US20030119820A1 - Substituted indoles - Google Patents
Substituted indoles Download PDFInfo
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- US20030119820A1 US20030119820A1 US10/263,691 US26369102A US2003119820A1 US 20030119820 A1 US20030119820 A1 US 20030119820A1 US 26369102 A US26369102 A US 26369102A US 2003119820 A1 US2003119820 A1 US 2003119820A1
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- United States
- Prior art keywords
- unsubstituted
- alkyl
- formula
- substituted
- ring members
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 0 [1*]C1=C([2*])C([3*])=C([4*])C2=C1N([5*])C([6*])=C2[9*] Chemical compound [1*]C1=C([2*])C([3*])=C([4*])C2=C1N([5*])C([6*])=C2[9*] 0.000 description 26
- DMIALZBVYUFTSP-QHCPKHFHSA-N CCN(C[C@H](NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1)C(N)=O)C1=CC=CC=C1 Chemical compound CCN(C[C@H](NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1)C(N)=O)C1=CC=CC=C1 DMIALZBVYUFTSP-QHCPKHFHSA-N 0.000 description 2
- OCAAZKAMXBBGEY-FQEVSTJZSA-N CC(=O)O.CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CCN3C=CC=C3)C(N)=O)C=C21 Chemical compound CC(=O)O.CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CCN3C=CC=C3)C(N)=O)C=C21 OCAAZKAMXBBGEY-FQEVSTJZSA-N 0.000 description 1
- GSIDHXDHQMKPIC-NRFANRHFSA-N CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CSC3=CC=CC=C3)C(=O)O)C=C21 Chemical compound CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CSC3=CC=CC=C3)C(=O)O)C=C21 GSIDHXDHQMKPIC-NRFANRHFSA-N 0.000 description 1
- UMVYWBDVHPTAEV-NRFANRHFSA-N CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CSC3=CC=CC=C3)C(N)=O)C=C21 Chemical compound CC1=C(C2=CC=NC=C2)NC2=CC=C(C(=O)N[C@@H](CSC3=CC=CC=C3)C(N)=O)C=C21 UMVYWBDVHPTAEV-NRFANRHFSA-N 0.000 description 1
- YZMHXPZUVKRPJD-MHZLTWQESA-N NC(=O)[C@H](CCC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=CC=C3)=C(C3=CC=CC=C3)C2=C1 Chemical compound NC(=O)[C@H](CCC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=CC=C3)=C(C3=CC=CC=C3)C2=C1 YZMHXPZUVKRPJD-MHZLTWQESA-N 0.000 description 1
- KFCLVPGSUJELJD-NRFANRHFSA-N NC(=O)[C@H](CCC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 Chemical compound NC(=O)[C@H](CCC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 KFCLVPGSUJELJD-NRFANRHFSA-N 0.000 description 1
- XTLWPRWKCQPKQN-NRFANRHFSA-N NC(=O)[C@H](CCCN1C=CC=C1)NC(=O)C1=CC2=C(C=C1)NC(C1=CC=NC=C1)=C2CC(=O)O Chemical compound NC(=O)[C@H](CCCN1C=CC=C1)NC(=O)C1=CC2=C(C=C1)NC(C1=CC=NC=C1)=C2CC(=O)O XTLWPRWKCQPKQN-NRFANRHFSA-N 0.000 description 1
- NQFPEVUXSAVPQV-NRFANRHFSA-N NC(=O)[C@H](CSC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 Chemical compound NC(=O)[C@H](CSC1=CC=CC=C1)NC(=O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 NQFPEVUXSAVPQV-NRFANRHFSA-N 0.000 description 1
- ZKCMVOTVUCGVRH-NRFANRHFSA-N O=C(N[C@@H](CSC1=CC=CC=C1)C(=O)O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 Chemical compound O=C(N[C@@H](CSC1=CC=CC=C1)C(=O)O)C1=CC=C2NC(C3=CC=NC=C3)=CC2=C1 ZKCMVOTVUCGVRH-NRFANRHFSA-N 0.000 description 1
Classifications
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the invention relates to novel substituted indoles, to processes for their preparation and to their use as pharmaceuticals.
- NF ⁇ B is a heterodimeric transcription factor which can activate a large number of genes which code, inter alia, for proinflammatory cytokines such as IL-1, IL-2, TNF ⁇ or IL-6.
- cytokines such as IL-1, IL-2, TNF ⁇ or IL-6.
- NF ⁇ B is present in the cytosole of cells, complexed with its naturally occurring inhibitor I ⁇ B.
- the stimulation of cells, for example by cytokines leads to the phosphorylation and subsequent proteolytic degradation of I ⁇ . This proteolytic degradation leads to the activation of NF ⁇ B, which subsequently migrates into the nucleus of the cell and there activates a large number of proinflammatory genes.
- NF ⁇ B is activated beyond the normal extent.
- the inhibition of NF ⁇ B is also of benefit in cancer therapy, since it is employed there for the reinforcement of the cytostatic therapy.
- pharmaceuticals such as glucocorticoids, salicylates or gold salts, which are employed in rheumatic therapy, intervene in an inhibitory manner at various points in the NF ⁇ B-activating signal chain or interfere directly with the transcription of the genes.
- the first step in the signal cascade mentioned is the degradation of I ⁇ B. This phosphorylation is regulated by the specific I ⁇ B kinase. To date, no inhibitors are known which specifically inhibit I ⁇ B kinase.
- indole derivatives according to the invention are potent and very specific inhibitors of I ⁇ B kinase.
- the invention therefore relates to the compounds of the formula I
- D is —C(O)—, —S(O)— or —S(O) 2 —,
- R 7 is hydrogen or —(C 1 -C 4 )-alkyl
- R 8 is R or the characteristic radical of an amino acid
- R 9 is 1. aryl, where aryl is unsubstituted or substituted
- heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or
- R 10 is a) hydrogen
- n is the integer zero, 1 or 2 and alkyl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by halogen or by —C(O)—OH, or
- Z is 1. aryl, where aryl is unsubstituted or substituted
- heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or
- R 11 is 1. —O—R 10 or
- R 7 and R 8 form, together with the nitrogen atom and carbon atom to which they are each bonded, a heterocyclic ring of the formula IIa,
- A is a nitrogen atom or the radical —CH 2 —
- B is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,
- X is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,
- Y is absent or is an oxygen atom, sulfur atom, sulfoatom or the radical —CH 2 -, or
- X and Y together form a phenyl, 1,2-diazine, 1,3-diazine or a 1,4-diazine radical,
- R 8 and Z form, together with the carbon atoms to which they each are bonded, a heterocyclic ring of the formula IIc,
- T is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,
- W is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 —,
- V is absent or is an oxygen atom, sulfur atom, nitrogen atom or the radical —CH 2 -, or
- T and V or V and W together form a phenyl, 1,2-diazine, 1,3-diazine or a 1,4-diazine radical,
- the ring system formed by N, T, V, W and two carbon atoms contains not more than one oxygen atom, not more than one sulfur atom and 1, 2, 3 or 4 nitrogen atoms, where an oxygen atom and sulfur atom do not occur at the same time, and where the ring system formed by N, T, V, W and two carbon atoms is unsubstituted or mono- to trisubstituted, independently of one another, by the substituents defined above under 1.1. to 1.19.,
- R 5 is 1. hydrogen
- R 6 is 1. aryl, where aryl is unsubstituted or substituted
- heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or mono- to trisubstituted, or
- heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or mono- to trisubstituted.
- a preferred compound of the formula I is one where one of the substituents R 1 , R 2 , R 3 and R 4 is a radical of the formula II, in which
- D is —C(O)—
- R 7 is hydrogen or —(C 1 -C 4 )-alkyl
- R 8 is 1. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and is mono- or disubstituted, independently of one another, by
- R 9 is 1. R 8 ,
- R10 is a) hydrogen
- n is the integer zero, 1 or 2 and alkyl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by halogen or by —C(O)—OH, or
- Z is 1. 1,3,4-oxadiazole, where 1,3,4-oxadiazole is unsubstituted or mono- to trisubstituted by —NH 2 , OH or —(C 1 -C 4 )-alkyl or
- R 11 is 1. —O—R 10 or
- R 7 and R 8 form, together with the nitrogen atom and carbon atom to which they are each bonded, a ring of the 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, isoxazolidine, morpholine, isothiazole, thiazole, thiadiazole, benzimidazole, thiomorpholine, isothiazolidine, indazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, pteridine, tetrahydroquinoline, isoquinoline, 1,2,
- R 8 and Z form, together with the carbon atoms to which they are each bonded, a ring of the formula IIc selected from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, 1,3,4-oxadiazole, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, tetrazole, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, te
- heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or substituted, or
- R 5 is hydrogen
- R 6 is 1. phenyl, mono- or disubstituted, independently of one another, by
- heteroaryl having 5 to 14 ring members, where heteroaryl is unsubstituted or mono-, di- or trisubstituted, independently of one another, by the substituents defined above under 1.1 to 1.9 or
- heterocycle having 5 to 12 ring members, where heterocycle is unsubstituted or mono-, di- or trisubstituted, independently of one another, by the substituents defined above under 1.1 to 1.9.
- a particularly preferred compound of the formula I is one where
- one of the substituents R 1 , R 2 , R 3 and R 4 is a radical of the formula II, in which
- D is —C(O)—
- R 7 is hydrogen
- Z is —C(O)—OH or —C(O)—NH 2 ,
- R 8 is 1. —(C 1 -C 4 )-alkyl, where alkyl is straight-chain or branched and is mono- or disubstituted, independently of one another, by
- R 10 is a) hydrogen
- R 5 is hydrogen
- R 6 is phenyl or pyridine
- R 9 is 1. hydrogen
- phenyl where phenyl is unsubstituted or mono- to trisubstituted, independently of one another, by halogen or —(C 1 -C 4 )-alkyl.
- halogen is understood as meaning fluorine, chlorine, bromine or iodine.
- (C 1 -C 8 )-alkyl”, “(C 1 -C 6 )-alkyl” or “(C 1 -C 4 )-alkyl” are understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 8, 1 to 6 and 1 to 4 carbon atoms, respectively. Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- R 7 and R 8 form, together with the nitrogen atom and carbon atom to which they are each bonded, a heterocyclic ring of the formula IIa”, is understood as meaning radicals which are 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, triazolones, tetrazol
- aryl is understood as meaning aromatic hydrocarbon radicals having 6 to 14 carbon atoms in the ring.
- (C 6 -C 14 )-Aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl.
- Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.
- Aryl radicals in particular phenyl radicals, can be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted or trisubstituted, by identical or different radicals, preferably by radicals from the group consisting of (C 1 -C 8 )-alkyl, in particular (C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkoxy, in particular (C 1 -C 4 )-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C 1 -C 4 )-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C 1 -C 4 )-alkoxycarbonyl, phenyl, phenoxy, benzyl,
- Arylalkyl radicals are, in particular, benzyl and also 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl.
- Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C 1 -C 8 )-alkyl radicals, in particular (C 1 -C 4 )-alkyl radicals, for example 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, by one or more (C 1 -C 8 )-alkoxy radicals, in particular (C 1 -C 4 )-alkoxy radicals, benzyl radicals and naphthylmethyl radicals substituted in the aryl
- the substituent can be located in the 2-position, the 3-position or the 4-position.
- Disubstituted phenyl can be substituted in the 2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the 3,4-position or the 3,5-position.
- trisubstituted phenyl radicals the substituents can be located in the 2,3,4-position, the 2,3,5-position, the 2,4,5-position, the 2,4,6-position, the 2,3,6-position or the 3,4,5-position.
- aryl radicals apply accordingly to divalent arylene radicals, for example to phenylene radicals which can be present, for example, as 1,4-phenylene or as 1,3-phenylene.
- Phenylene-(C 1 -C 6 )-alkyl is in particular phenylenemethyl (-C6H 4 —CH 2 -) and phenyleneethyl
- (C 1 -C 6 )-alkylenephenyl is in particular methylenephenyl (—CH 2 —C 6 H 4 —).
- Phenylene-(C 2 -C 6 )-alkenyl is in particular phenyleneethenyl and phenylenepropenyl.
- heteroaryl having 5 to 14 ring members represents a radical of a monocyclic or polycyclic aromatic system 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 a number of heteroatoms are contained, these can be identical or different.
- Heteroaryl radicals can likewise be monosubstituted or polysubstituted, preferably mono-substituted, disubstituted or trisubstituted, by identical or different radicals from the group consisting of (C 1 -C 8 )-alkyl, in particular (C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkoxy, in particular (C 1 -C 4 )-alkoxy, halogen, nitro, —N(R 10 ) 2 , trifluoromethyl, hydroxyl, hydroxy-(C 1 -C 4 )-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C 1 -C 4 )-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy,
- 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 consisting of N, O and S and which can be substituted by 1, 2, 3 or 4, in particular 1 to 3, identical or different substituents from the group consisting of (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, fluorine, chlorine, nitro, —N(R 10 ) 2 , trifluoromethyl, hydroxyl, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-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-membered or 6-membered monocyclic aromatic radical which contains 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms from the group consisting of N, O and S and can be substituted by 1 or 2 identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl, halogen, hydroxyl, —N(R 10 ) 2 , (C 1 -C 4 )-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.
- heterocycle having 5 to 12 ring members represents a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which is partly saturated or completely saturated. Examples of heteroatoms are N, O and S.
- the heterocycle is unsubstituted or substituted on one or more carbon atoms or on one or more heteroatoms by identical or different substituents. These substituents have been defined above for the radical heteroaryl.
- the heterocyclic ring is monosubstituted or polysubstituted, for example monosubstituted, disubstituted, trisubstituted or tetrasubstituted, on carbon atoms by identical or different radicals from the group consisting of (C 1 -C 8 )-alkyl, for example (C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkoxy, for example (C 1 -C 4 )-alkoxy such as methoxy, phenyl-(C 1 -C 4 )-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl and/or it is substituted on the ring nitrogen atom(s) in the heterocyclic ring by (C 1 -C 8 )-alkyl, for example (C 1 -C 4 )-alkyl such as methyl or ethyl, by
- heteroaryl having 5 to 14 ring members or heterocycle having 5 to 12 ring members are radicals which are derived from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles, which are substituted by F, —CN, —CF 3 or —C(O)—O—(C 1 -C 4 )-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline,
- radicals are 2- or 3-pyrrolyl, phenylpyrrolyl such as 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
- the ⁇ -amino acids differ from one another by the radical R, which in the context of the present application is described as a “characteristic radical” of an amino acid.
- R 8 is the characteristic radical of an amino acid
- the characteristic radicals employed are preferably those of the following naturally occurring ⁇ -amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid.
- Those particularly preferred are histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid.
- Preferred characteristic radicals of an amino acid which are furthermore employed as the radical R 8 are also non-naturally occurring amino acids such as 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, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleu
- Suitable protective groups for this are preferably the N-protective groups customarily used in peptide chemistry, for example protective groups of the urethane type, benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenyl-oxycarbonyl (Fmoc), allyloxycarbonyl (Aloc) or of the acid amide type, in particular formyl, acetyl or trifluoroacetyl, and of the alkyl type, for example benzyl.
- protective groups of the urethane type benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenyl-oxycarbonyl (Fmoc), allyloxycarbonyl (Aloc) or of the acid amide type, in particular formyl, acetyl or trifluoroacetyl, and of the alkyl type, for example benzyl.
- the sulfonic acid derivative of the formula IV employed for the sulfonamide formation is used as a protective group of the imidazole nitrogen, which can be removed again, in particular in the presence of bases such as aqueous sodium hydroxide solution.
- the invention further relates to a process for preparing compounds of the formula I and/or a stereoisomeric form of the compound of the formula I and/or of a physiologically acceptable salt of the compound of the formula I, which comprises
- Pg is a suitable protective group (for example methyl ester), an amide group or a hydroxyl group and Z, R 7 and R 8 are as defined in formula I, with an acyl chloride or an activated ester of the compound of the formula III,
- D1 is —OOOH or sulfonyl halogen and R 5 , R 6 and R 9 are as defined in formula I, in the presence of a base or, if appropriate, of a dehydrating agent in solution and, after removal of the protective group, converting into a compound of the formula I, or b) reacting a compound of the formula IVa,
- R 7 and R are as defined in formula I and E is an N-amino protective group, with its carbonyl group coupled via an intermediate chain L to a polymeric resin of the formula PS, a compound of the formula V
- process variant a the acid functions of the compounds of the formula IVa are provided with a protective group Pg; this selective carboxylic acid derivatization is carried out according to methods such as are described in Houben-Weyl “Methoden der Org. Chemie” [Methods of Organic Chemistry], Volume 15/1.
- process variant b the amino functions of the starting compounds of the formula IVa are provided with a protective group E; this selective amino groups derivatization is carried out according to methods such as are described in Houben-Weyl “Methoden der Org. Chemie” [Methods of Organic Chemistry], Volume 15/1.
- a suitable protective group Pg preferably used for this is the carboxyl protective groups customary in peptide chemistry, for example protective groups of the alkyl ester type, such as methyl, ethyl, tert-butyl, isopropyl, benzyl, fluorenylmethyl, allyl, aryl ester type, such as phenyl, amide type, such as amide or benzhydrylamine.
- the alkyl ester type such as methyl, ethyl, tert-butyl, isopropyl, benzyl, fluorenylmethyl, allyl, aryl ester type, such as phenyl, amide type, such as amide or benzhydrylamine.
- Suitable protective groups E used for this are preferably the N-protective groups customary in peptide chemistry, for example protective groups of the urethane type, such as benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc) or of the acid amide type, in particular formyl, acetyl or trifluoroacetyl of alkyl type such as benzyl.
- the (trimethylsilyl)ethoxycarbonyl (Teoc) group has also proven particularly suitable for this (P. Kociénski, Protecting Groups, Thieme Verlag 1994).
- the indolecarboxylic acid derivatives were prepared following a method described in Houben-Weyl “Methoden der Org. Chemie” [Methods of Organic Chemistry], Volume E6-2A and E6-2B.
- the hydrazinobenzoic acids required are prepared by methods known to the person skilled in the art, for example from the corresponding benzoic acid anilines.
- Aryl ketones or heteroaryl ketones are likewise prepared by methods familiar to the person skilled in the art, for example, from the corresponding acyl chlorides or nitriles by reaction with, for example, organometallic compounds.
- Suitable condensing agents or coupling reagents are compounds such as carbonyidiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC), O-((cyano(ethoxycarbonyl)methylene)-amino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) or propane-phosphonic anhydride (PPA).
- the condensations can be carried out under standard conditions. During the condensation, as a rule it is necessary for the non-reacting amino groups present to be protected by reversible protective groups. The same applies to carboxyl groups not involved in the reaction, which during the condensation are preferably present as (C 1 -C 6 )-alkyl esters, benzyl esters or tert-butyl esters. Amino group protection is unnecessary if the amino groups are still present in the form of precursors such as nitro groups or cyano groups and are only formed by hydrogenation after the condensation. After the condensation, the protective groups present are removed in a suitable manner.
- NO 2 groups (guanidino protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters can be removed by hydrogenation.
- the protective groups of the tert-butyl type are removed acidically, while the 9-fluorenylmethoxycarbonyl radical is removed by secondary amines.
- the polymeric support designated in the formulae V and VI by PS is a crosslinked polystyrene resin having a linker designated as the intermediate chain L.
- This linker carries a suitable functional group, for example amine, known, for example, as Rink amide resin, or an OH group, known, for example, as Wang resin or Kaiser's oxime resin.
- amine known, for example, as Rink amide resin
- OH group known, for example, as Wang resin or Kaiser's oxime resin.
- other polymeric supports such as glass, cotton or cellulose having various intermediate chains L can be employed.
- the intermediate chain designated by L is covalently bonded to the polymeric support and allows a reversible, amide-like or ester-like bond with the compound of the formula IVa, which remains stable during the further reaction on the bonded compound of the formula IVa; but under strongly acidic reaction conditions, e.g. mixtures with trifluoroacetic acid, releases the group located on the linker again.
- the resin was washed a number of times with dichloromethane.
- the cleavage solution (50% dichloromethane and 50% of a mixture of 95% TFA, 2% H 2 O, 3% triisopropylsilane) was then added and 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 residues usually contained the desired products in high purity or were fractionated, for example, on a reverse phase (eluent: A: H 2 O/0.1% TFA, B: acetonitrile/0.1% TFA) using preparative high-pressure liquid chromatography. Lyophilization of the fractions obtained yielded the desired products.
- both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid are suitable.
- the invention also relates to pharmaceuticals which comprise an efficacious amount of at least one compound of the formula I and/or of a physiologically tolerable salt of the compounds of the formula I and/or an optionally stereolsomeric form of the compounds of the formula I, together with a pharmaceutically suitable and physiologically tolerable excipient, additive and/or other active compounds and auxiliaries.
- the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in whose course an increased activity of IkB kinase is involved.
- compounds of the present invention are useful in the treatment of joint inflammation, Including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis.
- the compounds are useful in the treatment of acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, toxic shock syndrome, chronic pulmonary inflammatory diseases including asthma and adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejection and leprosy.
- the compounds are useful in the treatment of: infections such as viral infections, for example HIV, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, parasitic infections, for example malaria such as cerebral malaria, and yeast and fungal infections, for example fungal meningitis; fever and myalgias due to infection; AIDS; AIDS related complex (ARC); cachexia secondary to infection or malignancy; cachexia secondary to acquired immune deficiency syndrome (AIDS) or to cancer; keloid and scar tissue formation; pyresis; diabetes; and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
- infections such as viral infections, for example HIV, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, parasitic infections, for example malaria such as cerebral malaria, and yeast and fungal infections, for example fungal meningitis; fever and myalgias due to infection; AIDS; AIDS related complex (ARC); cachexia secondary to infection or malign
- the compounds of the invention are also useful in the treatment of diseases of or injury to the brain in which over-expression of TNF ⁇ has been implicated such as multiple sclerosis, and head trauma.
- the compounds according to the invention are also useful in the treatment of psoriasis, Alzheimer's disease, carcinomatous disorders (potentiation of cytotoxic therapies), cardiac infarct, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
- compositions according to the invention are in general administered orally or parenterally. Rectal or transdermal administration is also possible.
- the invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.
- Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations having protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.
- auxiliaries such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.
- auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
- the pharmaceutical preparations are preferably produced and administered in dose units, each unit containing as active constituent a certain dose of the compound of the formula I according to the invention.
- this dose can be up to approximately 1000 mg, preferably from approximately 50 mg to 300 mg and in the case of injection solutions in ampoule form up to approximately 300 mg, preferably from approximately 10 mg to 100 mg.
- daily doses for the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compound according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, preferably from approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, even higher or lower daily doses may be appropriate.
- the administration of the daily dose can be carried out both by single administration In the form of an individual dose unit or else of a number of smaller dose units and by multiple administration of subdivided doses at specific intervals.
- the activity of the I ⁇ B kinase was determined using an ELI SA comprising a biotinilated substrate peptide containing the amino acid sequence in the protein I ⁇ B of serines 32 to 36 and a specific poly- or monoclonal antibody (for example from New England Biolabs, Beverly, Mass., USA, cat.: 9240), which binds only to the phosphorylated form of the peptide I ⁇ B.
- This complex was immobilized on an antibody-binding plate (coated with protein A) and detected using a conjugate of a biotin-binding protein and HRP (for example streptavidine HRP). The activity could be quantified using a standard curve with substrate phosphopeptide.
- the sample was applied to a 320 ml Superose-6 FPLC column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) which had been equilibrated with SEC buffer and was operated at a flow rate of 2 ml/min at 4° C.
- the fractions which corresponded to the elution time of the 670 kDa molecular weight standard were combined for activation.
- Activation was achieved by a 45-minute-incubation with 100 nM MEKK1 ⁇ , 250 PM MgATP, 10 mM MgCl 2 , 5 mM dithiothreitol (DTT), 10 mM 2-glycerophosphate, 2.5 PM microcystin LR at 37° C.
- the activated enzyme was stored at ⁇ 80° C.
- test substances dissolved in DMSO (2 ⁇ l), were preincubated at 25° C. with 43 ⁇ l of activated enzyme (diluted 1:25 in reaction buffer 50 mM HEPES, pH 7.5, 10 mM MgCl 2 . 5 mM DTT, 10 mM ⁇ -glycerophosphate, 2.5 ⁇ M microcystin LR) for 30 minutes.
- activated enzyme diluted 1:25 in reaction buffer 50 mM HEPES, pH 7.5, 10 mM MgCl 2 . 5 mM DTT, 10 mM ⁇ -glycerophosphate, 2.5 ⁇ M microcystin LR
- cAMP-dependent protein kinase PKA
- PKC protein kinase C
- CK II casein kinase 11
- PDA cAMP-dependent protein kinase
- PLC protein kinase C
- CK II casein kinase 11
- phosphocellulose filters instead of phosphocellulose filters, multi-screen plates (Millipore; Phosphocellulose MS-PH, cat. MAPHNOB10) with the corresponding aspiration system were used. The plates were then measured in a Wallac MicroBeta scintillation counter. In each case, 100 ⁇ M of test substance were used.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US20040116494A1 (en) * | 2002-08-17 | 2004-06-17 | Aventis Pharma Deutschland Gmbh | Use of IkappaB-kinase inhibitors in pain therapy |
US20050004164A1 (en) * | 2003-04-30 | 2005-01-06 | Caggiano Thomas J. | 2-Cyanopropanoic acid amide and ester derivatives and methods of their use |
US20050197353A1 (en) * | 2002-08-17 | 2005-09-08 | Aventis Pharma Deutschland Gmbh | Indole derivatives or benzimidazole derivatives for modulating IkB kinase |
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US20040116494A1 (en) * | 2002-08-17 | 2004-06-17 | Aventis Pharma Deutschland Gmbh | Use of IkappaB-kinase inhibitors in pain therapy |
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