DE102005036656A1 - 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 - Google Patents

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 Download PDF

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DE102005036656A1
DE102005036656A1 DE102005036656A DE102005036656A DE102005036656A1 DE 102005036656 A1 DE102005036656 A1 DE 102005036656A1 DE 102005036656 A DE102005036656 A DE 102005036656A DE 102005036656 A DE102005036656 A DE 102005036656A DE 102005036656 A1 DE102005036656 A1 DE 102005036656A1
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piperidinyl
hydroxyphenyl
amino
cyclopropylmethoxy
dihydro
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DE102005036656A
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German (de)
Inventor
Olaf Dr. Weber
Karl Dr. Ziegelbauer
Peter Dr. Seiler
Thomas Dr. Krahn
Nicole Dr. Diedrichs
Bernd Dr. Riedl
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Bayer AG
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Bayer Healthcare AG
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Priority to DE102005036656A priority Critical patent/DE102005036656A1/en
Priority to EP06776386A priority patent/EP1912646A2/en
Priority to CA002617692A priority patent/CA2617692A1/en
Priority to JP2008524397A priority patent/JP2009502996A/en
Priority to PCT/EP2006/007299 priority patent/WO2007014671A2/en
Publication of DE102005036656A1 publication Critical patent/DE102005036656A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

Pharmaceutical composition (A) containing at least one inhibitor (I) of IKK-beta (I kappa B kinase) and at least one pharmaceutical (II) for treating inflammatory skin diseases or skin tumors. ACTIVITY : Dermatological; Antiinflammatory; Ophthalmological; Cytostatic; Uropathic. No details of tests for these activities are given. MECHANISM OF ACTION : Inhibition of IKKbeta .

Description

Die Anmeldung betrifft Arzneimittel enthaltend eine Kombination von IKK-β Inhibitoren mit anderen Arzneistoffen die zur Behandlung entzündlicher Hauterkrankungen sowie zur Behandlung von Hauttumoren eingesetzt werden können.The Application relates to medicaments containing a combination of IKK-β inhibitors with other drugs that are more inflammatory to treatment Skin diseases and used for the treatment of skin tumors can be.

Die Behandlung von entzündlichen Hauterkrankungen und von Tumorerkrankungen der Haut stellen ein großes unbefriedigend gelöstes medizinisches Problem dar.The Treatment of inflammatory Skin diseases and tumors of the skin set great unsatisfactorily solved medical problem.

Aufgabe der Erfindung war somit die Entwicklung eines innovativen und wirksamen Therapeutikums gegen entzündliche Hauterkrankungen und Tumorerkrankungen der Haut, das ein günstiges Nebenwirkungsprofil besitzt.task The invention was therefore the development of an innovative and effective Therapeutic against inflammatory Skin diseases and tumors of the skin, which has a favorable side effect profile has.

Es wurde nun überraschenderweise gefunden, dass eine Kombination von IKK-β Inhibitoren mit anderen Arzneistoffen die zur Behandlung entzündlicher Hauterkrankungen sowie zur Behandlung von Hauttumoren eingesetzt werden können, ausgesprochen gute Behandlungsergebnisse liefern.It was now surprisingly found that a combination of IKK-β inhibitors with other drugs the inflammatory for treatment Skin diseases and used for the treatment of skin tumors can be deliver exceptionally good treatment results.

Gegenstand der Anmeldung sind daher Kombinationen von Inhibitoren von IKK-β mit anderen Arzneistoffen die zur Behandlung entzündlicher Hauterkrankungen sowie zur Behandlung von Hauttumoren eingesetzt werden können.object The application therefore includes combinations of inhibitors of IKK-β with others Drugs used for the treatment of inflammatory skin diseases as well can be used for the treatment of skin tumors.

Als IKK-beta Inhibitoren kommen vorzugsweise die in der WO-0224679, WO02044153 und WO-03076447 beschriebenen Verbindungen in Frage. Im Wesentlichen handelt es bei den IKK-beta Inhibitoren um Verbindungen der Formel (I)

Figure 00010001
und deren Salze
in welcher
R1 für eine Gruppe der Formel
Figure 00010002
steht,
wobei
* für die Anknüpfstelle an den Pyridinring steht,
R11 für Wasserstoff, C1-12-Alkoxy oder -O-(CH2)n-R111 steht,
worin
n für 1 bis 6 steht
und R111 für Phenyl, C3-8-Cycloalkyl steht,
R2 für Wasserstoff steht,
R3 für 1,2,3,6-Tetrahydropyridin,
-CR31R32R33,
worin R31 für Wasserstoff steht,
und R32 und R33 zusammen mit dem angrenzenden Kohlenstoff einen 5- bis 8-gliedrigen gesättigten Ring bilden, der NH enthält. Dieser Ring kann substituiert sein durch Phenyl-C1-6-alkyl, C1-6-Alkoxy substituiertes Phenyl-C1-6-alkyl, C1-6-Alkyl, Amino, Carboxy, C1-6-Alkylamino, C1-6-Alkoxycarbonyl, Di(C1-6-Alkyl)-amino, Benzylamino, C1-6-Alkylsulfonyl, Piperidin-C1-6-alkylcarbonyl oder gegebenenfalls ankondensiertes Benzol;
oder
-NR34R35 steht,
worin R34 für Wasserstoff und
R35 für -(CH2)m-NR351R352 (m steht für 1 bis 6)
worin R351 für Wasserstoff oder C1-6-Alkyl
und R352 für Wasserstoff, C1-6-Alkyl, C1-6-Alkanoyl, C1-6-Alkyl-substituiertes Phenyl, Benzoyl, C1-6-Alkanoyl, Phenylaminocarbonyl oder Phenylsulfonyl steht und
R4 für Cyano, C1-6-Alkyl, welches gegebenenfalls durch Hydroxy oder C1-6-Alkoxy substituiert sein kann oder
-(CH2)pNHCOR41, -(CH2)pNHC(=S)R41,
worin p für 1 bis 6 steht und R41 für C1-6-Alkoxy, Amino, Phenylamino, C1-6-Alkyl, C1-6-Alkylamino, Di(C1-6-alkyl)amino oder C3-10-Cycloalkylamino steht,
R5 für Amino steht oder
R4 und R5 können zusammen
-R40-CO-NH, R40-SO2-NH-,
R40-C(=S)-NH- oder
R40-CH2-NH- sein,
worin R40 für -CHR401-O-, -CH2-NR401-, -CO-NR401-,
worin R401 für Wasserstoff, C1-6-Alkanoyl, C1-6-Alkoxycarbonyl, C1-6-Alkyl, Phenyl, C1-6-Alkylsulfonyl, C3-8-Cycloalkylaminocarbonyl, C1-6-Alkylaminocarbonyl, Carbamoyl, Di-(C1-6-alkyl)-aminocarbonyl,
oder für -CH2-CHR402-, -CH=CR402-,
worin R402 für Wasserstoff, Halogen, Nitro, Amino, Cyano, Benzoylamino, Phenylsulfonyl, Carbamoyl, Hydroxycarbonyl, C1-6-Alkoxycarbonyl, C1-12-Alkylaminocarbonyl, Halogen-substituiertes 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, Methylsulfonylaminocarbonyl steht,
oder -CR41=N-NH-, worin R41 für Hydroxy, Amino, C1-6-Alkanoylamino
oder -CR42=N-C=N, worin R42 für Amino steht
und deren Salze, Solvate und die Solvate der Salze.As IKK-beta inhibitors are preferably the compounds described in WO-0224679, WO02044153 and WO-03076447 in question. In essence, the IKK-beta inhibitors are compounds of the formula (I)
Figure 00010001
and their salts
in which
R 1 is a group of the formula
Figure 00010002
stands,
in which
* represents the point of attachment to the pyridine ring,
R 11 is hydrogen, C 1-12 -alkoxy or -O- (CH 2 ) n -R 111 ,
wherein
n is 1 to 6
and R 111 is phenyl, C 3-8 -cycloalkyl,
R 2 is hydrogen,
R 3 is 1,2,3,6-tetrahydropyridine,
-CR 31 R 32 R 33 ,
wherein R 31 is hydrogen,
and R 32 and R 33 together with the adjacent carbon form a 5- to 8-membered saturated ring containing NH. This ring may be substituted by phenylC 1-6 alkyl, C 1-6 alkoxy substituted phenylC 1-6 alkyl, C 1-6 alkyl, amino, carboxy, C 1-6 alkylamino, C 1-6 alkoxycarbonyl, di (C 1-6 alkyl) amino, benzylamino, C 1-6 alkylsulfonyl, piperidine C 1-6 alkylcarbonyl or optionally fused benzene;
or
-NR 34 R 35 stands,
wherein R 34 is hydrogen and
R 35 for - (CH 2 ) m -NR 351 R 352 (m stands for 1 to 6)
wherein R 351 is hydrogen or C 1-6 alkyl
and R 352 is hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkyl substituted phenyl, benzoyl, C 1-6 alkanoyl, phenylaminocarbonyl or phenylsulfonyl, and
R 4 is cyano, C 1-6 alkyl, which may optionally be substituted by hydroxy or C 1-6 alkoxy or
- (CH 2 ) p NHCOR 41 , - (CH 2 ) p NHC (= S) R 41 ,
wherein p is 1 to 6 and R 41 is C 1-6 -alkoxy, amino, phenylamino, C 1-6 -alkyl, C 1-6 -alkylamino, di (C 1-6 -alkyl) amino or C 3- 10 -cycloalkylamino,
R 5 is amino or
R 4 and R 5 may be together
R 40 -CO-NH, R 40 -SO 2 -NH-,
R 40 -C (= S) -NH- or
R 40 is -CH 2 -NH-,
wherein R 40 is -CHR 401 -O-, -CH 2 -NR 401 -, -CO-NR 401 -,
in which R 401 is hydrogen, C 1-6 -alkanoyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkyl, phenyl, C 1-6 -alkylsulfonyl, C 3-8 -cycloalkylaminocarbonyl, C 1-6 -alkylaminocarbonyl, Carbamoyl, di (C 1-6 alkyl) aminocarbonyl,
or for -CH 2 -CHR 402 -, -CH = CR 402 -,
wherein R 402 is hydrogen, halogen, nitro, amino, cyano, benzoylamino, phenylsulfonyl, carbamoyl, hydroxycarbonyl, C 1-6 -alkoxycarbonyl, C 1-12 -alkylaminocarbonyl, halo-substituted C 1-6 -alkylaminocarbonyl, C 1-6 Alkanoylamino, C 1-6 alkylamino, di (C 1-6 alkyl) aminocarbonyl, di (C 1-6 alkyl) amino C 1-6 alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C 1-6 -alkoxy-C 1-6 -alkylaminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, phenyl-C 1-6 -alkylaminocarbonyl, C 3-8 -cycloalkylaminocarbonyl, hydroxycarbonyl-C 1-6 -alkylaminocarbonyl, C 3-8 -cycloalkyl-C 1-6- alkylaminocarbonyl, hydroxy-C 1-6 -alkylaminocarbonyl, carboxyethylaminocarbonyl, methylsul is fonylaminocarbonyl,
or -CR 41 = N-NH-, where R 41 is hydroxy, amino, C 1-6 alkanoylamino
or -CR 42 = NC = N, where R 42 is amino
and their salts, solvates and solvates of salts.

Bevorzugt sind die folgenden Verbindungen und deren Salze, Solvate und Solvate der Salze:
7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on;
2-Amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril;
2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinnitril;
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-on;
2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril trifluoracetat;
7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on;
2-Amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril;
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-on;
Ethyl-7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat;
7-(2-Hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on;
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-naphthydrin-2(1H)-on;
Ehtyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on;
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-naphthydrin-2(1H)-on;
2-Amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril;
2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinnitril;
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-on;
2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril trifluoracetat;
7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on;
2-Amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril;
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-on;
Ethyl-7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat;
7-(2-Hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on;
2-[6-Amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethyoxy)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-naphthydrin-2(1H)-on;
Ethyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on;
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-naphthydrin-2(1H)-on;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluor-5-(3-piperidinyl)-1,8-naphthydrin-2(1H)-on;
7-(2-Hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2on;
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-naphthydrin-2(1H)-on;
N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}acetamid;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthydrin-3-carboxamid;
3-Acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-on;
2-Amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril;
2-Amino-4-[(2-aminoethyl)amino]-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinnitril;
N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}-N'-propylharnstoff;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-on;
Ethyl-2[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat;
2-Amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinnitril;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-l,8-naphthydrin-3-carboxamid;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthydrin-3-carboxamid;
Ethyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat;
N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}harnstoff;
2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinnitril;
N-Cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid;
2-Amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid;
2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinnitril;
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid;
Isopropyl-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat;
Isopropyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat;
Isobutyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat;
Neopentyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat;
Neopentyl-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat;
2-Amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril und
7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid.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) nicotinnitril;
2-Amino-6- (2-hydroxy-6-propoxyphenyl) -4- (3-piperidinyl) nicotinnitril;
phenol 2- [6-amino-5- [2- (hydroxymethyl) -4- (piperidinyl) -2-pyridinyl] -3- (benzyloxy);
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) nicotinonitrile trifluoroacetate;
7- (2-hydroxyphenyl) -5- (3-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one;
2-amino-6- [2- (cyclobutylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) nicotinnitril;
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] oxazine-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-naphthyridine-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-naphthyridine-2 (1H) -one;
Ehtyl-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'-bipyridine-3-ol;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (4-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one;
2-amino-6- [2- (benzyloxy) -6-hydroxyphenyl] -4- (3-piperidinyl) nicotinnitril;
2-Amino-6- (2-hydroxy-6-propoxyphenyl) -4- (3-piperidinyl) nicotinnitril;
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) nicotinonitrile trifluoroacetate;
7- (2-hydroxyphenyl) -5- (3-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one;
nicotinnitril 2-amino-6- [cyclobutylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl);
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] oxazine-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-naphthyridine-2 (1H) -one;
2- [6-amino-5- (hydroxymethyl) -4- (3-piperidinyl) -2-pyridinyl] -3- (cyclopropylmethyoxy) 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-naphthyridine-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'-bipyridine-3-ol;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (4-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -3-fluoro-5- (3-piperidinyl) -1,8-naphthyridine-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'-bipyridine-2'-yl] phenol;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl) -5- (3-piperidinyl) -1,8-naphthyridine-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-dihydro-pyrido [2,3-d] pyrimidin-2 (1H) -one;
2-Amino-6- [2-cyclopropylmethoxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinnitril;
2-Amino-4 - [2- (cyclopropylmethoxy) -6-hydroxyphenyl] [(2-aminoethyl) amino] -6- nicotinnitril;
N - {[2-amino-6- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl] methyl} -N'-propylurea;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (3-pi piperidinyl) -3,4-dihydro-pyrido [2,3-d] pyrimidin-2 (1H) -one;
Ethyl 2 [amino-6- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl] methylcarbamate;
nicotinnitril -4- (4-piperidinyl) - 2-Amino-6- {[(4-methylpentyl) oxy] phenyl 2-hydroxy-6};
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,2,3,4-tetrahydro-l, 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-dihydro-pyrido [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) nicotinnitril;
N-cyclohexyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide ;
2-amino-6- [2- (cyclobutylmethoxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinnitril;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -N, N-dimethyl-2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide;
2-amino-6- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (1-methyl-3-piperidinyl) nicotinnitril;
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide;
Isopropyl [[2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl 2-amino-6-] methylcarbamate;
Isopropyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate;
Isobutyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate;
Neopentyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate;
Neopentyl [[2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl 2-amino-6-] methylcarbamate;
2-amino-6- [2- (hexyloxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinonitrile and
7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -N-ethyl-2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide ,

Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen bevorzugt. Umfasst sind aber auch Salze, die für pharmazeutische Anwendungen selbst nicht geeignet sind aber beispielsweise für die Isolierung oder Reinigung der erfindungsgemäßen Verbindungen verwendet werden können.When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

Physiologisch unbedenkliche Salze der Verbindungen der Formel (I) umfassen Säureadditionssalze von Mineralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfonsäure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Trifluoressigsäure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure, Oxalsäure, p-Bromphenylsulfonsäure und Benzoesäure.physiological Safe salts of the compounds of formula (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid and Benzoic acid.

Physiologisch unbedenkliche Salze der Verbindungen der Formel (I) umfassen auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kaliumsalze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C-Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Methylmorpholin, Arginin, Lysin, Ethylendiamin und N-Methylpiperidin.physiological acceptable salts of the compounds of formula (I) also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, Prokain, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Die Verbindungen oder Salze dieser Erfindung können in Abhängigkeit ihrer Substituenten in niedrige Alky1- oder andere Ester und/oder ihre Hydrate oder andere Solvate umgewandelt werden. Diese Ester, Hydrate und Solvate sind im Rahmen der Erfindung eingeschlossen.The Compounds or salts of this invention may vary depending on their substituents in lower alky1 or other esters and / or their hydrates or other solvates are converted. These esters, hydrates and solvates are included within the scope of the invention.

Als Solvate werden im Rahmen der Erfindung solche Formen der erfindungsgemäßen Verbindungen bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungsmittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt.When Solvates are in the context of the invention, such forms of the compounds of the invention designated, which in solid or liquid state by coordination with solvent molecules one Complex form. Hydrates are a special form of solvate, at which is coordinated with water.

Im Rahmen der vorliegenden Erfindung haben die Substituenten, soweit nicht anders spezifiziert, die folgende Bedeutung:
Alkyl per se und "Alk" und "Alkyl" in Alkoxy und Alkylcarbonyloxy stehen für einen linearen oder verzweigten Alkylrest mit 1 bis 4 Kohlenstoffatomen, beispielhaft und vorzugsweise für Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl und tert-Butyl.Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se and "Alk" and "alkyl" in alkoxy and alkylcarbonyloxy represent 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 steht beispielhaft und vorzugsweise für Methoxy, Ethoxy, n-Propoxy, Isopropoxy, n-Butoxy und tert-Butoxy.alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy and tert-butoxy.

Alkylcarbonyloxy steht beispielhaft und vorzugsweise für Methylcarbonyloxy, Ethylcarbonyloxy, n-Propylcarbonyloxy, Isopropylcarbonyloxy, n-Butylcarbonyloxy und tert-Butylcarbonyloxy.alkylcarbonyloxy is exemplary and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, Isopropylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.

Cycloalkyl steht für eine mono- oder bicyclische Cycloalkylgruppe mit in der Regel 3 bis 7, bevorzugt 5 oder 6 Kohlenstoffatomen, beispielhaft und vorzugsweise für Cycloalkyl seien genannt Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl und Cycloheptyl.cycloalkyl stands for a mono- or bicyclic cycloalkyl group with usually 3 to 7, preferably 5 or 6 carbon atoms, by way of example and by way of example for cycloalkyl may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Cycloheptyl.

Heteroaryl steht für einen aromatischen monocyclischen Rest mit 5 oder 6 Ringatomen und bis zu 4, vorzugsweise bis zu 3 Heteroatomen aus der Reihe S, O und N, beispielhaft und vorzugsweise für Thienyl, Furyl, Pyrrolyl, Thiazolyl, Oxazolyl, Oxadiazolyl, Pyrazolyl, Imidazolyl, Triazolyl, Pyridyl, Pyrimidyl, Pyridazinyl und Pyrazinyl.heteroaryl stands for an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl, pyrrolyl, Thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, Pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.

Halogen steht für Fluor, Chlor, Brom und Jod, vorzugsweise für Fluor und Chlor.halogen stands for Fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Wenn Reste in den Verbindungen der Formel (I), ihre Salze, ihre Solvate oder die Solvate ihrer Salze substituiert sind, können die Reste, soweit nicht anders spezifiziert, ein- oder mehrfach gleich oder verschieden substituiert sein. Eine Substitution mit bis zu drei gleichen oder verschiedenen Substituenten ist bevorzugt. Ganz besonders bevorzugt ist die Substitution mit einem Substituenten.If Radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the Remainders, unless otherwise specified, one or more times the same or substituted differently. A substitution with up to three identical or different substituents are preferred. All particularly preferred is substitution with a substituent.

Die Herstellung der Verbindungen der Formel (I) ist bekannt und wird in der Literatur beschrieben.The Preparation of the compounds of the formula (I) is known and is described in the literature.

Arzneistoffen die zur Behandlung entzündlicher Hauterkrankungen eingesetzt werden können sind insbesondere Arzneimittel zur Behandlung von Dermatitis, Kontaktdermatitis, Kontaktallergie, Psoriasis und atopische Dermatitis.drugs the inflammatory for treatment Skin diseases can be used are especially drugs for the treatment of dermatitis, contact dermatitis, contact allergy, Psoriasis and atopic dermatitis.

Arzneistoffen die zur Behandlung von Hauttumoren eingesetzt werden können sind insbesondere Arzneimittel zur Behandlung z.B. Basaliome, Spinaliome, Melanome, kutane Manifestationen von T-Zell-Lymphomen, kutane Metastasen anderer Tumoren und deren Vorstufen wie z.B. aktinische Keratosen und Morbus Bowen.drugs which can be used to treat skin tumors in particular, medicaments for the treatment of e.g. Basaliomas, spinaliomas, Melanoma, cutaneous manifestations of T-cell lymphoma, cutaneous metastasis other tumors and their precursors such as e.g. actinic keratoses and Bowen's disease.

Bevorzugt sind Kombinationen von IKK-beta Inhibitoren mit folgenden Arzneistoffen:
Kortikosteroiden, Retinoiden (z.B. Acitretin), Cyclosprin, Methothrexat oder Fumarsäure Efalizumab, Etanercept, Onecerpt, Adalimumab, Infliximab, Pimecrolimus oder Tacrolimus Efomycinen bzw. Elaiophyllinen, Dacarbazin, Doxorubicin, Interferonen (z.B. Interferon alfa-2b, Intron-A), Imiquimod (Aldara, R-837, S-26308), Resiquimod (R-848, S-28436), Interleukin 2 (IL-2), therapeutische Melanom-Vakzinen (z.B. präparierte oder synthetische Antigene oder transfizierte Zellen), Temozolomid, Preferred are combinations of IKK-beta inhibitors with the following drugs:
Corticosteroids, retinoids (eg acitretin), cyclosprin, methothrexate or fumaric acid efalizumab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus or tacrolimus efomycins or elaiophyllines, dacarbazine, doxorubicin, interferons (eg interferon alfa-2b, intron A), imiquimod ( Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2), therapeutic melanoma vaccines (eg, prepared or synthetic antigens or transfected cells), temozolomide,

Eine Kombinierte Anwendung von IKK-beta Inhibitoren oder den erfindungsgemäßen Arzneimittelkombinationen mit Radiotherapien, Bestrahlungstherapie mit sichtbarem Licht, ionisierender Strahlung, UV-Strahlung, photodynamischer Therapie zeigt ebenfalls einen überraschend guten Therapieerfolg.A Combined use of IKK-beta inhibitors or the drug combinations according to the invention with radiotherapy, radiation therapy with visible light, ionizing Radiation, UV radiation, photodynamic therapy also shows a surprise good therapy success.

Insbesondere wurde gefunden, dass die erfindungsgemäßen Arzneimittelkombinationen zur Behandlung von Kontaktdermatitis, Kontaktallergie, Psoriasis, Dermatitis, atopischer Dermatitis, diskoidem Lupus erythematodes und/oder von Ekzemen und zur Behandlung von Hauttumoren wie z.B. Basaliome, Spinaliome, Melanome, kutane Manifestationen von T-Zell-Lymphomen, kutane Metastasen anderer Tumore und ihrer Vorstufen, wie insbesondere aktinische Keratosen und Morbus Bowen, eingesetzt werden können.Especially it was found that the drug combinations according to the invention for the treatment of contact dermatitis, contact allergy, psoriasis, Dermatitis, atopic dermatitis, discoid lupus erythematosus and / or eczema and for the treatment of skin tumors, such as Basaliomas, spinaliomas, melanomas, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumors and their precursors, in particular actinic Keratoses and Bowen's disease, can be used.

Die Behandlung erfolgt vorzugsweise systemisch und/oder topisch. Bei einer systemischen Behandlung kann die Applikation des Wirkstoffes oral mit Tabletten, Säften, Emulsionen, Kapseln oder anderen pharmazeutischen Zubereitungen erfolgen. Eine systemische Behandlung kann auch parenteral (intravenös, subkutan) erfolgen. Die topische Behandlung erfolgt durch Auftragen des Wirkstoffes in geeigneten Formulierungen auf die befallene Haut (Hautläsion) oder in die Nähe der zu behandelnden Hautläsionen. Die verwendeten Formulierungen können Salben, Cremes, Puder, Emulsionen, Lösungen sein. Darüber hinaus können mit Wirkstoff imprägnierte Pflaster oder Verbände verwendet werden. Die systemische und/oder topische Behandlung kann nach verschiedenen zeitlichen Schemata erfolgen (einmalige Behandlung bis zu mehrfach täglich über einen festgelegten Zeitraum).The Treatment is preferably systemic and / or topical. at a systemic treatment may be the application of the drug orally with tablets, juices, Emulsions, capsules or other pharmaceutical preparations respectively. Systemic treatment may also be parenteral (intravenous, subcutaneous) respectively. The topical treatment is carried out by applying the active ingredient in appropriate formulations on the affected skin (skin lesion) or in the vicinity the skin lesions to be treated. The formulations used can Ointments, creams, powders, emulsions, solutions. Furthermore can impregnated with active ingredient Plasters or bandages be used. The systemic and / or topical treatment may be after different temporal schemes take place (one-time treatment up to several times a day over one fixed period).

Bevorzugt ist die topische Behandlung von Entzündungen des Auges (Keratitis, Uveitis, Retinitis) und des Ohres sowie die Behandlung von Tumoren des Auges und Metastasen anderer Tumoren am Auge sowie von Tumoren des Ohres (und Metastasen anderer Tumoren am Ohr) und von Tumoren der äußeren Genitalien (und Metastasen anderer Tumoren an den äußeren Genitalien) Dies schließt Tumoren, die durch Virusinfektionen hervorgerufen werden (z.B. durch Infektion mit unterschiedlichen Typen des humanen Papillomvirus hervorgerufene Genitalwarzen, Kaposisarkome der Haut und Schleimhaut, Epidermodysplasia verucciformis oder andere neoplastischen Veränderungen) ein und die Topische Behandlung von Tumoren des Urogenitalsystems z.B. durch Instillation einer Lösung oder einer Suspension der erfindungsgemäßen Arzneimittelkombination oder anderen geeigneten pharmazeutischen Zubereitungen der erfindungsgemäßen Arzneimittelkombination (z.B. Emulsionen, Gelen).Prefers is the topical treatment of inflammation of the eye (keratitis, Uveitis, retinitis) and the ear as well as the treatment of tumors of the eye and metastases of other tumors on the eye as well as tumors of the ear (and metastases of other tumors on the ear) and tumors the external genitals (and metastasis of other tumors on the external genitalia) This includes tumors, which are caused by viral infections (e.g., by infection with different types of human papillomavirus Genital warts, Kaposisarkome of the skin and mucous membrane, epidermodysplasia verucciformis or other neoplastic changes) and the topicals Treatment of tumors of the genitourinary system e.g. by instillation a solution or a suspension of the drug combination according to the invention or other suitable pharmaceutical preparations of the drug combination of the invention (e.g. Emulsions, gels).

Claims (8)

Arzneimittelkombination enthaltend mindestens einen IKK-beta Inhibitor sowie mindestens einen Arzneistoff der zur Behandlung von entzündlichen Hauterkrankungen oder von Hauttumoren eingesetzt werden kann.Drug combination containing at least an IKK-beta inhibitor and at least one drug of the for the treatment of inflammatory skin diseases or of skin tumors. Arzneimittelkombination gemäß Anspruch 1, enthaltend als IKK-beta Inhibitor eine Verbindung der Formel (I)
Figure 00110001
und deren Salze in welcher R1 für eine Gruppe der Formel
Figure 00110002
steht, wobei * für die Anknüpfstelle an den Pyridinring steht, R11 für Wasserstoff, C1-12-Alkoxy oder -O-(CH2)n-R111 steht, worin n für 1 bis 6 steht und R111 für Phenyl, C3-8-Cycloalkyl steht, R2 für Wasserstoff steht, R3 für 1,2,3,6-Tetrahydropyridin, -CR31R32R33, worin R31 für Wasserstoff steht, und R32 und R33 zusammen mit dem angrenzenden Kohlenstoff einen 5- bis 8-gliedrigen gesättigten Ring bilden, der NH enthält. Dieser Ring kann substituiert sein durch Phenyl-C1-6-alkyl, C1-6-Alkoxy substituiertes Phenyl-C1-6-alkyl, C1-6-Alkyl, Amino, Carboxy, C1-6-Alkylamino, C1-6-Alkoxycarbonyl, Di(C1-6-Alkyl)-amino, Benzylamino, C1-6-Alkylsulfonyl, Piperidin-C1-6-alkylcarbonyl oder gegebenenfalls ankondensiertes Benzol; oder -NR34R35 steht, worin R34 für Wasserstoff und R35 für -(CH2)m-NR351R352 (m steht für 1 bis 6) worin R351 für Wasserstoff oder C1-6-Alkyl und R352 für Wasserstoff, C1-6-Alkyl, C1-6-Alkanoyl, C1-6-A1kyl-substituiertes Phenyl, Benzoyl, C1-6-Alkanoyl, Phenylaminocarbonyl oder Phenylsulfonyl steht und R4 für Cyano, C1-6-Alkyl, welches gegebenenfalls durch Hydroxy oder C1-6-Alkoxy substituiert sein kann oder -(CH2)pNHCOR41, -(CH2)pNHC(=S)R41, worin p für 1 bis 6 steht und R41 für C1-6-Alkoxy, Amino, Phenylamino, C1-6-Alkyl, C1-6-Alkylamino, Di(C1-6-alkyl)amino oder C3-10-Cycloalkylamino steht, R5 für Amino steht oder R4 und R5 können zusammen -R40-CO-NH, R40-SO2-NH-, R40-C(=S)-NH- oder R40-CH2-NH- sein, worin R40 für -CHR401-O-, -CH2-NR401-, -CO-NR401-, worin R401 für Wasserstoff, C1-6-Alkanoyl, C1-6-Alkoxycarbonyl, C1-6-Alkyl, Phenyl, C1-6-Alkylsulfonyl, C3-8-Cycloalkylaminocarbonyl, C1-6-Alkylaminocarbonyl, Carbamoyl, Di-(C1-6-alkyl)-aminocarbonyl, oder für -CH2-CHR402-, -CH=CR402-, worin R402 für Wasserstoff, Halogen, Nitro, Amino, Cyano, Benzoylamino, Phenylsulfonyl, Carbamoyl, Hydroxycarbonyl, C1-6-Alkoxycarbonyl, C1-12-Alkylaminocarbonyl, Halogen-substituiertes 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, Morpholinocarhonyl, Piperazinocarbonyl, Phenyl-C1-6-alkylaminocarbonyl, C3-8-Cycloalkylaminocarbonyl, Hydroxycarbonyl-C1-6-alkylaminocarbonyl, C3-8-Cycloalkyl-C1-6-alkylaminocarbonyl, Hydroxy-C1-6-alkylaminocarbonyl, Carboxyethylaminocarbonyl, Methylsulfonylaminocarbonyl steht, oder -CR41=N-NH-, worin R41 für Hydroxy, Amino, C1-6-Alkanoylamino oder -CR42=N-C=N, worin R42 für Amino steht und deren Salze, Solvate und die Solvate der Salze.Medicament combination according to Claim 1, containing as IKK-beta inhibitor a compound of the formula (I)
Figure 00110001
and their salts in which R 1 is a group of the formula
Figure 00110002
where * is the point of attachment to the pyridine ring, R 11 is hydrogen, C 1-12 -alkoxy or -O- (CH 2 ) n -R 111 , where n is 1 to 6 and R 111 is phenyl, C 3-8 -cycloalkyl, R 2 is hydrogen, R 3 is 1,2,3,6-tetrahydropyridine, -CR 31 R 32 R 33 , wherein R 31 is hydrogen, and R 32 and R 33 together with form the contiguous carbon 5- to 8-membered saturated ring containing NH. This ring may be substituted by phenylC 1-6 alkyl, C 1-6 alkoxy substituted phenylC 1-6 alkyl, C 1-6 alkyl, amino, carboxy, C 1-6 alkylamino, C 1-6 alkoxycarbonyl, di (C 1-6 alkyl) amino, benzylamino, C 1-6 alkylsulfonyl, piperidine C 1-6 alkylcarbonyl or optionally fused benzene; or -NR 34 R 35 , where R 34 is hydrogen and R 35 is - (CH 2 ) m -NR 351 R 352 (m is 1 to 6) in which R 351 is hydrogen or C 1-6 -alkyl and R 352 is hydrogen, C 1-6 -alkyl, C 1-6 -alkanoyl, C 1-6 -alkyl-substituted phenyl, benzoyl, C 1-6 -alkanoyl, phenylaminocarbonyl or phenylsulfonyl, and R 4 is cyano, C 1 6 -alkyl, which may optionally be substituted by hydroxy or C 1-6 alkoxy or - (CH 2 ) p NHCOR 41 , - (CH 2 ) p NHC (= S) R 41 , wherein p is 1 to 6 and R 41 is C 1-6 alkoxy, amino, phenylamino, C 1-6 alkyl, C 1-6 alkylamino, di (C 1-6 alkyl) amino or C 3-10 cycloalkylamino, R 5 is Amino or R 4 and R 5 may together be -R 40 -CO-NH, R 40 -SO 2 -NH-, R 40 -C (= S) -NH- or R 40 -CH 2 -NH-, wherein R 40 is -CHR 401 -O-, -CH 2 -NR 401 -, -CO-NR 401 -, in which R 401 is hydrogen, C 1-6 -alkanoyl, C 1-6 -alkoxycarbonyl, C 1-6 - Alkyl, phenyl, C 1-6 -alkylsulfonyl, C 3-8 -cycloalkylaminocarbonyl, C 1- 6- alkylaminocarbonyl, carbamoyl, di- (C 1-6 -alkyl) -aminocarbonyl, or for -CH 2 -CHR 402 -, -CH = CR 402 -, in which R 402 represents hydrogen, halogen, nitro, amino, cyano, Benzoylamino, phenylsulfonyl, carbamoyl, hydroxycarbonyl, C 1-6 -alkoxycarbonyl, C 1-12 -alkylaminocarbonyl, halo-substituted C 1-6 -alkylaminocarbonyl, C 1-6 -alkanoylamino, C 1-6 -alkylamino, di- (C 1-6 alkyl) -aminocarbonyl, di (C 1-6 alkyl) amino C 1-6 alkylaminocarbonyl, hydroindenylaminocarbonyl, diphenylmethylaminocarbonyl, pyrrolidinocarbonyl, C 1-6 alkoxyC 1-6 alkylaminocarbonyl, morpholinocarhonyl , Piperazinocarbonyl, phenylC 1-6 alkylaminocarbonyl, C 3-8 cycloalkylaminocarbonyl, hydroxycarbonylC 1-6 alkylaminocarbonyl, C 3-8 cycloalkylC 1-6 alkylaminocarbonyl, hydroxyC 1-6 alkylaminocarbonyl , Carboxyethylaminocarbonyl, methylsulfonylaminocarbonyl, or -CR 41 = N-NH-, where R 41 is hydroxy, amino, C 1-6 alkanoylamino or -CR 42 = NC = N, where R 42 is amino and its salts, S olvate and the solvates of salts. Arzneimittelkombination gemäß Anspruch 1, enthaltend als IKK-beta Inhibitor 7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on; 2-Amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril; 2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinnitril; 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-on; 2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril trifluoracetat; 7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on; 2-Amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril; 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-on; Ethyl-7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat; 7-(2-Hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on; 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-naphthydrin-2(1H)-on; Ehtyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on; 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-naphthydrin-2(1H)-on; 2-Amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril; 2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinnitril; 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-on; 2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril trifluoracetat; 7-(2-Hydroxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on; 2-Amino-6-[cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinnitril; 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-on; Ethyl-7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat; 7-(2-Hydroxy-6-propoxyphenyl)-5-(3-piperidinyl)-3,4-dihydro-1,8-naphthydrin-2(1H)-on; 2-[6-Amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethyoxy)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-naphthydrin-2(1H)-on; Ethyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxylat; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on; 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-naphthydrin-2(1H)-on; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-3-fluor-5-(3-piperidinyl)-1,8-naphthydrin-2(1H)-on; 7-(2-Hydroxy-6-propoxyphenyl)-5-(4-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-on; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2on; 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-naphthydrin-2(1H)-on; N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}acetamid; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthydrin-3-carboxamid; 3-Acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-on; 2-Amino-6-[2-cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril; 2-Amino-4-[(2-aminoethyl)amino]-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]nicotinnitril; N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}-N'-propylharnstoff; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-on; Ethyl-2[amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat; 2-Amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinnitril; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,2,3,4-tetrahydro-1,8-naphthydrin-3-carboxamid; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N-isopropyl-2-oxo-5-(3-piperidinyl)-1,2-dihydro-1,8-naphthydrin-3-carboxamid; Ethyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat; N-{[2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}harnstoff; 2-Amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinnitril; N-Cyclohexyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid; 2-Amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N,N-dimethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid; 2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinnitril; 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid; Isopropyl-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat; Isopropyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat; Isobutyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat; Neopentyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxylat; Neopentyl-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamat; 2-Amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinnitril und 7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-N-ethyl-2-oxo-5-(3-piperidinyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-carboxamid und/oder deren Salze, Solvate und Solvate der Salze.Drug combination according to claim 1, containing as IKK-beta inhibitor 7- (2-hydroxyphenyl) -5- (3-piperidinyl) -1,4-dihydro-2H-pyrido [2,3-d] [1,3] oxazine 2-one; 2-amino-6- [2- (benzyloxy) -6-hydroxyphenyl] -4- (3-piperidinyl) nicotinnitril; 2-Amino-6- (2-hydroxy-6-propoxyphenyl) -4- (3-piperidinyl) nicotinnitril; phenol 2- [6-amino-5- [2- (hydroxymethyl) -4- (piperidinyl) 2-pyridinyl] -3- (benzyloxy); 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) nicotinonitrile trifluoroacetate; 7- (2-hydroxyphenyl) -5- (3 piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one; 2-amino-6- [2- (cyclobutylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) nicotinnitril; 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] oxazine-2-one; Ethyl 7- (2-hydroxy-6-propoxyphenyl) -2-oxo-5- (3-piperidinyl) -1,2,3,4-tetrahydro-1,8-naphthyridine-3-carb ethoxylate; 7- (2-hydroxy-6-propoxyphenyl) -5- (3-piperidinyl) -3,4-dihydro-1,8-naphthyridine-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-naphthyridine-2 (1H) -one; Ehtyl-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'-bipyridine-3-ol; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (4-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one; 2-amino-6- [2- (benzyloxy) -6-hydroxyphenyl] -4- (3-piperidinyl) nicotinnitril; 2-Amino-6- (2-hydroxy-6-propoxyphenyl) -4- (3-piperidinyl) nicotinnitril; 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) nicotinonitrile trifluoroacetate; 7- (2-hydroxyphenyl) -5- (3-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one; nicotinnitril 2-amino-6- [cyclobutylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl); 2- [6-amino-5- (hydroxymethyl) -4- (3-piperidinyl) -2-pyridinyl] -3-propoxyphenol; 7- (2-hydroxy-6-propoxyphenyl) -5- (3-piperidinyl) -1,4--2H-pyrido dihydro [2,3-e] [1,3] oxazine-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-naphthyridine-2 (1H) -one; 2- [6-amino-5- (hydroxymethyl) -4- (3-piperidinyl) -2-pyridinyl] -3- (cyclopropylmethyoxy) 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-naphthyridine-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'-bipyridine-3-ol; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (4-piperidinyl) -3,4-dihydro-1,8-naphthyridine-2 (1H) -one; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -3-fluoro-5- (3-piperidinyl) -1,8-naphthyridine-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'-bipyridine-2'-yl] phenol; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -5- (3-piperidinyl) -1,8-naphthyridine-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-dihydro-pyrido [2,3-d] pyrimidin-2 (1H) -one; 2-Amino-6- [2-cyclopropylmethoxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinnitril; 2-Amino-4 - [2- (cyclopropylmethoxy) -6-hydroxyphenyl] [(2-aminoethyl) amino] -6- nicotinnitril; 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-dihydro-pyrido [2,3-d] pyrimidin-2 (1H) -one; Ethyl 2 [amino-6- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl] methylcarbamate; nicotinnitril -4- (4-piperidinyl) - 2-Amino-6- {[(4-methylpentyl) oxy] phenyl 2-hydroxy-6}; 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-dihydro-pyrido [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) nicotinnitril; N-cyclohexyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide ; 2-amino-6- [2- (cyclobutylmethoxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinnitril; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -N, N-dimethyl-2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide; 2-amino-6- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (1-methyl-3-piperidinyl) nicotinnitril; 7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl nyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxamide; Isopropyl [[2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl 2-amino-6-] methylcarbamate; Isopropyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate; Isobutyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate; Neopentyl-7- [2- (cyclopropylmethoxy) -6-hydroxyphenyl] -2-oxo-5- (3-piperidinyl) -1,4-dihydro-pyrido [2,3-d] pyrimidine-3 (2H) -carboxylate; Neopentyl [[2- (cyclopropylmethoxy) -6-hydroxyphenyl] -4- (3-piperidinyl) -3-pyridinyl 2-amino-6-] methylcarbamate; 2-Amino-6- [2- (hexyloxy) -6-hydroxyphenyl] -4- (4-piperidinyl) nicotinonitrile 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. Arzneimittelkombination gemäß Anspruch 1, enthaltend als weiteren Arzneistoff Arzneimittel zur Behandlung von Dermatitis, Kontaktdermatuitis, Kontaktallergie, Psoriasis und atopische Dermatitis.Medicament combination according to claim 1, containing as another drug for the treatment of dermatitis, Contact dermatitis, contact allergy, psoriasis and atopic dermatitis. Arzneimittelkombination gemäß Anspruch 1, enthaltend als weiteren Arzneistoff Arzneimittel zur Behandlung z.B. Basaliome, Spinaliome, Melanome, kutane Manifestationen von T-Zell-Lymphomen, kutane Metastasen anderer Tumoren und deren Vorstufen wie z.B. aktinische Keratosen und Morbus Bowen.Medicament combination according to claim 1, containing as another drug, medicaments for the treatment of e.g. basal cell carcinomas, Spinaliomas, melanomas, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumors and their precursors, e.g. actinic Keratoses and Bowen's disease. Arzneimittelkombination gemäß Anspruch 1, enthaltend als weiteren Arzneistoff Kortikosteroide, Retinoiden (z.B. Acitretin), Cyclosprin, Methothrexat oder Fumarsäure Efalizumab, Etanercept, Onecerpt, Adalimumab, Infliximab, Pimecrolimus oder Tacrolimus Efomycinen bzw. Elaiophyllinen, Dacarbazin, Doxorubicin, Interferonen (z.B. Interferon alfa-2b, Intron-A), Imiquimod (Aldara, R-837, S-26308), Resiquimod (R-848, 5-28436), Interleukin 2 (IL-2), therapeutische Melanom-Vakzinen (z.B. präparierte oder synthetische Antigene), Temozolomid.Medicament combination according to claim 1, containing as another drug corticosteroids, retinoids (e.g., acitretin), Cyclosprin, methothrexate or fumaric acid efalizumab, etanercept, Onecerpt, adalimumab, infliximab, pimecrolimus or tacrolimus efomycins or elaiophyllines, dacarbazine, doxorubicin, interferons (e.g. Interferon alfa-2b, intron A), imiquimod (Aldara, R-837, S-26308), Resiquimod (R-848, 5-28436), Interleukin 2 (IL-2), melanoma therapeutic vaccines (e.g., Prepared or synthetic antigens), temozolomide. Arzneimittelkombinationen wie in den Ansprüchen 1 bis 6 definiert, zur topischen Behandlung.Pharmaceutical combinations as in claims 1 to 6 defined for topical treatment. Arzneimittelkombinationen wie in den Ansprüchen 1 bis 6 definiert, zur topischen Behandlung von entzündlichen Hauterkrankungen und zur Behandlung von Tumoren des Auges und Metastasen anderer Tumoren am Auge, von Tumoren des Ohres und Metastasen anderer Tumoren am Ohr, von Tumoren der äußeren Genitalien und Metastasen anderer Tumoren an den äußeren Genitalien sowie Tumoren des Urogenitalsystems.Pharmaceutical combinations as in claims 1 to 6 defines, for the topical treatment of inflammatory skin diseases and for the treatment of tumors of the eye and metastases of other tumors on the eye, tumors of the ear and metastases of other tumors on the Ear, from tumors of the external genitalia and metastases of other tumors on the outer genitalia and tumors of the Genitourinary.
DE102005036656A 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 Withdrawn DE102005036656A1 (en)

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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
EP06776386A EP1912646A2 (en) 2005-08-04 2006-07-25 Combinations containing ikk-beta inhibitors
CA002617692A CA2617692A1 (en) 2005-08-04 2006-07-25 Combinations containing ikk-.beta. inhibitors
JP2008524397A JP2009502996A (en) 2005-08-04 2006-07-25 Combination with IKK-β inhibitor
PCT/EP2006/007299 WO2007014671A2 (en) 2005-08-04 2006-07-25 Combinations containing ikk-beta inhibitors

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