HK1049671B - Substituted indoles - Google Patents

Description

Substituted indoles

The present invention relates to substituted indoles, processes for their preparation and their use as pharmaceuticals.

Patent application WO 94/12478 describes indole derivatives that inhibit platelet aggregation. WO 94/08962 describes fibrinogen receptor antagonists which inhibit fibrinogen binding and platelet aggregation.

NF-. kappa.B is a heterodimeric transcription factor that activates a number of genes encoding proinflammatory cytokines, such as IL-1, IL-2, TNF. alpha. or IL-6. NF κ B is present in the cytosol of cells, complexed with its naturally occurring inhibitor, I κ B. Cells are stimulated, for example, by cytokines, leading to phosphorylation and subsequent proteolytic degradation of I.kappa.B. This proteolytic degradation causes activation of NF κ B, which then migrates into the nucleus where a number of pro-inflammatory genes are activated.

In disorders such as rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, myocardial infarction, alzheimer's disease or atherosclerosis, nfkb is activated beyond normal. Inhibition of NF κ B is also beneficial in cancer therapy because it is used for potentiation of cytostatic therapy. It is possible to show that drugs such as glucocorticoids, salicylates or gold salts used in rheumatism therapy interfere in an inhibitory manner with different points of the NF-. kappa.B-activation signal chain or directly with the transcription of genes.

The first step of the signaling cascade is the degradation of I κ B. This phosphorylation is regulated by specific I κ B kinases. No inhibitors are known to date to specifically inhibit I κ B kinase.

In an effort to obtain active compounds for the treatment of rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, myocardial infarction, alzheimer's disease, cancerous disorders (potentiation of cytotoxic therapy) or atherosclerosis, it has now been found that the indole derivatives according to the invention are potent and very specific inhibitors of ikb kinase.

The invention therefore relates to compounds of the formula I

And/or stereoisomeric forms of the compounds of the formula I and/or physiologically acceptable salts of the compounds of the formula I, in which the substituent R¹、R²、R³And R⁴One of which is a group of the formula II

Wherein

D is-C (O) -, -S (O) -or-S (O)₂-，

R⁷Is hydrogen or- (C)₁-C₄) -an alkyl group,

R⁸is R⁹Or a characteristic group of an amino acid,

R⁹is an aryl group, wherein the aryl group is unsubstituted or substituted,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

3. a heterocycle having 5 to 12 ring members wherein the heterocycle is unsubstituted or substituted, or

4.-(C₁-C₆) -alkyl, wherein alkyl is linear or branched and is unsubstituted or mono-, di-or tri-substituted independently of each other by:

4.1 aryl, wherein aryl is unsubstituted or substituted,

4.2 heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

4.3 heterocyclic rings having 5 to 12 ring members, where the heterocyclic ring is unsubstituted or substituted,

4.4 -O-R¹⁰，

4.5 ＝O，

4.6 of a halogen,

4.7 -CN，

4.8 -CF₃，

4.9 -S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

4.10 -C(O)-O-R¹⁰，

4.11 -C(O)-N(R¹⁰)₂，

4.12 -N(R¹⁰)₂，

4.13 -(C₃-C₆) -RingAn alkyl group, a carboxyl group,

4.14 radicals of the formula

Or

4.15 radicals of the formula

R¹⁰Is a) a hydrogen atom, and is,

b)-(C₁-C₆) -an alkyl group, wherein the alkyl group is unsubstituted or mono-to trisubstituted, independently of each other, by the following substituents:

1. an aryl group, a heteroaryl group,

2. heteroaryl having 5 to 14 ring members,

3. a heterocyclic ring having 5 to 12 ring members,

4. the halogen(s) are selected from the group consisting of,

5.-N-(C₁-C₆)_n-alkyl, wherein n is the integer 0, 1 or 2, alkyl being unsubstituted or mono-, di-or tri-substituted independently of each other by halogen or-C (O) -OH, or

6.-C(O)-OH，

c) An aryl group, a heteroaryl group,

d) heteroaryl having 5 to 14 ring members, or

e) A heterocycle having 5 to 12 ring members, and

in (R)¹⁰)₂In the case of (1), R¹⁰Independently of one another have the meanings a) to e),

z is 1. aryl, wherein aryl is unsubstituted or substituted,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

3. a heterocycle having 5 to 12 ring members wherein the heterocycle is unsubstituted or substituted, or

4.-C(O)-R¹¹Wherein

R¹¹Is 1.-O-R¹⁰Or is or

2.-N(R¹⁰)₂Or is or

R⁷And R⁸Together with the nitrogen atom to which they are each bound, and the carbon atom form a heterocycle of the formula IIa

Wherein D, Z and R¹¹Is as defined in formula II,

a is a nitrogen atom or a group-CH₂-，

B is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

X is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

Y is absent or is an oxygen atom, a sulfur atom, a sulfoatom or a group-CH₂-, or

X and Y together form a phenyl, 1, 2-diazine, 1, 3-diazine or 1, 4-diazine group,

wherein the ring system formed by N, A, X, Y, B and the carbon atoms contains not more than one oxygen atom, if A is a nitrogen atom, X is not an oxygen atom, a sulfur atom or a nitrogen atom, contains not more than one sulfur atom, contains 1, 2, 3 or 4 nitrogen atoms, oxygen and sulfur atoms are not present at the same time,

wherein the ring system formed by N, A, X, Y, B and carbon atoms is unsubstituted or independently of one another by- (C)₁-C₈) Alkyl mono-to trisubstituted, unsubstituted or mono-to trisubstituted by the following substituentsDi-substitution:

1.1.-OH，

1.2.-(C₁-C₈) -an alkoxy group,

1.3. the halogen(s) are selected from the group consisting of,

1.4.-NO₂，

1.5.-NH₂，

1.6.-CF₃，

1.7. a methylene-dioxy group,

1.8.-C(O)-CH₃，

1.9.-CH(O)，

1.10.-CN，

1.11.-C(O)-OH，

1.12.-C(O)-NH₂，

1.13.(C₁-C₄) -an alkoxycarbonyl group, a carbonyl halide group,

1.14. a phenyl group,

1.15. a phenoxy group,

1.16. a benzyl group, a phenyl group,

1.17. a benzyloxy group,

1.18. tetrazolyl, or

1.19.-OH，

R⁸And Z together with the carbon atom to which they are each bonded form a heterocycle of formula IIc

Wherein

D、R⁷And R¹⁰Is as defined in formula II,

t is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

W is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

V is absent or is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-, or

T and V or V and W together form a phenyl, 1, 2-diazine, 1, 3-diazine or 1, 4-diazine group,

wherein the ring system formed by N, T, V, W and two carbon atoms contains no more than one oxygen atom, no more than one sulfur atom and 1, 2, 3 or 4 nitrogen atoms, wherein the oxygen and sulfur atoms are not present at the same time,

wherein the ring system formed by N, T, V, W and two carbon atoms is unsubstituted or mono-to trisubstituted, independently of one another, by substituents as defined under 1.1 to 1.19 above,

other substituents R¹、R²、R³And R⁴Independently of each other are

1. The presence of hydrogen in the presence of hydrogen,

2. the halogen(s) are selected from the group consisting of,

3. aryl, wherein aryl is unsubstituted or substituted,

4. heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

5. a heterocycle having 5 to 12 ring members, wherein the heterocycle is unsubstituted or substituted,

6.-(C₁-C₆) -an alkyl group,

7.-CN，

8.-O-R¹⁰，

9.-N(R¹⁰)₂，

10.-S(O)x-R¹⁰wherein x is an integer of 0, 1 or 2, or

11.-CF₃，

R⁵Is a mixture of 1. hydrogen,

2.-OH, or

3.＝O，

R⁶Is an aryl group, wherein the aryl group is unsubstituted or substituted,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or mono-to trisubstituted, or

3. A heterocycle having 5 to 12 ring members wherein the heterocycle is unsubstituted or mono-to tri-substituted.

In a preferred compound of the formula I,

substituent R¹、R²、R³And R⁴One of which is a radical of the formula II in which

D is-C (O) -,

R⁷is hydrogen or- (C)₁-C₄) -an alkyl group,

R⁸is 1- (C)₁-C₄) -alkyl, wherein the alkyl is linear or branched, mono-or di-substituted independently of each other by the following substituents:

1.1 heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

1.2 heterocyclic rings having 5 to 12 ring members, where the heterocyclic ring is unsubstituted or substituted,

1.3-O-R¹⁰，

1.4-S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

1.5-N(R¹⁰)₂，

1.6 radicals of the formula

Or

1.7 radicals of the formula

Or

2. The characteristic groups of the amino acids are,

R⁹is 1.R⁸，

2.-(C₁-C₄) -alkyl, wherein alkyl is linear or branched and is mono-, di-or tri-substituted independently of each other by the following substituents:

2.1 aryl, wherein aryl is unsubstituted or substituted,

2.2 of the halogen, in the presence of hydrogen,

2.3-CN, or

2.4-CF₃Or is or

3. Aryl, wherein aryl is unsubstituted or substituted,

R¹⁰is a) a hydrogen atom, and is,

b)-(C₁-C₆) -an alkyl group, wherein the alkyl group is unsubstituted or mono-to trisubstituted, independently of each other, by the following substituents:

1. an aryl group, a heteroaryl group,

2. heteroaryl having 5 to 14 ring members,

3. a heterocyclic ring having 5 to 12 ring members,

4. the halogen(s) are selected from the group consisting of,

5.-N-(C₁-C₆)_n-alkyl, wherein n is the integer 0, 1 or 2, alkyl being unsubstituted or mono-, di-or tri-substituted independently of each other by halogen or-C (O) -OH, or

6.-C(O)-OH，

c) An aryl group, a heteroaryl group,

d) heteroaryl having 5 to 14 ring members, or

e) A heterocycle having 5 to 12 ring members, and

in (R)¹⁰)₂In the case of (1), R¹⁰Independently of one another have the meanings a) to e),

z is 1.1, 3, 4-oxadiazole, wherein the 1, 3, 4-oxadiazole is unsubstituted or substituted by-NH₂OH or- (C)₁-C₄) -alkyl is mono-to tri-substituted, or

2.-C(O)-R¹¹Wherein

R¹¹Is 1.-O-R¹⁰Or is or

2.-N(R¹⁰)₂Or is or

R⁷And R⁸The nitrogen atom to which they are each bonded together with a carbon atom forming a ring of formula IIa selected from the group consisting of pyrrole, pyrroline, indole, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, purine, isoxazole, 2-isoxazolidine, morpholine, isothiazole, thiazole, thiadiazole, benzimidazole, thiomorpholine, isothiazolidine, indazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, pteridine, tetrahydroquinoline, isoquinoline, 1, 2, 3, 5-oxathiadiazole 2-oxide, tetrazole, oxadiazolone, isoxazolone, triazolone, oxadiazolidinedione, F, -CN, -CF₃or-C (O) -O- (C)₁-C₄) -alkyl-substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazole and tetrahydroisoquinoline, or

R⁸And Z together with the carbon atom to which they are each bonded form a ring of formula IIc selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazolePyrazoline, 1, 3, 4-oxadiazole, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, tetrazole, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline, triazolone, tetrahydroisoquinoline, 1, 2, 3, 5-oxathiadiazole 2-oxide, oxadiazolone, isoxazolidone, oxadiazolidinedione, cinnoline, cinn₃or-C (O) -O- (C)₁-C₄) -alkyl substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazoles and isoquinolines,

other substituents R¹、R²、R³And R⁴Independently of each other are

1. The presence of hydrogen in the presence of hydrogen,

2. the halogen(s) are selected from the group consisting of,

3. aryl, wherein aryl is unsubstituted or substituted,

4. heteroaryl having 5 to 14 ring members, wherein heteroaryl is unsubstituted or substituted,

5. a heterocycle having 5 to 12 ring members, wherein the heterocycle is unsubstituted or substituted,

6.-(C₁-C₆) -an alkyl group,

7.-CN，

8.-CF₃，

9.-O-R¹⁰，

10.-N(R¹⁰)₂or is or

11.-S(O)_x-R¹⁰Wherein x is an integer of 0, 1 or 2,

R⁵is a hydrogen atom, and is,

R⁶is 1. phenyl, mono-or di-substituted independently of each other by the following substituents:

1.1-CN，

1.2-CF₃or is or

1.3 of a halogen,

1.4-O-R¹⁰，

1.5-N(R¹⁰)₂，

1.6-NH-C(O)-R¹¹，

1.7-S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

1.8-C(O)-R¹¹or is or

1.9-(C₁-C₄) -alkyl-NH₂，

2. Heteroaryl having 5 to 14 ring members, wherein the heteroaryl is unsubstituted or mono-, di-or trisubstituted, independently of one another, by substituents as defined under 1.1 to 1.9 above, or

3. Heterocycle having 5 to 12 ring members, wherein the heterocycle is unsubstituted or mono-, di-or tri-substituted independently of each other by substituents as defined under 1.1 to 1.9 above.

Among the particularly preferred compounds of formula I,

substituent R¹、R²、R³And R⁴One of which is a radical of the formula II in which

D is-C (O) -,

R⁷is a hydrogen atom, and is,

z is-C (O) -OH or-C (O) -NH₂，

R⁸Is 1- (C)₁-C₄) -alkyl, wherein the alkyl is linear or branched, mono-or di-substituted independently of each other by the following substituents:

1.1-S(O)-R¹⁰wherein R is¹⁰Is as defined in the following, and is,

1.2-N(R¹⁰)₂wherein R is¹⁰Is as defined below, or

1.3 pyrrole, or

2. The characteristic groups of the amino acids are,

R¹⁰is a) a hydrogen atom, and is,

b)-(C₁-C₆) Alkyl, wherein the alkyl is unsubstituted or mono-to trisubstituted independently of one another by halogen,

c) phenyl, wherein the phenyl is unsubstituted or independently of one another is halogen or- (C)₁-C₄) -alkyl mono-to tri-substituted,

in (R)¹⁰)₂In the case of (1), R¹⁰Independently of one another have the meanings a) to c),

other substituents R¹、R²、R³And R⁴In each case hydrogen, is present in the reaction mixture,

R⁵is a hydrogen atom, and is,

R⁶is a phenyl group or a pyridine group,

R⁹is a mixture of 1. hydrogen,

2.-(C₁-C₄) -alkyl, wherein alkyl is linear or branched and is independently from each other-C (O) -OH, -OH or-C (O) -NH₂Mono-, di-or tri-substituted, or

3. Phenyl, wherein the phenyl is unsubstituted or independently of one another is halogen or- (C)₁-C₄) -alkyl mono-to tri-substituted.

The term "halogen" is taken to mean fluorine, chlorine, bromine or iodine. Term "(C)₁-C₈) -alkyl "," (C)₁-C₆) -alkyl "or" (C)₁-C₄) Alkyl is taken to mean a hydrocarbon radical whose carbon chain is linear or branched and contains 1 to 8, 1 to 6 and respectively1 to 4 carbon atoms. A cyclic alkyl group is, for example, a 3 to 6 membered monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "R⁷And R⁸The nitrogen atom to which they are each bound, together with the carbon atom, forming a heterocycle of formula IIa "is taken to mean a radical derived from: pyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, isoxazole, tetrazole, isoxazoline, isoxazolidine, morpholine, thiazole, isothiazole, isothiazoline, purine, isothiazolidine, thiomorpholine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine, indole, isoindole, indazole, benzimidazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, pteridine, triazolone, tetrazole, 1, 2, 3, 5-oxathiadiazole 2-oxide, oxadiazolone, isoxazolone, oxadiazolidinedione, substituted F, -CN, -CF₃or-C (O) -O- (C)₁-C₄) Alkyl-substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazoles, imidazolidines, carbolines and benzo-fused derivatives of these heterocycles.

The term aryl is taken to mean an aromatic hydrocarbon radical having from 6 to 14 carbon atoms in the ring. (C)₆-C₁₄) Aryl radicals are for example phenyl; naphthyl, such as 1-naphthyl, 2-naphthyl; biphenyls such as 2-biphenyl, 3-biphenyl and 4-biphenyl; anthracenyl or fluorenyl. Biphenyl groups, naphthyl groups, especially phenyl groups are preferred aryl groups. The aryl radical, in particular the phenyl radical, may be mono-or polysubstituted, preferably mono-, di-or trisubstituted, identically or differently, the substituents preferably being selected from (C)₁-C₈) Alkyl, especially (C)₁-C₄) -alkyl, (C)₁-C₈) Alkoxy, especially (C)₁-C₄) Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy- (C)₁-C₄) Alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) -an alkoxycarbonyl group, a phenyl group,phenoxy, benzyl, benzyloxy, tetrazolyl. The same applies, for example, to radicals such as arylalkyl or arylcarbonyl. Arylalkyl is, in particular, benzyl, and also 1-and 2-naphthylmethyl and 2-, 3-and 4-biphenylmethyl and 9-fluorenylmethyl. Substituted arylalkyl is, for example, one or more (C) substituents on the aryl part thereof₁-C₈) Alkyl, especially (C)₁-C₄) Alkyl-substituted benzyl and naphthylmethyl radicals, such as the 2-, 3-and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3, 5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7-and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7-and 8-methyl-2-naphthylmethyl radicals; in the aryl part thereof by one or more (C)₁-C₈) Alkoxy, especially (C)₁-C₄) Alkoxy-substituted benzyl radicals and naphthylmethyl radicals, such as 4-methoxybenzyl, 4-neopentyloxybenzyl, 3, 5-dimethoxybenzyl, 3, 4-methylenedioxybenzyl, 2, 3, 4-trimethoxybenzyl; nitrobenzyl groups, such as 2-, 3-and 4-nitrobenzyl; halobenzyl groups, for example 2-, 3-and 4-chlorobenzyl, 2-, 3-and 4-fluorobenzyl, 3, 4-dichlorobenzyl, pentafluorobenzyl; trifluoromethylbenzyl radicals, for example 3-and 4-trifluoromethylbenzyl or 3, 5-bis (trifluoromethyl) benzyl.

In monosubstituted phenyl groups, the substituent may be located at the 2-position, 3-position or 4-position. The disubstituted phenyl groups may be substituted in the 2, 3-position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position or 3, 5-position. In the trisubstituted phenyl group, the substituents may be in the 2, 3, 4-position, 2, 3, 5-position, 2, 4, 6-position, 2, 3, 6-position or 3, 4, 5-position.

The explanations with respect to aryl groups apply correspondingly to divalent arylene groups, for example phenylene groups, which can be, for example, 1, 4-phenylene or 1, 3-phenylene.

Phenylene- (C)₁-C₆) Alkyl radicals, in particular the phenylenemethyl radical (-C)₆H₄-CH₂-) and phenylethenyl, (C)₁-C₆) Alkylene-phenyl radicals, especially methylene-phenyl radicals (-CH₂-C₆H₄-). Phenylene- (C)₂-C₆) Alkenyl is in particular phenyleneethylene and phenylenepropylene.

The expression "heteroaryl having 5 to 14 ring members" denotes a monocyclic or polycyclic aromatic group having 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, O and S. If there are a plurality of heteroatoms, they may be the same or different. The heteroaryl radical may likewise be mono-or polysubstituted, preferably mono-, di-or trisubstituted, identically or differently, by radicals selected from (C)₁-C₈) Alkyl, especially (C)₁-C₄) -alkyl, (C)₁-C₈) Alkoxy, especially (C)₁-C₄) -alkoxy, halogen, nitro, -N (R)¹⁰)₂Trifluoromethyl, hydroxy- (C)₁-C₄) Alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. Heteroaryl having 5 to 14 ring members preferably represents a monocyclic or bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different heteroatoms from the group N, O and S and may be substituted by 1, 2, 3 or 4, in particular 1 to 3, identical or different substituents from the group (C)₁-C₆) Alkyl radicals, (C)₁-C₆) Alkoxy, fluoro, chloro, nitro, -N (R)¹⁰)₂Trifluoromethyl, hydroxy- (C)₁-C₄) Alkyl radicals, (C)₁-C₄) -alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Heteroaryl particularly preferably represents a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-or 6-membered monocyclic aromatic radical, which contains 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms from the group N, O and S and may be substituted by 1 or 2 identical or different substituents from the group (C)₁-C₄) Alkyl, haloElement, hydroxy, -N (R)¹⁰)₂、(C₁-C₄) -alkoxy, phenyl, phenoxy, benzyloxy and benzyl.

The expression "heterocyclic ring having 5 to 12 ring members" denotes a monocyclic or bicyclic 5-to 12-membered heterocyclic ring which is partially or fully saturated. Examples of heteroatoms are N, O and S. Heterocycles are unsubstituted or substituted on one or more carbon atoms or one or more heteroatoms with the same or different substituents. These substituents are as defined above for the heteroaryl group. The heterocyclic ring is in particular mono-or polysubstituted on carbon atoms by identical or different radicals, e.g. mono-, di-, tri-or tetrasubstituted, the substituents being selected from (C)₁-C₈) Alkyl radicals, e.g. (C)₁-C₄) -alkyl, (C)₁-C₈) Alkoxy radicals, e.g. (C)₁-C₄) Alkoxy, e.g. methoxy, phenyl- (C)₁-C₄) Alkoxy, such as benzyloxy, hydroxy, oxo, halogen, nitro, amino or trifluoromethyl; and/or substituted on a ring nitrogen atom in the heterocyclic ring by: (C)₁-C₈) Alkyl radicals, e.g. (C)₁-C₄) Alkyl, such as methyl or ethyl, optionally substituted phenyl, or phenyl- (C)₁-C₄) Alkyl, for example benzyl, substitution. The nitrogen heterocycles can also be in the form of N-oxides or quaternary salts.

Examples of the wording heteroaryl having 5 to 14 ring members or heterocycle having 5 to 12 ring members are groups derived from the following heterocycles: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1, 2, 3, 5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone, oxadiazolidinedione, tegafur, -CN, -CF₃or-C (O) -O- (C)₁-C₄) -alkyl-substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazoles, pyridines, pyrazines, pyrimidines, indoles, isoindoles, indazoles, phthalazines, quinolines, isoquinolines, quinoxalines, quinazolines, cinnolines, carbolines and benzo-fused, cyclopenta-, cyclohexa-or cyclohepta-fused heterocycles of these heterocyclesAnd (d) a derivative of (a) a compound. Particularly preferred radicals are 2-or 3-pyrrolyl, phenylpyrrolyl, for example 4-or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4-or 5-imidazolyl, 1, 3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3-or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4-or 5-pyrimidinyl, 2-, 3-or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-), 5-methoxy-, 5-benzyloxy-, 5-chloro-or 4, 5-dimethyl-2-indolyl, 1-benzyl-2-or-3-indolyl, 4, 5, 6, 7-tetrahydro-2-indolyl, cyclohepta [ b ] or a pharmaceutically acceptable salt thereof]-5-pyrrolyl, 2-, 3-or 4-quinolyl, 1-, 3-or 4-isoquinolyl, 1-oxo-1, 2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or benzothiazolyl or dihydropyridinyl, pyrrolidinyl, e.g. 2-or 3- (N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl or benzodioxolyl.

The structural formula of the alpha-amino acid is as follows:

alpha-amino acids differ from each other by a group R, which in the context of the present application is referred to as "characteristic group" of the amino acid. At R⁸In the case of the characteristic groups of amino acids, the characteristic groups are preferably those of the following naturally occurring alpha-amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid. Particularly preferred are histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid, and aspartic acid. Preference is furthermore given to using as radicals R⁸The amino acid characteristic group of (A) is also a non-naturally occurring amino acid, e.g. 2-aminohexylDiacid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2, 3-diaminopropionic acid, 2, 4-diaminobutyric acid, 1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylic acid, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, phenylglycine, 3- (2-thienyl) alanine, 3- (3-thienyl) alanine, 2- (2-thienyl) glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, alloisoleucine, allothreonine, allohydroxylysine, 4-hydroxyproline, isohydroxylysine, isovalerine, 4-hydroxyp, 3-hydroxyproline, 3- (2-naphthyl) alanine, 3- (1-naphthyl) alanine, homophenylalanine, homocysteine, 2-amino-3-anilinoethylpropionic acid, homocysteic acid, homotryptophan, cysteic acid, 3- (2-pyridyl) alanine, 3- (3-pyridyl) alanine, 3- (4-pyridyl) alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, 2-amino-3-anilinopropionic acid, Methionine sulphone, methionine sulphoxide or-NH-NR¹⁰-CON(R¹⁰)₂They are optionally also substituted. In the case of naturally and non-naturally occurring amino acids having functional groups, the group may also be protected, for example, amino, hydroxyl, carboxyl, mercapto, guanidino, imidazolyl or indolyl.

Suitable protecting groups for this purpose are preferably the N-protecting groups customary for peptide chemistry, for example protecting groups of the urethane type, benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Aloc) or of the amide type, in particular formyl, acetyl or trifluoroacetyl, and protecting groups of the alkyl type, for example benzyl. For example at R⁸In the case of imidazole groups, the sulfonic acid derivatives of the formula IV used for the formation of the sulfonamides are used as protecting groups for the imidazole nitrogen, which can in turn be removed, in particular in the presence of bases, for example aqueous sodium hydroxide. The starting materials for the chemical reactions are known or can be prepared according to methods known from the literatureIs easy to prepare.

The invention further relates to a process for the preparation of a compound of the formula I and/or of a stereoisomeric form of a compound of the formula I and/or of a physiologically tolerable salt of a compound of the formula I, which process comprises

a) Reacting a compound of the formula IV in solution in the presence of a base or, if appropriate, in the presence of a dehydrating agent

Where Pg is a suitable protecting group (e.g. methyl ester), amide or hydroxyl group, Z, R⁷And R⁸Is as defined in formula I,

with an acid chloride or activated ester of a compound of formula III,

wherein D1 is-COOH or sulfonyl halide, R⁵、R⁶And R⁹Is as defined in formula I,

after removal of the protecting group, are converted into compounds of the formula I, or

b) Reacting a compound of the formula IVa in the presence of a base or, if appropriate, in the presence of a dehydrating agent

Wherein R is⁷And R⁸Is as defined for formula I, E is an N-amino protecting group,

coupling the carbonyl group of the compound with a polymeric resin of the formula PS via an intermediate chain L, and selectively removing the protecting group E to obtain a compound of the formula V

Reacting it with a compound of formula III, wherein R⁵、R⁶And R⁹As defined for formula I, to give a compound of formula VI,

after cleavage from the carrier, the compound of formula VI is converted to a compound of formula I, or

c) Converting the compound of formula I into a physiologically acceptable salt.

In process variant a), the acid function of the compound of the formula IVa carries a protecting group Pg; such selective carboxylic acid derivatization is carried out according to the methods described in the literature, for example Houben-Weyl "method der org. Chemie" (methods of organic chemistry), Vol. 15/1. In process variant b), the amino function of the starting compound of the formula IVa carries a protecting group E; this selective amino derivatization is carried out according to the methods described in the literature, for example Houben-Weyl "method der org. Chemie" (methods of organic chemistry), Vol. 15/1.

Preferred protecting groups Pg suitable for this purpose are carboxyl protecting groups customary for peptide chemistry, for example protecting groups of the alkyl ester type, for example methyl, ethyl, tert-butyl, isopropyl, benzyl, fluorenylmethyl, allyl, aryl ester type, for example phenyl, protecting groups of the amide type, for example amide or benzhydrylamine. Suitable protecting groups E for this purpose are preferably the N-protecting groups customary for peptide chemistry, for example protecting groups of the urethane type, such as benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc), or protecting groups of the amide type, in particular formyl, acetyl or trifluoroacetyl, and protecting groups of the alkyl type, such as benzyl.

(trimethylsilyl) ethoxycarbonyl (Teoc) has also proven particularly suitable for this (P.Kocienski, Protecting Groups, Thieme Verlag 1994).

Indole carboxylic acid derivatives were prepared as described in Houben-Weyl "method der org. Chemie" (methods of organic chemistry), volumes E6-2A and E6-2B. Thus, for the preparation of the indole carboxylic acid derivatives of formula III, it is preferred to react hydrazinobenzoic acid with an aryl or heteroaryl ketone at 145 ℃ in the presence of solvent polyphosphoric acid. The desired hydrazinobenzoic acid is prepared according to methods known to those skilled in the art, for example from the corresponding phenylamine benzoate. Aryl or heteroaryl ketones are likewise prepared according to methods familiar to the person skilled in the art, for example from the corresponding acid chlorides or nitriles, for example by reaction with organometallic compounds.

As regards the condensation of the compounds of the formula IV with the compounds of the formula III, coupling methods which are known per se to those skilled in the art are advantageously employed (see, for example, Houben-Weyl "Methodender Organischen Chemie" (methods of organic chemistry) volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). Suitable condensing or coupling agents are, for example, carbonyldiimidazole, carbodiimides, such as dicyclohexylcarbodiimide or Diisopropylcarbodiimide (DIC), O- ((cyano (ethoxycarbonyl) methylene) amino) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TOTU) or propanephosphonic anhydride (PPA).

The condensation may be carried out under standard conditions. During the condensation, it is often necessary to protect the unreacted amino groups present with reversible protecting groups. The same applies to carboxyl groups which do not participate in the reaction, preferably in the form of (C) during the condensation₁-C₆) -in the form of alkyl, benzyl or tert-butyl esters. Amino protection is not necessary if the amino groups are still present in the form of precursors, such as nitro or cyano groups, and are only formed by hydrogenation after condensation. After condensation, the protecting groups present are removed in a suitable manner. For example, NO₂(guanidino protection of amino acids), benzyloxycarbonyl and benzyl esters the benzyl group of which can be removed by hydrogenation. Protecting groups of the tert-butyl typeThe group is removed by acid and the 9-fluorenylmethoxycarbonyl group is removed with a secondary amine.

The polymeric support designated by PS in formulas V and VI is a crosslinked polystyrene resin having a linking group, referred to as the intermediate chain L. The linker carries a suitable functional group, for example an amine, such as the known Rink amide resin, or an OH group, such as the known Wang resin or Kaiser oxime resin. Alternatively, other polymeric carriers may be employed, such as glass, cotton or cellulose with various intermediate chains L.

The intermediate chain designated by L is covalently bonded to the polymeric carrier, forms a reversible amide or ester linkage with the compound of formula IVa, and remains stable during further reaction of the bonded compound of formula IVa; however, under strongly acidic reaction conditions, for example in a mixture with trifluoroacetic acid, the groups on the linker are released again.

The desired release of the compound of formula I from the linker may be carried out at various positions in the reaction sequence.

A. General procedure for coupling of protected aminocarboxylic acids of formula IVa to solid supports:

the synthesis was carried out in reactors each having a reaction volume of 15 ml. Each reactor was charged with 0.179g Rink amide AM resin (Fmoc-Rink amide AM/Nova-Biochem; loading 0.56 mmol/g; i.e., 0.1 mmol/reactor). For removal of the Fmoc protecting group from the resin, 30% piperidine/DMF solution was metered into each reactor and the mixture was shaken for 45 minutes (min). Then filtered and the resin washed 3 times with Dimethylformamide (DMF).

For the coupling of the protected amino acid, 0.5 mol of the corresponding Fmoc-amino acid solution (0.3mmol in DMF), HOBt solution (0.33mmol in DMF) and DIC solution (0.33mmol in DMF) were added to each of the prepared resins and the mixture was shaken for 16 h (h) at 35 ℃. The resin was then washed several times with DMF. To check for coupling, some resin beads were removed and subjected to a KAISER test; the test was negative in all cases.

Removal of the Fmoc protecting group was performed as described above with 30% piperidine/DMF solution.

For the coupling of benzimidazole carboxylic acid, a solution of 0.1 mol of the corresponding 4-or 5-substituted acid (0.4mmol in DMF), a solution of 0.5 mol of the coupling agent TOTU (0.44mmol in DMF) and a solution of 0.5 mol of DIPEA (0.6mmol in DMF) were added and the mixture was shaken at 40 ℃ for 16 h. Then washed several times with DMF.

To check the reaction, some of the resin beads were removed again and subjected to the KAISER test.

For removal of the desired material from the solid support, the resin was washed several times with dichloromethane. Cleavage solution (50% dichloromethane and 50% 95% TFA, 2% H) was then added₂Mixture of O, 3% triisopropylsilane) the mixture was shaken at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was precipitated with diethyl ether and filtered.

The solid residue usually contains the desired product in high purity or is fractionated, for example by preparative high-pressure liquid chromatography, on reversed phase (eluent: A: H)₂O/0.1% TFA, B: acetonitrile/0.1% TFA). The resulting fractions were freeze-dried to give the desired product.

The preparation of the compounds of the formula I capable of salt formation, including their stereoisomeric forms, of the physiologically tolerable salts is carried out in a manner known per se. With basic reagents, such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia, or organic bases, such as trimethylamine or triethylamine, ethanolamine or triethanolamine, or with basic amino acids, such as lysine, ornithine or arginine, carboxylic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the compounds of the formula I contain basic groups, stable acid addition salts can also be prepared using strong acids. For this purpose, both inorganic and organic acids are suitable, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexanesulfamidosulfonic acid, trifluoromethanesulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid or trifluoroacetic acid.

The invention also relates to medicaments comprising an effective amount of at least one compound of the formula I and/or physiologically tolerated salts of the compounds of the formula I and/or optionally stereoisomeric forms of the compounds of the formula I, and pharmaceutically suitable and physiologically tolerated excipients, additives and/or further active compounds and auxiliaries.

In view of their pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and treatment of all those disorders whose course involves an increase in I.kappa.B kinase activity. They include, for example, chronic motor organ disorders, such as inflammatory, immunological or metabolic acute and chronic arthritis, arthrosis, rheumatoid arthritis, or degenerative joint disorders, such as osteoarthropathy, spondylosis, meniscus or patella injury or cartilage damage following joint trauma or secondary to long-term arthrodesis after ligament rupture, or connective tissue disorders, such as collagenous and periodontal diseases, myalgia and bone metabolism disorders, or disorders caused by tumor necrosis factor α (TNF α) overexpression or increased TNF α concentration, such as cachexia, multiple sclerosis, cranio-cerebral trauma, crohn's disease and intestinal tumors, or disorders such as: atherosclerosis, stenosis, ulcer formation, alzheimer's disease, muscle wasting, cancerous disorders (intensification of cytotoxic compound therapy), myocardial infarction, gout, sepsis, septic shock, endotoxic shock, viral infections (e.g., influenza, hepatitis, HIV infection, AIDS, or disorders caused by adenovirus or herpes virus), parasitic infections (e.g., malaria or leprosy), fungal or yeast infections, meningitis, chronic inflammatory lung diseases (e.g., chronic bronchitis or asthma), acute respiratory distress syndrome, acute synovitis, tuberculosis, psoriasis, diabetes, acute or chronic rejection of organ recipients to transplanted organs, graft-versus-host disorders, and inflammatory vascular disorders.

The medicaments according to the invention are generally administered orally or parenterally. Rectal or transdermal administration is also possible.

The invention also relates to a process for the preparation of a medicament, which comprises bringing at least one compound of the formula I into a suitable administration form using pharmaceutically suitable and physiologically tolerable excipients and, if appropriate, suitable active compounds, additives or auxiliaries.

Suitable solid or pharmaceutical dosage forms are, for example, granules, powders, coated tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injection solutions, and sustained-release preparations of the active compounds in which the customary auxiliaries, such as excipients, disintegrants, binders, coatings, swelling agents, glidants or lubricants, flavors, sweeteners and solubilizers are used. As customary auxiliaries may be mentioned magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils (for example cod-liver oil, sunflower oil, peanut oil or sesame oil), polyethylene glycols and solvents (for example sterile water and monohydric or polyhydric alcohols, for example glycerol). Pharmaceutical preparations are preferably prepared and administered in dosage units, each unit containing a dose of a compound of formula I according to the invention as active ingredient. In the case of solid dosage units, such as tablets, capsules, coated tablets or suppositories, such doses may be up to about 1000mg, preferably from about 50mg to 300mg, and in the case of injectable solutions in the form of ampoules, up to about 300mg, preferably from about 10mg to 100 mg. For the treatment of adult patients weighing about 70kg, the daily dose is about 20mg to 1000mg of active compound, preferably about 100mg to 500mg, depending on the efficacy of the compound of formula I. Although higher or lower daily doses may be appropriate in some cases. In the case of daily dosage administration, the dosage may be administered either in a single dose, in a plurality of small dosage units, or in divided doses, in a plurality of doses at specific intervals.

Typically, the final product is determined by mass spectrometry (FAB-, ESI-MS). Temperatures are given in degrees Celsius and RT denotes room temperature (22-26 ℃). Abbreviations used have been explained or otherwise agreed with convention.

Examples

Preparation of substituted indole carboxylic acids

Process variant a)2, 3-diphenyl-1H-indole-5-carboxylic acid:

1.96g (10mmol) of deoxybenzoin and 1.52g of 4-hydrazinobenzoic acid were ground in a mortar and then melted in an open flask at 160 ℃ for 15 minutes. The cooled melt was mixed with 100ml of acetic acid and 30ml of concentrated hydrochloric acid and heated under reflux for 3 hours. The cooled solution is mixed with water, resulting in the precipitation of the product 2, 3-diphenyl-1H-indole-5-carboxylic acid. The product is filtered off with suction and the residue is washed with water and dried. For purification, the crude product is stirred with hot toluene, filtered off with suction again and dried. To obtain the 2, 3-diphenyl-1H-indole-5-carboxylic acid.

Method variant B) 2-pyridin-4-yl-1H-indole-5-carboxylic acid:

20g P₂O₅And 12.5ml of H₃PO₄(85%) mixing resulted in a dramatic increase in the temperature of the reaction mixture. The reaction mixture was then cooled to 60 ℃ and 8.90g (65.84mmol) of 4-propionylpyridine and 4.20g (27.60mmol) of 4-hydrazinobenzoic acid were added. The mixture was then stirred at 145 ℃ for 45 minutes. The reaction mixture was poured into water, resulting in the precipitation of the yellow product 2-pyridin-4-yl-1H-indole-5-carboxylic acid. The precipitate was suction filtered and washed with water to neutrality. The 2-pyridin-4-yl-1H-indole-5-carboxylic acid quantitatively obtained by this method was used without further purification for coupling with amino acid derivatives.

Coupling of amino acid derivatives with substituted indole carboxylic acid derivatives

Method variants C)

Example 1

N- (1-carbamoyl-3-phenylpropyl) -2, 3-diphenyl-1H-indole-5-carboxamide:

0.16g (0.5mmol) of 2, 3-diphenyl-1H-indole-5-carboxylic acid (see process variant A) are dissolved in 10ml of anhydrous Dimethylformamide (DMF) at RT and admixed in succession with 0.11g (0.5mmol) of L-homophenylalaninamide hydrochloride, 0.16g of TOTU (O- [ (cyano (ethoxycarbonyl) methylene) amino-1, 1, 3, 3-tetramethyl ] uronium tetrafluoroborate) and 0.14ml (1mmol) of diisopropylamine. The reaction mixture was stirred at RT for 6 hours, then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase is washed successively with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. To obtain N- (1-carbamoyl-3-phenylpropyl) -2, 3-diphenyl-1H-indole-5-carboxamide with a melting point of 120 ℃ to 125 ℃.

Example 7

N- (1-carbamoyl-3-pyrrol-1-ylpropyl) -3-methyl-2-pyridin-4-yl-1H-indole-5-carboxamide:

0.13g (0.5mmol) of 3-methyl-2-pyridin-4-yl-1H-indole-5-carboxylic acid (see method variant A) are dissolved in 10ml of anhydrous Dimethylformamide (DMF) at RT and successively mixed with 0.083g (0.5mmol) of 4- (1-pyrrolyl) -L-2-benzyloxycarbonylaminobutanamide, 0.16g (0.5mmol) of TOTU (O- [ (cyano (ethoxycarbonyl) methylene) amino-1, 1, 3, 3-tetramethyl ] uronium tetrafluoroborate) and 0.14ml (1mmol) of ethyldiisopropylamine. The reaction mixture was stirred at RT for 6 hours, then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase is washed successively with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC.

a: 4- (1-pyrrolyl) -L-2-benzyloxycarbonylamino butyric acid

A60 ml aqueous solution of 1.25g (5.0mmol) of N.alpha. -Z-L-2, 4-diaminobutyric acid flushed with argon was mixed with 0.668(5.0mmol) of 2, 5-dimethoxytetrahydrofuran, then 1.7ml of glacial acetic acid was added, and the mixture was stirred at 20 ℃ for 12 hours. The reaction mixture was repeatedly extracted with ethyl acetate, the organic phases were combined, dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH)₂Cl₂/CH₃OH/CH₃COOH: 100/5/1). Removal of mobile phase1.3g (87%) of 4- (1-pyrrolyl) -L-2-benzyloxycarbonylamino butyric acid were obtained.

b: 4- (1-pyrrolyl) -L-2-benzyloxycarbonylaminobutanamide

1.2g (4.0mmol) of 4- (1-pyrrolyl) -L-2-benzyloxycarbonylamino butyric acid and 0.61g (4.0mmol) of N-hydroxybenzotriazole ammonium salt are dissolved together in 10ml of DMF and mixed at 0 ℃ with 0.82g (4.0mmol) of N, N' -dicyclohexylcarbodiimide and 0.68ml (4.0mmol) of N-ethyldiisopropylamine, the mixture is stirred at 0 ℃ for 30 minutes and at 20 ℃ for 3 hours. The precipitated urea was filtered off with suction and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel (CH)₂Cl₂/CH₃OH/CH₃COOH: 100/5/1). Yield: 0.89g (74%).

c: 4- (1-pyrrolyl) -L-2-aminobutanamide

A solution of 0.80g (2.65mmol) of 4- (1-pyrrolyl) -L-2-benzyloxycarbonylaminobutanamide in 20ml of methanol is mixed under inert gas with 80mg of catalyst (10% Pd-C) and then hydrogen is introduced until the Z protecting group is completely cleaved. The catalyst is filtered off and the filtrate is concentrated to yield 0.4g (90.5%) of 4- (1-pyrrolyl) -L-2-aminobutanamide.

2. Method variants D)

Example 3

N- (1-carbamoyl-2-phenylthioethyl) -2-pyridin-4-yl-1H-indole-5-carboxamides

0.20g (0.84mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid and 0.21g (1.07mmol) of 2-amino-3-thiophenylpropionic acid are mixed in 40ml of DMF, 0.66g (1.27mmol) of benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate and 0.37ml (2.12mmol) of N-ethyl-N, N-diisopropylamine are added at 0 ℃ and the solution is stirred for 2 hours at 20 ℃. The solution was concentrated under reduced pressure and purified by medium pressure column Chromatography (CH)₂Cl₂/CH₃OH: 9/1). 0.19g (54%) of N- (1-carbamoyl-2-phenylthioethyl) -2-pyridin-4-yl-1H-indole-5-carboxamide are obtained.

Example 9

3-phenylaminoethyl-2- [ (2-pyridin-4-yl-1H-indole-5-carbonyl) amino ] propanamide

a) L-2-amino-3-phenylamino ethyl propionic acid

54.8g (0.209mol) of triphenylphosphine were suspended in 600ml of acetonitrile, freed of moisture and cooled to-35 ℃ to-45 ℃. Then, at this temperature, 36.4g (0.209mol) of diethyl azodicarboxylate was added dropwise over 50 minutes. The mixture was stirred at-35 ℃ for an additional 15 minutes. To this mixture was added dropwise a solution of 50g (0.209mol) of N-benzyloxycarbonyl-L-serine in 500ml of acetonitrile, the temperature being kept at-35 ℃ or lower. The mixture was then allowed to react at 5 ℃ for another 12 hours, warming to RT. The solvent was removed from the reaction solution under reduced pressure and the crude product was purified by medium pressure silica gel chromatography (DCM/AcCN: 25/1). The solvent was removed to give 20.8g (yield 45%) of pure N-benzyloxycarbonyl-L-serine- β -lactone as fine needles (see also org. Synth. (organic Synthesis) 1991(70)1 ff.). Empirical formula C₁₁H₁₁NO₄；M.W.＝221.2；MS(M+H)222.1

To a solution of 7.3ml (57.36mmol) of N-ethylaniline in 250ml of acetonitrile under a protective argon atmosphere was added 15.5ml (63.51mmol) of N, O-bis (trimethylsilyl) acetamide and the mixture was stirred at 50 ℃ for 3 hours. A solution of the above lactone (10.7g, 48.37mmol) in 250ml acetonitrile is then added at 20 ℃ and the mixture is heated at reflux for 17 hours. The solvent was removed and the residue was then mixed with a saturated sodium carbonate solution, the pH of the solution being kept below 9. The aqueous suspension was washed with a small amount of diethyl ether, then acidified with concentrated hydrochloric acid to a pH of 6 to 7, and then treated with NaHPO₄The buffer adjusted the pH to 5. The aqueous solution was then extracted repeatedly with ethyl acetate. Evaporation of the solvent gave the desired product in 45% yield (7.4 g). Empirical formula C₁₉H₂₂N₂O₄(ii) a M.w. 342.4; MS (M + H) 343.2. 6.5ml (89.1mmol) of thionyl chloride are added dropwise to 75ml of methanol at-10 deg.CThe mixture was stirred for 30 minutes. Then 8.6g (25.12mmol) of L-2-aminoethyl-3-phenylaminopropionic acid in 75ml of methanol were added and the mixture was stirred at-10 ℃ for 30 minutes and at room temperature for a further 3 hours. The solvent was evaporated, then the residue was dissolved in ethyl acetate and washed with sodium carbonate solution. The solvent was evaporated and purified by flash chromatography (n-heptane/ethyl acetate 7: 3) to give 4.43g (yield 50%) of methyl L-2-aminoethyl-3-phenylaminopropionate. Empirical formula C₂₀H₂₄N₂O₄；M.W.＝356.4；MS(M+H)357.3

To remove the protecting groups, 4.4g (12.35mmol) of the Z-protected derivative are dissolved in 500ml of methanol and 100mg of catalyst (10% Pd (OH))₂-C), hydrogen is introduced until complete cleavage of the Z protecting group. The catalyst was filtered off and the filtrate was concentrated to give 2.8g L-2-aminoethyl-3-phenylamino propionic acid (quantitative). Empirical formula C₁₂H₁₈N₂O₂；M.W.＝223.3；MS(M+H)223.1

Method step b)

0.63g (2.64mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid prepared as described in method variant B) are suspended in 150ml of DMF and combined successively with 1.01g (3.08mmol) of TOTU and 0.63ml (3.71mmol) of ethyldiisopropylamine. The mixture is stirred for 20 minutes at RT, and 0.73g (3.28mmol) of the methyl (S) -2-amino-3-phenylaminoethylpropionate prepared according to a) are added to the clear solution obtained. The mixture was stirred under reduced pressure for 15 hours, then the methyl ester of the title compound was isolated by flash chromatography on silica gel (DCM: MeOH ═ 19: 1). Yield: 0.44g, empirical formula C₂₆H₂₆N₄O₃；M.W.＝442.2；MS(M+H)443.3

0.22g (0.497mmol) of the methyl ester obtained are dissolved in 100ml of methanol, cooled to 0 ℃ and then ammonia is introduced for 1.5 hours. The solution was left at room temperature overnight and then methanol was evaporated. The crude product was purified by flash chromatography on silica gel (DCM: MeOH ═ 19: 1). Yield: 0.096g (45.2%) empirical formula C₂₅H₂₅N₅O₂；M.W.＝427.2；MS(M+H)428.3

The following compounds of table 1 were prepared analogously to methods a) to D).

TABLE 1

pr.v. ═ method variants

Pharmacological examples ikb kinase ELISA:

i κ B kinase activity was determined using an ELISA comprising a biotinylated substrate peptide containing the amino acid sequence of serine 32 to 36 in the I κ B protein and a specific poly-or monoclonal antibody (e.g. from New England Biolabs, Beverly, MA, USA, cat.: 9240) which binds only to the phosphorylated form of the I κ B peptide. This complex is immobilized on an antibody-binding plate (coated with protein a) and detected using a conjugate of biotin-binding protein and HRP (e.g., streptavidin HRP). Activity can be quantified using a standard curve of the substrate phosphopeptide.

The operation is as follows:

to obtain the kinase complex, 10ml of HeLa S3 cell extract S100 was diluted with 40ml of 50mM HEPES, pH7.5, adjusted to 40% ammonium sulfate, and incubated on ice for 30 minutes. The precipitate was dissolved in 5ml SEC buffer (50mM HEPES, pH7.5, 1mM DTT, 0.5mM EDTA, 10mM 2-glycerophosphate), centrifuged at 20,000Xg for 15 minutes, and filtered through a 0.22 μm filter. Samples were applied to a 320ml Superose-6 FPLC column (Amersham pharmacia Biotech AB, Uppsala, Sweden) which had been equilibrated with SEC buffer and operated at a flow rate of 2ml/min at 4 ℃. Pooled molecular weight standards corresponding to 670kDaQuasi-elution time fraction, activation was performed. Activation was performed at 37 ℃ with 100nM MEKK 1. delta., 250. mu.M MgATP, 10mM MgCl₂5mM Dithiothreitol (DTT), 10mM 2-glycerophosphate, and 2.5 μm microcystin LR were incubated for 45 minutes. The activated enzyme was stored at-80 ℃.

The test substance was dissolved in DMSO (2. mu.l), and 43. mu.l of the activating enzyme (diluted 1: 25 in reaction buffer: 50mM HEPES, pH7.5, 10mM MgCl) was added at 25 ℃₂5mM DTT, 10mM beta-glycerophosphate, 2.5 μm microcystin LR) for 30 minutes. Add 5. mu.l of substrate peptide (Biotin- (CH)₂)₆-DRHDSGLDSMKD-CONH₂) (200. mu.M), the mixture was incubated for one hour with 150. mu.l of 50mM HEPES, pH7.5, 0.1% BSA, 50mM EDTA, antibody [ 1: 200 ]]The reaction was quenched. Then 100. mu.l of quenched reaction mixture or standard phosphopeptide dilution series (biotin- (CH)₂)₆-DRHDS[PO₃]GLDSMKD-CONH₂) Transferred to protein A plates (Pierce Chemical Co., Rockford, IL, USA) and incubated for 2 hours with shaking.

After 3 washes with PBS, 100. mu.l of 0.5. mu.g/ml streptavidin-HRP (horseradish peroxidase) (diluted in 50mM HEPES/0.1% BSA) was added over 30 minutes. After 5 washes with PBS, 100. mu.l TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg, Md., USA) was added and 100. mu.l 0.18M sulfuric acid was added to stop the color development. The absorption at 450nm was measured. Standard curves were generated by linear regression based on the 4-parameter dose-activity relationship. Using this standard curve, the enzymatic activity or the inhibitory effect of the test substances on them is quantified.

PKA, PKC, CK II methods

cAMP-dependent Protein Kinase (PKA), Protein Kinase C (PKC) and casein kinase II (CK II) were measured at an ATP concentration of 50 μm using the corresponding kit from UpstateBiotechnology according to the manufacturer's instructions. However, instead of the Phosphocellulose filter, a multi-sieve plate (Millipore; Phosphocellulose MS-PH, cat. MAPHHNOB10) and corresponding suction system were used. The plates were then measured in a Wallac MicroBeta scintillation counter. In each case 100. mu.M of test substance was used.

The test was repeated twice for each substance. The mean value of the blank (no enzyme) was subtracted from the mean value (enzyme with and without substance) to calculate the% inhibition. IC Using GraFit 3.0 software Package₅₀And (4) calculating. The results are shown in table 2 below.

Table 2: kinase inhibition or IC at a substrate concentration of 100. mu.M₅₀μ M value of

Example numbering	IkappaB kinase IC50	PKA% inhibition	PKC% inhibition	CK II% inhibition
					1	32	n.d.	n.d.	n.d.
2	0.61	24	15	35
					3	0.55	35	39	37
4	0.50	42	33	47
					5	1.8	55	8	27
6	4.9	60	58	39
					7	3.0	n.d.	n.d.	18
9	1.0	0	23	0

n.d. indicates not determined.

Claims (8)

1. A compound of formula I

And/or stereoisomeric forms of the compounds of the formula I and/or physiologically acceptable salts of the compounds of the formula I, in which the substituent R¹、R²、R³And R⁴One of which is a group of the formula II

Wherein

D is-C (O) -, -S (O) -or-S (O)₂-，

R⁷Is hydrogen or- (C)₁-C₄) -an alkyl group,

R⁸is R⁹Or a characteristic group of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, aspartic acid, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2, 3-diaminopropionic acid, 2, 4-diaminobutyric acid, 1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylic acid, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, phenylglycine, 3- (2-thienyl) alanine, 3- (3-thienyl) alanine, 2- (2-thienyl) glycine, arginine, lysine, arginine, lysine, arginine, lysine, arginine, glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, alloisoleucine, allothreonine, allohydroxylysine, 4-hydroxyproline, 3- (2-naphthyl) alanine, 3- (1-naphthyl) alanine, homophenylalanine, homocysteine, 2-amino-3-phenylaminoethylpropionic acid, homocysteic acid, homotryptophan, cysteic acid, 3- (2-pyridyl) alanine, 3- (3-pyridyl) alanine, 3- (4-pyridyl) alanine, phosphinothricin, 4-fluorophenylalanine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyp, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, 2-amino-3-phenylaminopropionic acid, methionine sulfone, methionine sulfoxide and-NH-NR¹⁰-CON(R¹⁰)₂，

R⁹Is that

1. Aryl, wherein aryl is a radical selected from the group consisting of phenyl, naphthyl, biphenyl, anthracenyl and fluorenyl, the aryl radical is unsubstituted or mono-, di-or trisubstituted by identical or different radicals, the substituents are selected from the group consisting of (C)₁-C₈) Alkyl radicals, (C)₁-C₈) Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy- (C)₁-C₄) -alkyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, or tetrazolyl,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is a monocyclic or polycyclic aromatic radical having 5 to 14 ring members and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring members, where a number of the heteroatoms may be identical or different, which is unsubstituted or mono-, di-or trisubstituted by identical or different substituents selected from- (C)₁-C₈) Alkyl, - (C)₁-C₈) -alkoxy, halogen, nitro, -N (R)¹⁰)₂Trifluoromethyl, hydroxy- (C)₁-C₄) -alkyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, - (C)₁-C₄) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl,

3. heterocycle having 5 to 12 ring members, wherein the heterocycle is a monocyclic or bicyclic 5-to 12-membered heterocycle which is partially or fully saturated and contains a heteroatom selected from N, O and S, wherein the heterocycle is unsubstituted or substituted on one or more carbon atoms or one or more heteroatoms with the same or different substituents selected from- (C)₁-C₈) Alkyl, - (C)₁-C₈) -alkoxy, halogen, nitro, -N (R)¹⁰)₂Trifluoromethyl, hydroxy- (C)₁-C₄) -alkyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, - (C)₁-C₄) -alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl, or

4.-(C₁-C₆) -alkyl, wherein the alkyl is linear or branched and is unsubstituted or mono-substituted independently of each other by the following substituents-, di-or tri-substituted:

4.1 aryl, wherein aryl is as defined above, unsubstituted or substituted as defined above,

4.2 heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, unsubstituted or substituted as defined above,

4.3 heterocyclic rings having 5 to 12 ring members, where the heterocyclic ring is as defined above, unsubstituted or substituted as defined above,

4.4 -O-R¹⁰，

4.5 ＝O，

4.6 of a halogen,

4.7 -CN，

4.8 -CF₃，

4.9 -S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

4.10 -C(O)-O-R¹⁰，

4.11 -C(O)-N(R¹⁰)₂，

4.12 -N(R¹⁰)₂，

4.13 -(C₃-C₆) -a cycloalkyl group,

4.14 radicals of the formula

Or

4.15 radicals of the formula

5. The presence of hydrogen in the presence of hydrogen,

R¹⁰is a) a hydrogen atom, and is,

b)-(C₁-C₆) -an alkyl group, wherein the alkyl group is unsubstituted or mono-to trisubstituted, independently of each other, by the following substituents:

1. aryl, wherein aryl is as defined above,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above,

3. heterocyclic having 5 to 12 ring members, wherein the heterocyclic is as defined above,

4. the halogen(s) are selected from the group consisting of,

5.-N-(C₁-C₆)_n-alkyl, wherein n is the integer 0, 1 or 2, alkyl being unsubstituted or mono-, di-or tri-substituted independently of each other by halogen or-COOH, or

6.-COOH，

c) Aryl, wherein aryl is as defined above,

d) heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, or

e) A heterocycle having 5 to 12 ring members, wherein the heterocycle is as defined above, and

in (R)¹⁰)₂In the case of (1), R¹⁰Independently of one another have the meanings a) to e),

z is 1. aryl, wherein aryl is as defined above, unsubstituted or substituted as defined above,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, unsubstituted or substituted as defined above,

3. a heterocycle having 5 to 12 ring members, wherein the heterocycle is as defined above and is unsubstituted or substituted as defined above, or

4.-C(O)-R¹¹Wherein

R¹¹Is 1.-O-R¹⁰Or is or

2.-N(R¹⁰)₂Or is or

R⁷And R⁸Together with the nitrogen atom to which they are each bound, and the carbon atom form a heterocycle of the formula IIa

Wherein D, Z and R¹¹Is as defined in formula II,

a is a nitrogen atom or a group-CH₂-，

B is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

X is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

Y is absent or is an oxygen, sulfur, nitrogen or radicalgroup-CH₂-, or

X and Y together form a phenyl, 1, 2-diazine, 1, 3-diazine or 1, 4-diazine group,

wherein the ring system formed by N, A, X, Y, B and the carbon atoms contains not more than one oxygen atom, if A is a nitrogen atom, X is not an oxygen atom, a sulfur atom or a nitrogen atom, contains not more than one sulfur atom, contains 1, 2, 3 or 4 nitrogen atoms, oxygen and sulfur atoms are not present at the same time,

wherein the ring system formed by N, A, X, Y, B and carbon atoms is unsubstituted or independently of one another by- (C)₁-C₈) -alkyl is mono-to tri-substituted, unsubstituted or mono-to di-substituted with the following substituents:

1.1. -OH，

1.2. -(C₁-C₈) -an alkoxy group,

1.3. the halogen(s) are selected from the group consisting of,

1.4. -NO₂，

1.5. -NH₂，

1.6. -CF₃，

1.7. a methylene-dioxy group,

1.8. -C(O)-CH₃，

1.9. -CH(O)，

1.10.-CN，

1.11.-COOH，

1.12.-C(O)-NH₂，

1.13. (C₁-C₄) -an alkoxycarbonyl group, a carbonyl halide group,

1.14. a phenyl group,

1.15. a phenoxy group,

1.16. a benzyl group, a phenyl group,

1.17. a benzyloxy group,

1.18. tetrazolyl, or

1.19.-OH，

R⁸And Z together with the carbon atom to which they are each bonded form a heterocycle of formula IIc

Wherein

D、R⁷And R¹⁰Is as defined in formula II,

t is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

W is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-，

V is absent or is an oxygen atom, a sulfur atom, a nitrogen atom or a group-CH₂-, or

T and V or V and W together form a phenyl, 1, 2-diazine, 1, 3-diazine or 1, 4-diazine group,

wherein the ring system formed by N, T, V, W and two carbon atoms contains no more than one oxygen atom, no more than one sulfur atom and 1, 2, 3 or 4 nitrogen atoms, wherein the oxygen and sulfur atoms are not present at the same time,

wherein the ring system formed by N, T, V, W and two carbon atoms is unsubstituted or mono-to trisubstituted, independently of one another, by substituents as defined under 1.1 to 1.19 above,

other substituents R¹、R²、R³And R⁴Independently of each other are

1. The presence of hydrogen in the presence of hydrogen,

2. the halogen(s) are selected from the group consisting of,

3. aryl, wherein aryl is as defined above, unsubstituted or substituted as described above,

4. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, unsubstituted or substituted as defined above,

5. heterocyclic having 5 to 12 ring members, wherein the heterocyclic is as defined above and is unsubstituted or substituted as defined above,

6. -(C₁-C₆) -an alkyl group,

7. -CN，

8. -O-R¹⁰，

9. -N(R¹⁰)₂，

10.-S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2, or

11.-CF₃，

R⁵Is a mixture of 1. hydrogen,

2.-OH, or

3.＝O，

R⁶Is an aryl group, wherein aryl is as defined above, unsubstituted or substituted as defined above,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, or

3. A heterocycle having 5 to 12 ring members, wherein the heterocycle is as defined above.

2. A compound of formula I as claimed in claim 1, wherein

Substituent R¹、R²、R³And R⁴One of which is a radical of the formula II in which

D is-C (O) -,

R⁷is hydrogen or- (C)₁-C₄) -an alkyl group,

R⁸is 1- (C)₁-C₄) -alkyl, wherein the alkyl is linear or branched, mono-or di-substituted independently of each other by the following substituents:

1.1 heteroaryl having 5 to 14 ring members or heterocycle having 5 to 12 ring members, wherein heteroaryl and heterocycle are selected from pyrrole, pyridine, pyrazine, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazolone, 1, 2, 3, 5-oxathiadiazole 2-oxide, oxadiazolone, isoxazolone, oxadiazolidinedione, oxadiazinedione, F, -CN, -CF₃or-C (O) -O- (C)₁-C₄) Alkyl-substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazoles, pyrimidines, indoles, isoindoles, indazoles, phthalazines, quinolines, isoquinolines, quinoxalines, quinazolines, cinnolines, carbolines and benzo-fused, cyclopenta-, cyclohexo-and cyclohepta-fused derivatives of these heterocycles,

1.2 -O-R¹⁰，

1.3 -S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

1.4 -N(R¹⁰)₂，

1.5 radicals of the formula

Or

1.6 radicals of the formula

Or

2. A characteristic group of an amino acid selected from the group consisting of histidine, serine, tryptophan, threonine, cysteine, methionine, asparagine, glutamic acid and aspartic acid,

R⁹is 1.R⁸，

2.-(C₁-C₄) -alkyl, wherein alkyl is linear or branched and is mono-, di-or tri-substituted independently of each other by the following substituents:

2.1 aryl, wherein aryl is as defined in claim 1, which is unsubstituted or substituted as defined in claim 1,

2.2 of the halogen, in the presence of hydrogen,

2.3-CN, or

2.4 -CF₃，

3. Aryl, wherein aryl is as defined in claim 1, unsubstituted or substituted as defined in claim 1,

4. the presence of hydrogen in the presence of hydrogen,

R¹⁰is a) a hydrogen atom, and is,

b)-(C₁-C₆) -an alkyl group, wherein the alkyl group is unsubstituted or mono-to trisubstituted, independently of each other, by the following substituents:

1. the aryl group is as defined in claim 1,

2. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above

In the meaning of,

3. heterocyclic having 5 to 12 ring members, wherein the heterocyclic is as defined above,

4. the halogen(s) are selected from the group consisting of,

5.-N-(C₁-C₆)_n-alkyl, wherein n is the integer 0, 1 or 2, alkyl being unsubstituted or mono-, di-or tri-substituted independently of each other by halogen or-COOH, or

6.-COOH，

c) Aryl, wherein aryl is as defined in claim 1,

d) heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above

Meaning, or

e) Heterocyclic having 5 to 12 ring members, wherein the heterocyclic is as defined above,

and is

In (R)¹⁰)₂In the case of (1), R¹⁰Independently of one another have the meanings a) to e),

z is 1.1, 3, 4-oxadiazole, wherein the 1, 3, 4-oxadiazole is unsubstituted or substituted by-NH₂OH or- (C)₁-C₄) -alkyl is mono-to tri-substituted, or

2.-C(O)-R¹¹Wherein

R¹¹Is 1.-O-R¹⁰Or is or

2.-N(R¹⁰)₂Or is or

R⁷And R⁸Together with the carbon atom to which they are each bound, form a ring of formula IIa, selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, tetrazole, 1, 2, 3, 5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone, oxadiazolidinedione, unsubstituted or substituted with F, -CN, -CF₃or-C (O) -O- (C)₁-C₄) -alkyl substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazole, isoxazole, 2-isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, isoquinoline, tetrahydroquinoline, and tetrahydroisoquinoline, or

R⁸And Z together with the carbon atom to which they are each bonded form a ring of formula IIc selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, pyrazoline, phthalazine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, 1, 3, 4-oxadiazole, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, and,2-isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, tetrazole, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline, 1, 2, 3, 5-oxathiadiazole 2-oxide, oxadiazolone, isoxazolidone, triazolone, oxadiazolidinedione, unsubstituted or substituted with F, -CN, -CF₃or-C (O) -O- (C)₁-C₄) -alkyl substituted triazoles, 3-hydroxypyrrole-2, 4-diones, 5-oxo-1, 2, 4-thiadiazoles and isoquinolines,

other substituents R¹、R²、R³And R⁴Independently of each other are

1. The presence of hydrogen in the presence of hydrogen,

2. the halogen(s) are selected from the group consisting of,

3. aryl, wherein aryl is as defined in claim 1, unsubstituted or substituted as defined in claim 1,

4. heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, unsubstituted or substituted as defined in claim 1,

5. a heterocycle having 5 to 12 ring members wherein the heterocycle is as defined above and is unsubstituted or substituted as defined in claim 1, or

6.-(C₁-C₆) -an alkyl group,

7.-CN，

8.-CF₃，

9.-O-R¹⁰，

10.-N(R¹⁰)₂or is or

11.-S(O)_x-R¹⁰Wherein x is an integer of 0, 1 or 2,

R⁵is a hydrogen atom, and is,

R⁶is 1. phenyl, mono-or di-substituted independently of each other by the following substituents:

1.1 -CN，

1.2 -CF₃or is or

1.3 of a halogen,

1.4 -O-R¹⁰，

1.5 -N(R¹⁰)₂，

1.6 -NH-C(O)-R¹¹，

1.7 -S(O)_x-R¹⁰wherein x is an integer of 0, 1 or 2,

1.8 -C(O)-R¹¹or is or

1.9 -(C₁-C₄) -alkyl-NH₂，

2. Heteroaryl having 5 to 14 ring members, wherein heteroaryl is as defined above, unsubstituted or mono-, di-or trisubstituted independently of one another by substituents as defined under 1.1 to 1.9 above, or

3. Heterocycles having 5 to 12 ring members, wherein the heterocycle is as defined above, unsubstituted or mono-, di-or tri-substituted independently of one another by substituents as defined above under 1.1 to 1.9.

3. A compound of formula I as claimed in claim 1 or 2, wherein

Substituent R¹、R²、R³And R⁴One of which is a radical of the formula II in which

D is-C (O) -,

R⁷is a hydrogen atom, and is,

z is-COOH or-C (O) -NH₂，

R⁸Is 1- (C)₁-C₄) -alkyl, wherein the alkyl is linear or branched, mono-or di-substituted independently of each other by the following substituents:

1.1 -S(O)-R¹⁰wherein R is¹⁰Is as defined in the following, and is,

1.2 -N(R¹⁰)₂wherein R is¹⁰Is as defined below, or

1.3 pyrrole, or

2. A characteristic group of an amino acid selected from the group consisting of histidine, serine, tryptophan, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid,

R⁹is a mixture of 1. hydrogen,

2.-(C₁-C₄) -alkyl, wherein alkylIs linear or branched and is independently of one another substituted by-COOH, -OH or-C (O) -NH₂Mono-, di-or tri-substituted, or

3. Phenyl, wherein the phenyl is unsubstituted or independently of one another is halogen or- (C)₁-C₄) -alkyl mono-to tri-substituted,

R¹⁰is a) a hydrogen atom, and is,

b)-(C₁-C₆) Alkyl, wherein the alkyl is unsubstituted or mono-to trisubstituted independently of one another by halogen,

c) phenyl, wherein the phenyl is unsubstituted or independently of one another is halogen or- (C)₁-C₄) -alkyl mono-to tri-substituted,

other substituents R¹、R²、R³And R⁴In each case hydrogen, is present in the reaction mixture,

R⁵is a hydrogen atom, and is,

R⁶is phenyl or pyridine.

4. A process for the preparation of a compound of formula I as claimed in any one of claims 1 to 3, which process comprises

a) Reacting a compound of the formula IV in solution in the presence of a base or, if appropriate, in the presence of a dehydrating agent

Wherein Pg is a suitable protecting group, amide group or hydroxyl group, Z, R⁷And R⁸Is as defined in formula I,

with an acid chloride or activated ester of a compound of formula III,

wherein D1 is-COOH or sulfonyl halide, R⁵、R⁶And R⁹Is as defined in formula I,

after removal of the protecting group, are converted into compounds of the formula I, or

b) Reacting a compound of the formula IVa in the presence of a base or, if appropriate, in the presence of a dehydrating agent

Wherein R is⁷And R⁸Is as defined for formula I, E is an N-amino protecting group,

coupling the carbonyl group of the compound with a polymeric resin of the formula PS via an intermediate chain L, and selectively removing the protecting group E to obtain a compound of the formula V

Reacting it with a compound of formula III, wherein R⁵、R⁶And R⁹Is as defined in formula I,

to obtain the compound of the formula VI,

after cleavage from the carrier, the compound of formula VI is converted to a compound of formula I, or

c) Converting the compound of formula I into a physiologically acceptable salt.

5. Medicament comprising an effective amount of at least one compound of the formula I as claimed in any of claims 1 to 3 and pharmaceutically suitable and physiologically tolerable excipients, additives and/or further active compounds and auxiliaries.

6. The use of at least one compound of the formula I as claimed in any of claims 1 to 3 for the preparation of medicaments for the prophylaxis and treatment of diseases which are associated with an increased nfkb activity.

7. The use as claimed in claim 6 for the treatment of chronic motor organ disorders, or degenerative joint disorders, or connective tissue disorders, or disorders caused by TNF α overexpression or increased TNF α concentration, or the following disorders: atherosclerosis, stenosis, ulcer formation, alzheimer's disease, muscle wasting, cancerous disorders, myocardial infarction, gout, sepsis, septic shock, endotoxic shock, disorders resulting from viral infection, parasitic infection, fungal or yeast infection, meningitis, chronic inflammatory lung disease, acute respiratory distress syndrome, acute synovitis, tuberculosis, psoriasis, diabetes, acute or chronic rejection of transplanted organs by organ recipients, graft-versus-host disorders, and inflammatory vascular disorders.

8. A process for the preparation of a medicament, which comprises bringing at least one compound of the formula I as claimed in any of claims 1 to 3 into a suitable administration form with pharmaceutically suitable and physiologically tolerable excipients, optionally also suitable active compounds, additives or auxiliaries.