO2-NH-, R40-C(=S)-NH- or R40-CH2-NH-, in which R40 represents -CHR401-O-, -CH2-NR401-, -CO-NR401-, in which R401 represents hydrogen, C1-6-alkanoyl, C1-6-alkoxycarbonyl, C1-6-alkyl, phenyl, C1-6-alkylsulphonyl, C3-8-cycloalkylaminocarbonyl, C1-6-alkylaminocarbonyl, carbamoyl, di(C1-6-alkyl)aminocarbonyl, or represents -CH2-CHR402-, -CH=CR402-, in which R402 represents hydrogen, halogen, nitro, amino, cyano, benzoylamino, phenylsulphonyl, carbamoyl, hydroxycarbonyl, C1-6-alkoxycarbonyl, C1-12-alkylaminocarbonyl, halogen-substituted C1-6-alkylaminocarbonyl, C1-6-alkanoylamino, C1-6-alkylamino, di(C1-6-alkyl)aminocarbonyl, di(C1-6-alkyl)amino-C1-6-alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C1-6-alkoxy-C1-6-alkylaminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, phenyl-C1-6-alkylaminocarbonyl, C3-8-cycloalkylaminocarbonyl, hydroxycarbonyl-C1-6-alkylaminocarbonyl, C3-8-cycloalkyl-C1-6-alkylaminocarbonyl, hydroxy-C1-6-alkylaminocarbonyl, carboxyethylaminocarbonyl, methylsulphonylaminocarbonyl, or -CR41=N-NH-, in which R41 represents hydroxyl, amino, C1-6-alkanoylamino or -CR42=N-C=N, in which R42 represents amino and their salts, solvates and the solvates of the salts.
3. Medicament combination according to Claim 1, comprising as an IKK-beta inhibitor 7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-[2-(hydroxymethyl)-4-(piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
ethyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6'-amino-5'-(hydroxymethyl)-4'-(3-piperidinyl)-2,2'-bipyridin-3-ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6'-amino-5'-(hydroxymethyl)-4'-(3-piperidinyl)-2,2'-bipyridin-3-ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluoro-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one;
7-(2-hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
3-(cyclopropylmethoxy)-2-[5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-7-yl]phenol;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(neopentyloxy)phenol;
2-[6'-amino-5'-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4'-bipyridin-2'-yl]phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}acetamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one;
2-amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
2-amino-4-[(2-aminoethyl)amino]-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinenitrile;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}-N'-propyl urea;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one;
ethyl 2-[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}urea;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinenitrile;
N-cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
isopropyl[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-pyridinyl]methylcarbamate;
isopropyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
isobutyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
neopentyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
neopentyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile and 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide and/or their salts, solvates and solvates of the salts.
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-[2-(hydroxymethyl)-4-(piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
ethyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6'-amino-5'-(hydroxymethyl)-4'-(3-piperidinyl)-2,2'-bipyridin-3-ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;
7-[2-(benzyloxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile trifluoroacetate;
7-(2-hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinenitrile;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one;
ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-(2-hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
6'-amino-5'-(hydroxymethyl)-4'-(3-piperidinyl)-2,2'-bipyridin-3-ol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluoro-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one;
7-(2-hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one;
3-(cyclopropylmethoxy)-2-[5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-7-yl]phenol;
2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(neopentyloxy)phenol;
2-[6'-amino-5'-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4'-bipyridin-2'-yl]phenol;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,8-naphthyridin-2(1H)-one;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}acetamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one;
2-amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
2-amino-4-[(2-aminoethyl)amino]-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinenitrile;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}-N'-propyl urea;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one;
ethyl 2-[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide;
ethyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}urea;
2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinenitrile;
N-cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinenitrile;
7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide;
isopropyl[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-pyridinyl]methylcarbamate;
isopropyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
isobutyl7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
neopentyl 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate;
neopentyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;
2-amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinenitrile and 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxamide and/or their salts, solvates and solvates of the salts.
4. Medicament combination according to Claim 1, comprising as a further pharmaceutical medicaments for the treatment of dermatitis, contact dermatitis, contact allergy, psoriasis and atopic dermatitis.
5. Medicament combination according to Claim 1, comprising as a further pharmaceutical medicaments for the treatment of, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages such as, for example, actinic keratoses and Bowen's disease.
6. Medicament combination according to Claim 1, comprising as a further pharmaceutical corticosteroids, retinoids (e.g. acitretin), cyclosporin, methothrexate or fumaric acid, efalizumab, etanercept, onercept, adalimumab, infliximab, pimecrolimus or tacrolimus, efomycins and elaiophyllins, dacarbazine, doxorubicin, interferons (e.g.
interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2), therapeutic melanoma vaccines (e.g. prepared or synthetic antigens), temozolomide.
interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2), therapeutic melanoma vaccines (e.g. prepared or synthetic antigens), temozolomide.
7. Medicament combinations as defined in Claims 1 to 6, for topical treatment.
8. Medicament combinations as defined in Claims 1 to 6, for the topical treatment of inflammatory skin diseases and for the treatment of tumours of the eye and metastases of other tumours on the eye, of tumours of the ear and metastases of other tumours on the ear, of tumours of the external genitalia and metastases of other tumours on the external genitalia and tumours of the urogenital system.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005036656A DE102005036656A1 (en) | 2005-08-04 | 2005-08-04 | Pharmaceutical composition containing IKK-beta inhibitor and agent for treating inflammation or tumor of the skin, useful for topical treatment of e.g. inflamed skin and tumors of the eye |
| DE102005036657.0 | 2005-08-04 | ||
| DE102005036656.2 | 2005-08-04 | ||
| DE102005036657 | 2005-08-04 | ||
| PCT/EP2006/007299 WO2007014671A2 (en) | 2005-08-04 | 2006-07-25 | Combinations containing ikk-beta inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2617692A1 true CA2617692A1 (en) | 2007-02-08 |
Family
ID=37708965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002617692A Abandoned CA2617692A1 (en) | 2005-08-04 | 2006-07-25 | Combinations containing ikk-.beta. inhibitors |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1912646A2 (en) |
| JP (1) | JP2009502996A (en) |
| CA (1) | CA2617692A1 (en) |
| WO (1) | WO2007014671A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876984B (en) * | 2015-05-20 | 2017-10-03 | 武汉大学 | The bacterial strain of one plant height production elaiophylin class compound and preparation method and the application of such compound |
| CN111991410B (en) * | 2020-09-21 | 2021-08-06 | 中国医学科学院医药生物技术研究所 | Application of oleanolic acid derivatives in preparation of antitumor drugs |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030045515A1 (en) * | 2001-05-24 | 2003-03-06 | Lise Binderup | Combination medicament for treatment of neoplastic diseases |
| WO2004041285A1 (en) * | 2002-10-31 | 2004-05-21 | Amgen Inc. | Antiinflammation agents |
-
2006
- 2006-07-25 CA CA002617692A patent/CA2617692A1/en not_active Abandoned
- 2006-07-25 WO PCT/EP2006/007299 patent/WO2007014671A2/en active Application Filing
- 2006-07-25 EP EP06776386A patent/EP1912646A2/en not_active Withdrawn
- 2006-07-25 JP JP2008524397A patent/JP2009502996A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1912646A2 (en) | 2008-04-23 |
| WO2007014671A3 (en) | 2007-08-16 |
| WO2007014671A2 (en) | 2007-02-08 |
| JP2009502996A (en) | 2009-01-29 |
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