CA2304451A1 - Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents - Google Patents
Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents Download PDFInfo
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Abstract
New specific immunophilin ligands of general formula (I) have anti-asthmatic, anti-allergic, anti-rheumatic, anti-inflammatory, immunosuppressive, antipsoriatic and neuroprotective effects and are suitable for preparing medicaments.
Description
~WO 99/15501 PCT/EP98105300 SPECIFIC IMMUNOPHILIN LIGANDS AS ANTIASTHMATICS, ANTIALLERGICS, ANTIRHEUMATICS, IMMUNOSUPPRESSANTS, ANTIPSORIATICS AND NEUROPROTECTANTS
The invention relates to novel specific immunophilin ligands of the formula B
R3 A N.D.Y-Z'R
O=S=O X
"2 The radicals R1, R2, R3, X, Y, Z, A, B and D have the following meaning:
R, - hydrogen, (C~-C~2)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] .. amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
R~ can additionally be the amine radical of the following amino acid methyl esters: histidine, leucine, valine, serine(Bzl), threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, s-NHZ-lysine, s-Z-NH-lysine, s-(2CI-Z~NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine(Tos), asparagine, citrulline, homocitrulline, ornithine, thiazolecarboxylic acid, proline, REPLACEMENT PAGE (RULE 26) 2-indolinecarboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid.
R2 = hydrogen, (C~-C~Z~alkyl or (C2-Cs~alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-Csralkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-Cs)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aryl- or heteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C~-C~2)-alkyl, 2U carboxycyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols.
R2 = amino-(C~-C~2~alkyl or amino-(C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves REPLACEMENT PAGE (RULE 26) ..
The invention relates to novel specific immunophilin ligands of the formula B
R3 A N.D.Y-Z'R
O=S=O X
"2 The radicals R1, R2, R3, X, Y, Z, A, B and D have the following meaning:
R, - hydrogen, (C~-C~2)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] .. amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
R~ can additionally be the amine radical of the following amino acid methyl esters: histidine, leucine, valine, serine(Bzl), threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, s-NHZ-lysine, s-Z-NH-lysine, s-(2CI-Z~NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine(Tos), asparagine, citrulline, homocitrulline, ornithine, thiazolecarboxylic acid, proline, REPLACEMENT PAGE (RULE 26) 2-indolinecarboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid.
R2 = hydrogen, (C~-C~Z~alkyl or (C2-Cs~alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-Csralkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-Cs)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aryl- or heteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C~-C~2)-alkyl, 2U carboxycyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols.
R2 = amino-(C~-C~2~alkyl or amino-(C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves REPLACEMENT PAGE (RULE 26) ..
are in tum substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aminoaryl- or aminoheteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C~-C12)-alkyl, carboxycyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C,-C6)-alkanols.
R3 = H, F, OR4, Br, NHR4.
R4 = hydrogen, (C3-C~)-cycloalkyl, (C,-C6)-alkyl or carboxy-(C~-Cs~alkyl, where the alkyl group can be straight-chain or branched and can be substituted by a mono- bi- or tricyclic carbonylaryl or carbonylhetero-aryl having 1-4 heteroatoms, preferably N, S and O, where aryl or heteroaryl itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C,-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl.
A = without a ring, aromatic, non-aromatic, aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O.
B=CHZ
D=CH
B-D = CH=C
X = O, S, H2 Y = S, C, single bond Z = S, O, NR5 RS = hydrogen, (C~-C~2)-alkyl or (C2-Csralkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, indole, indazole, REPLACEMENT PAGE (RULE 26) phthalazine, thiophene, furan, imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring can itself be mono-or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-Cs~alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
The invention furthermore relates to the physiologically tolerable salts of the compounds according to formula 1, the processes for the preparation of the compounds according to formula I, and their pharmaceutical use.
Cyclosporin A (CsA) and FK 506 are immunosuppressant natural substances derived from fungi which inhibit the Ca+2-dependent [sicJ signal transmission pathway in some cell types. In T cells, both agents inhibit the transcription of a number of genes, including the gene for IL-2, which is activated by stimulation of the T cell receptors (TCR). FK 506 and CsA
both bind with high affinity to -soluble receptor proteins (G. Fischer et al., Nature 337, 476-478, 1989; M.W. Harding et al., Nature 341, 755-760, 1989). The FK 506 receptor was called FKBP, the CsA receptor cyclophilin (Cyp). Both proteins catalyse the isomerization of cis- and traps-amide bond rotamers of peptides and are also frequently called immunophilins.
The supramolecule of CsA-Cyp or FK 506-FKBP binds calcineurin (CN) and inhibits its phosphatase activity. A cellular target molecule of CN was recognized as the cytosolic, phosphorylated component of the transcription factor NF-AT which, with inadequate CN activity for the action in the cell nucleus, cannot be dephosphorylated and thus the active transcription complex on the IL-2 promoter cannot be switched on (M.K. Rosen, S.L. Schreiber, Angew. Chem. 104 (1992); 413-430; G. Fischer, Angew.
Chem. 106 ( 1994), 1479-1501;
The allergic, asthmatic disorders are based on an inflammatory reaction which is controlled by T cells and their mediators. Corticosteroids are still the agent of choice in the treatment of many allergic disorders. CsA and FK 506 also proved in animal experiments and in clinical studies to be a favorable therapeutic in bronchial asthma and underlying inflammations. In REPLACEMENT PAGE (RULE 26) animal experiments, it was possible to show the blockade of various cytokines such as IL-2, IL-4 and IL-5, which cause allergically induced inflammations.
Despite the multiplicity of attempts at the identification of novel active immunophilin inhibitors, it was not possible until now to prepare or isolate any more efficacious structures than CsA, FK 506, rapamycin or derivatives of these natural substances. The high inhibitory potential of CsA, FK 506 or rapamycin, however, is very considerably reduced by the manifold side effects, in particular of the kidneys, and neurotoxicity.
(N.H. Sigal et al., J. Exp. Med. 173, 619-628, 1991). What lies behind this fact is the non-specificity of the interaction between immunophilin ligands and the cell-specific binding proteins. As a result, the known medicinal therapeutic action of these immunosuppressants is considerably restricted.
Furthermore, the inadequate selectivity of the compounds proves problematical, particularly in long-term therapy.
A further compound having immunosuppressant properties was discovered during the screening of combinatorial substance mixtures (G. Quinkert, i-i. Bang and D. Reichert, Helv. Chim. Acta 1996, 79, 1260). The structure published there is an indoline-2-carboxamide which at 10 Nmol exhibited an inhibition of IL-2 proliferation of 77% and at 1 Nmol an inhibition of IL-2 proliferation of 12%. New measurements at a concentration of 10 Nmol showed an IL-2-dependent inhibition of proliferation of 29%.
The compounds described in this invention markedly stand out at the C
terminus and in their optical purity of the indolinecarboxylic acid from the structure mentioned in the publication and additionally show a markedly better antiasthmatic, antiallergic, antirheumatic, anti-inflammatory, anti psoriatic and immunosuppressant activity.
A substance class which likewise contains indolinecarboxylic acid as a central unit and exhibits immunosuppressant properties as well as anti-asthmatic properties was described in the patent DE 196 16 509.1. The substances described there differ significantly at the N terminus from the substances described in this invention.
REPLACEMENT PAGE (RULE 26) 5.
R3 = H, F, OR4, Br, NHR4.
R4 = hydrogen, (C3-C~)-cycloalkyl, (C,-C6)-alkyl or carboxy-(C~-Cs~alkyl, where the alkyl group can be straight-chain or branched and can be substituted by a mono- bi- or tricyclic carbonylaryl or carbonylhetero-aryl having 1-4 heteroatoms, preferably N, S and O, where aryl or heteroaryl itself can be mono- or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C,-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl.
A = without a ring, aromatic, non-aromatic, aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O.
B=CHZ
D=CH
B-D = CH=C
X = O, S, H2 Y = S, C, single bond Z = S, O, NR5 RS = hydrogen, (C~-C~2)-alkyl or (C2-Csralkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S
and O, such as morpholine, piperazine, piperidine, indole, indazole, REPLACEMENT PAGE (RULE 26) phthalazine, thiophene, furan, imidazole, or can be mono- or polysubstituted by a phenyl ring. This phenyl ring can itself be mono-or polysubstituted by halogen, (C~-C6)-alkyl, (C3-C~)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C~-Cs~alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
The invention furthermore relates to the physiologically tolerable salts of the compounds according to formula 1, the processes for the preparation of the compounds according to formula I, and their pharmaceutical use.
Cyclosporin A (CsA) and FK 506 are immunosuppressant natural substances derived from fungi which inhibit the Ca+2-dependent [sicJ signal transmission pathway in some cell types. In T cells, both agents inhibit the transcription of a number of genes, including the gene for IL-2, which is activated by stimulation of the T cell receptors (TCR). FK 506 and CsA
both bind with high affinity to -soluble receptor proteins (G. Fischer et al., Nature 337, 476-478, 1989; M.W. Harding et al., Nature 341, 755-760, 1989). The FK 506 receptor was called FKBP, the CsA receptor cyclophilin (Cyp). Both proteins catalyse the isomerization of cis- and traps-amide bond rotamers of peptides and are also frequently called immunophilins.
The supramolecule of CsA-Cyp or FK 506-FKBP binds calcineurin (CN) and inhibits its phosphatase activity. A cellular target molecule of CN was recognized as the cytosolic, phosphorylated component of the transcription factor NF-AT which, with inadequate CN activity for the action in the cell nucleus, cannot be dephosphorylated and thus the active transcription complex on the IL-2 promoter cannot be switched on (M.K. Rosen, S.L. Schreiber, Angew. Chem. 104 (1992); 413-430; G. Fischer, Angew.
Chem. 106 ( 1994), 1479-1501;
The allergic, asthmatic disorders are based on an inflammatory reaction which is controlled by T cells and their mediators. Corticosteroids are still the agent of choice in the treatment of many allergic disorders. CsA and FK 506 also proved in animal experiments and in clinical studies to be a favorable therapeutic in bronchial asthma and underlying inflammations. In REPLACEMENT PAGE (RULE 26) animal experiments, it was possible to show the blockade of various cytokines such as IL-2, IL-4 and IL-5, which cause allergically induced inflammations.
Despite the multiplicity of attempts at the identification of novel active immunophilin inhibitors, it was not possible until now to prepare or isolate any more efficacious structures than CsA, FK 506, rapamycin or derivatives of these natural substances. The high inhibitory potential of CsA, FK 506 or rapamycin, however, is very considerably reduced by the manifold side effects, in particular of the kidneys, and neurotoxicity.
(N.H. Sigal et al., J. Exp. Med. 173, 619-628, 1991). What lies behind this fact is the non-specificity of the interaction between immunophilin ligands and the cell-specific binding proteins. As a result, the known medicinal therapeutic action of these immunosuppressants is considerably restricted.
Furthermore, the inadequate selectivity of the compounds proves problematical, particularly in long-term therapy.
A further compound having immunosuppressant properties was discovered during the screening of combinatorial substance mixtures (G. Quinkert, i-i. Bang and D. Reichert, Helv. Chim. Acta 1996, 79, 1260). The structure published there is an indoline-2-carboxamide which at 10 Nmol exhibited an inhibition of IL-2 proliferation of 77% and at 1 Nmol an inhibition of IL-2 proliferation of 12%. New measurements at a concentration of 10 Nmol showed an IL-2-dependent inhibition of proliferation of 29%.
The compounds described in this invention markedly stand out at the C
terminus and in their optical purity of the indolinecarboxylic acid from the structure mentioned in the publication and additionally show a markedly better antiasthmatic, antiallergic, antirheumatic, anti-inflammatory, anti psoriatic and immunosuppressant activity.
A substance class which likewise contains indolinecarboxylic acid as a central unit and exhibits immunosuppressant properties as well as anti-asthmatic properties was described in the patent DE 196 16 509.1. The substances described there differ significantly at the N terminus from the substances described in this invention.
REPLACEMENT PAGE (RULE 26) 5.
The invention is based on the object of finding novel compounds having useful pharmacological properties and making them available by targeted synthesis.
A class of substance which binds immunophilins surprisingly specifically, inhibits IL-2-dependent proliferation, and also inhibits the release of TNF-a and GM-CSF and surprisingly blocks a Ca++-dependent signal transmission pathway is represented by the compounds of the formula I according to the invention. This class of compounds and their pharmaceutically acceptable salts has [sic] a high affinity for immunophilins such as CypA, CypB, CypC
and FKBP12. Moreover, substances of the formula I inhibit various cytokine syntheses, as ~nrell as a Ca++-dependent signal transmission pathway.
-(hose compounds of the formula I which contain asymmetric carbon atoms and therefore as a rule occur as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid. However, the possibility also exists of. employing optically active starting substances to begin with, corresponding optically active or diastereoisomeric compounds then being obtained as the final product.
The invention thus comprises compounds of the formula I which contain an asymmetric carbon atom, the R form, the S form and R, S mixtures, and, the case of a number of asymmetric carbon atoms, the diastereoisomeric forms.
Depending on the process conditions and starting substances, the compounds of the formula I can be obtained as free compounds or in the form of their salts. The salts obtained can be converted into the free bases or acids in a manner known per se, for example using acids, alkali or ion exchangers.
The compounds of the formula I liberated in this way can be converted into the corresponding physiologically tolerable acid addition salts using inorganic or organic acids or bases.
Both the free bases and their salts are biologically active. The compounds of the formula I can be administered in free form or as a salt with a physio-REPLACEMENT PAGE (RULE 26) logically tolerable acid or base. Administration can be carried out orally, parenterally, intravenously, transdermally or by inhalation.
The invention further relates to pharmaceutical preparations which contain at least one compound of the formula I or its salts with physiologically tolerable inorganic or organic acids or bases and, if appropriate, pharma ceutically utilizable excipients and auxiliaries.
Suitable administration forms are, for example, tablets or coated tablets, capsules, solutions or ampoules, suppositories, patches or powder preparations which can be employed in inhalers.
The dose of the abovementioned pharmaceutical preparations depends on the condition of the patient and on the administration form. The daily dose of active compound is between 0.01 and 100 mg per kg of body weight per day.
Examples of compounds of the formula I which may be mentioned are:
Example 1 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl~
2U carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2 (2R~1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide Example 3 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl~
carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 (2R,S~1-[((2R,S~1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 7 (2S~1-[((2Sr1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide Example 11 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl~
carbonyl]-N-leucine Example 12 (S~Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl)carbonyl)-4-(aminophenyl)acrylate Example 14 (2S)-1-[((2S~1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 (2S~1-[((2Sr1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 (2S~1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-NZ-(N-ethylmorpholine)indoline-2-carbamide Example 18 (2S}-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) _g_ Example 19 (2S}-1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(-4-pyridine)indoline-2-carbamide Example 20 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 (2R~[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate Example 23 (2RS~1-({(2RS~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)indoline-2-carboxylic acid REPLACEMENT PAGE (RULE 26) 1 ' According to the present invention, the compounds of the formula I can be prepared by the following processes.
1 St process:
B
A N.D.Y.ON + N'Z'R, A N.D.Y.Z.R
'~ R~ ~ ~~ ~ --Boc X III BoC X
II IV
d~ ;O
A B + O S~Rx A 8 .D. .Z, -~ .D. .Z
R' H X Rt ~ R3 N Y ~fl~
or VIII O=S_-O X
V I
In the first process, the compounds of the formula I according to the invention, in which R~, Rz, R3, A, B, D, X, Y and Z have the meaning mentioned, are prepared by reacting a carboxylic acid derivative of the formula II, in which R3, A, B, D, X, Y and Z have the meaning mentioned, with an amine, alkanol, halogen compound or tosylate III to give an amide, ester or ether IV, in which R~, R3, A, B, D, X, Y and Z have the meaning mentioned, reacting this derivative IV, after deprotection with acid, to give an intermediate V, in which R~, R3, A, B, D, X, Y and Z have the meaning mentioned, and reacting in a continuing reaction with a compound VI, in which R2 has the meaning mentioned, or with a compound VIII (see 2~d process), in which R2, R3, A, B, D, X, Y and Z has [sic] the meaning mentioned, to give the target compound I.
REPLACEMENT PAGE (RULE 26) 2"d process:
a. , o A B + O ~S\~ 8 + N.Z.R, B
~O.y.ON~ ~D. .OH ~ A .D. _Z, N Y ~ y H X
VI O=S_O X or R' O;S X
V ~' O
YII VOI I
In the second process, the compounds of the formula I according to the invention, in which R~, R2, R3, A, B, D, X, Y and Z have the meaning mentioned, are prepared by reacting a carboxylic acid derivative of the formula VII, in which R3, A, B, D, X, Y and Z have the meaning mentioned, with a sulphonyl chloride VI, in which R2 have [sic] the meaning mentioned, and reacting in a continuing reaction with a compound III, in which R~ has the meaning mentioned, or with a compound V, in which R~, R3, A, B, D, X, Y and Z has [sicJ the meaning mentioned, to give the target compound I.
for the preparation of the physiologically tolerable salts, the compounds of '35 the formula I are reacted in a known manner with inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, malefic acid, lactic acid or embonic acid, or with inorganically [sic]
or inorganic [sicJ bases.
Pharmaceutical preparations contain at least one compound of the general formula I or its salts with physiologically tolerable inorganic or organic acids or bases and, if appropriate, pharmaceutically utilizable excipients and auxiliaries.
The compounds of the formula I can be administered orally, parenterally, intravenously, transdermally or by inhalation, in free form or as a salt with a physiologically tolerable acid or base.
Suitable administration forms are, for example, tablets or coated tablets, capsules, solutions or ampoules, suppositories, patches or powder preparations which can be employed in inhalers.
REPLACEMENT PAGE (RULE 26) The dose of these abovementioned pharmaceutical preparations depends on the condition of the patient and on the administration form. The daily dose of active compound is between 0.01 and 100 mg per kg of body weight.
The compounds of formula (I) according to the invention are distinguished by immunophilin binding and inhibit its isomerase activity. This prolyl isomerase activity is tested according to an enzyme test which is customary worldwide: G. Fischer, H. Bang, A. Schellenberger, Biochim.
8iophys. Acta, 791, 87-97, 1984; D.H. Rich et al., J. Med. Chem. 38, 4164-4170, 1995).
Without the peptidyl cis-trans isomerase activity of the immunophilins being affected in each case, such compounds surprisingly specifically inhibit the TNF-a, GM-CSF, IL-2, IL-4 and IL-5 proliferation of mast cells, macrophages and activated T cells. The compounds according to the invention can be employed, like cyclosporin A (Sandimrnun~, CsA), FK 506 or rapamycin (Tacrolimus) as immunosuppressants (R.Y. Galne et al., Br.
Med. J. 282, 934-936, 1981 ), for the treatment of autoimmune disorders (R.H. Wiener et al., Hepatology 7, 1025, Abst. 9, 1987; L. Fry, J:
Autoimmun. 5, 231-240, 1992, G.J. Feutren, J. Autoimmun. 5, 183-195, 1992, EP 610,743), allergic inflammations (P. Zabel et al., Lancet 343, 1984), [lacuna] antiasthmatics (C. Bachert, Atemw.-Lungenkrkh. 20, 59, 1994), [lacuna] insulin-dependent diabetes mellitus (C.R. Stiller, Science, 223, 1362-1367, 1984), sepsis, as a neuroprotectant or for neuroregeneration in multiple sclerosis, Alzheimer's and Parkinson's disease (US 5 614 547, JP 08 333 334, Nature Medicine, 3, 4, 1997), antirheumatics, psoriasis (SANDORMA, 4, 1995) and also in combination with known immunophilin ligands such as CsA, FK 506 or rapamycin (M.J. Wyvratt, N.H. Sigal, Perspectives in Drug Discovery and Design, Immunosuppression, 2, 1, 1994; WO 92121313, US 5 330 993).
The invention is illustrated in greater detail below with the aid of working examples. The abbreviations used here are:
AcOEt ethyl acetate Boc tert-butyloxycarbonyl (Boc)20 tert-butyloxycarbonyl [sic] anhydride REPLACEMENT PAGE (RULE 26) CN calcineurin CsA cyclosporin A
Cyp cyclophilin DMAP N,N-dimethylaminopyridine EA elementary analysis EE ethyl acetate [sic]
FKBP FK 506 binding protein HPLC high-pressure liquid chromatography in OPV in an oil pump vacuum soln solution MeOH methanol PPlase peptidyl-proline cis-trans isomerase in RE in a rotary evaporator in vac. in vacuo RT room temperature rac racemic ent enantio -tFA trifluoroacetic acid Z benzyloxycarbonyl REPLACEMENT PAGE (RULE 26) General procedure stage fsicl for the preparation of carboxamides of the general formula IV:
[lacuna] (3.3 mmol) of the Boc-protected carboxylic acid, 1 eq (3.3 mmol) of the appropriate amine and 1.5 eq (4.9 mmol) of 2-chloro-1-methyl pyridinium iodide and 2.5 eq (8.1 mmol, 1.13 ml) of TEA were dissolved or suspended together in DCM, and the mixture was stirred for 30 min and refluxed for 6 h. The solvent was distilled off on a rotary evaporator and the residue was taken up in AcOEt. This suspension was washed twice each with aqueous KHS04 soln, with aqueous NaOH soln and once with aqueous, satd NaCI soln, dried over Na2S04 and purified by chromatography on silica gel using AcOEt/hexane or using CH2C12/MeOH
mixtures.
General procedure for the preparation of sulphonamides of the general formula VIII:
100 mmol of the amino acid was [sic] suspended in water and treated with 300 mmol of NaOH and with 110 mmol of sulphonyl chloride and the mixture was heated at 90°C for 4 h. After cooling, it is [sic]
acidified with aqueous 2N HCI, and the precipitated product was filtered off with suction and dried at 40°C.
General procedure for the preparation of compounds of the general formula I:
4.7 mmol of Boc-protected carboxamides [sic] of the general formula IV
were stirred at room temp. for 2 h in DCM/TFA 4:1. The solvt and excess TFA were removed in vac. The oily residue was stirred at 35°C for 24 h in 120 ml of DCM with a (7 mmol) sulphonamide [sic] of the general formula VI, with 11.7 mmol of TEA and 7.7 mmol of Mukaiyama reagent. The solvent was distilled off on a rotary evaporator and the residue was taken up in AcOEt. This suspension was washed twice each with aqueous KHS04 soln, with aqueous NaOH soln and once with aqueous satd NaCI
soln, dried over Na2S04 and purified by chromatography on silica gel using AcOEt/hexane or using CH2CI2/MeOH mixtures.
The following compounds of the general formula I were prepared according to these general procedures:
REPLACEMENT PAGE (RULE 26) Example 1 (2S)-1-[((2Sr1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.01 (s, 3H); 3.08 (s, 3H); 3.09-3.83 (m, 8H); 4.70-5.45 (m, 2H); 6.93-7.41 (m, 7H); 7.62-8.16 (m, 5H); 8.45-8.73 (m, 1 H); 10.44 (s, 1 H).
EA: cal. for C29H3oN406S C 61.91 H 5.37 N 9.96;
found: C 60.42 H 5.15 N 9.64.
Example 2 (2R)-1-[((2S~1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 223-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.09 (s, 3H); 3.10-3.70 (m, 8H); 4.77-5.51 (m, 2H); 6.89-7.39 (m, 7H); 7.60-8.21 (m, 5H); 8.31-8.59 (m, 1 H); 10.39 (s, 1 H).
MS (ESI+): cal. for C29H3oN406S, M = 562.65: found: M+ = 563.72.
example 3 (2S~1-[((2R)-1-(4-Acetylamino)phenylsulphonyf)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.02 (s, 3H); 3.00 (s, 3H); 3.15-3.80 (m, 8H); 4.72-5.40 (m, 2H); 6.98-7.44 (m, 7H); 7.66-8.22 (m, 5H); 8.48-8.70 (m, 1 H); 10.52 (s, 1 H).
MS (ESI+): cal. for C29H3oN406S, M = 562.65; found: M' = 563.71.
Example 4 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 221-225°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.08 (s, 3H); 3.00 (s, 3H); 3.11-3.76 (m, 8H); 4.72-5.39 (m, 2H); 6.88-7.47 (m, 7H); 7.62-8.17 (m, 5H); 8.41-8.68 (m, 1 H); 10.43 (s, 1 H).
MS (ESI''): cal. for CZ9H3oN40sS M = 562.65 found: M+ = 563.7.
REPLACEMENT PAGE (RULE 26) Example 5 (2R,S~1-[((2R,S~1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 220-225C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H); 3.10 (s, 3H); 3.06-3.75 (m, 8H); 4.72-5.40 (m, 2H); 6.91-7.41 (m, 7H);
7.68-8.26 (m, 5H); 8.46-8.79 (m, 1 H); 10.41 (s, 1 H).
EA: cal. for C29H3oN406S x'/. H20 (567.15) C 61.41 H 5.42 N 9.87;
found: C 61.23 H 5.51 N 9.63.
Example 6 (2S~1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.16.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.02-3.8 (m, 8H); 4.72-5.35 (m, 2H); 6.15 (s, NH2); 6.91-7.41 (m, 7H); 7.68-8.26 (m, 5H); 8.3-8.7 (m, 1 H).
Example 7 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.12.
'H NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (m, 6H); 4.5 (m, 1 H); 5.1 (m, 1 H); 6.05 (s, NH2);
7.0-7.65 (m, 7H); 8.2 (m, 1 H).
Example 8 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)-4-piperidinyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide [sic]
TLC: DCM/MeOH 95:5; Rf 0.14.
'H NMR (270 MHz, (Ds) DMSO): 1.55 (m, 2H); 1.85 (m, 2H); 2.03 (s, 3H); 2.3-2.4 (m, 2H); 2.85-3.65 (m, 6H); 4.1 (m, 1 H); 5.15 (m, 1 H); 6.05 (s, NH2); 7.0-7.65 (m, 8H); 8.4 (m, 1 H).
Example 9 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.42.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (m, 6H); 4.54 (m, 1 H); 5.1 (m, 1 H); 7.0-7.75 (m, 8H); 8.25 (m, 1 H).
Example 10 (2S~1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide TLC: DCM/MeOH 95:5; Rf 0.46.
'H NMR (270 MHz, (D6) DMSO): 3.08 (s, 3H); 3.09-3.83 (m, 4H); 6.15 (m, 1 H); 6.65-8.65 (m, 10H); 9.15 (s, 1 H).
Example 11 1-[(2Sr1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-leucine MS (ESI+): cal. for C23H2~N405S, M = 471.56; found: M+ = 471.9, M++Na+ = 495.3 Example 12 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester M.p.: 189-192°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.3.
'H NMR (270 MHz, DMSO): 1.2-1.45 (m, 4H); 1.6-1.76 (m, 2H); 2.08 (s, 3H); 2.78-3.21 (m, 5H); 3.63 (s, 3H); 4.25 (m, 1 H); 4.8-4.92 (m, 1 H); 5.02 (s, 2H); 6.93-7.45 (m, 9H); 7.65-7.75 (m, 4H); 8.40 (m, 1 H); 10.33 (s, 1 H) EA: cal. for C32H36N4O8S (636.83) C 60.36 H 5.70 N 8.8;
found: C 60.27 H 5.93 N 8.92.
Example 13 Methyl (E)-(f(2S~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonylr4-(aminophenyl)acrylate M.p.: 167-171 °C (AcOEt) TLC: DCM/MeOH 95:5; Rf 0.63.
'H NMR (270 MHz, DMSO): 2.11 (s, 3H); 3.05-3.11 (m, 1 H); 3.27-3.36 (m, 1 H); 3.71 (s, 3H); 4.95 (dd, J1 = 4.1, J2 = 13, 1 H); 6.68 (d, J = 16.1, 1 H); 7.00-7.83 (m, 12H); 10.37 (s, 1 H); 10.48 (s, 1 H).
EA: cal. for C2~H25N306S x 1 /8 H20 (521.83): C 62.14 H 4.87 N 8.01;
found: C 62.28 H 5.10 N 7.72.
REPLACEMENT PAGE (RULE 26) Example 14 (2S)-1-[((2S~1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H); 3.10 (s, 3H); 3.0-3.7 (m, 8H); 4.8-5.2 (m, 2H); 6.93-7.41 (m, 7H); 7.7-8.4 (m, 9H).
Example 15 (2S~1-[((2S~1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.06 (s, 3H); 3.1-3.8 (m, 8H); 4.75-5.5 (m, 2H); 6.93-7.41 (m, 7H); 7.7-8.4 (m, 9H).
Example 16 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.26.
'H NMR (270 MHz, (Ds) DMSO): 1.95 (m, 2H); 2.3 (s, 3H); 3.~1 (m, 2H); 4.05 (m, 2H); 4.64 (m, 1 H); 5.1 (m, 1 H); fi.9-7.85 (m, 15H); 8.2 (m, 1 H).
Example 17 (2S)-1-[((2S~1-(4-Methylphenyisulphonyl)indolin-2-yl)carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.24.
'H NMR (270 MHz, (D6) DMSO): 1.5-1.7 (m, 4H); 1.9 (m, 4H); 2.25 (s, 3H); 2.75 (m, 2H); 3.65 (m, 2H); 4.72-5.35 (m, 2H); 6.91-7.71 (m, 12H); 8.4 (m, 1 H).
Example 18 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.19.
'H NMR (270 MHz, (D6) DMSO): 2.2 (s, 3H); 2.6 (m, 2H); 3.4 (m, 2H);
4.72-5.35 (m, 2H); 6.85-7.9 (m, 12H); 8.4 (m, 1 H).
Example 19 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl)-(4-pyridine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.24.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, (D6) DMSO): 2.4 (s, 3H); 3.25 (m, 2H); 4.72-5.35 (m, 2H); 6.85-8.1 (m, 16H); 8.4 (m, 1 H).
Example 20 Methyl (2Rr[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate M.p.: 172-176°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.44.
'H NMR (270 MHz, (D6) DMSO): 2.22 (s, 3H); 3.0-3.22 (m, 2H); 3.83 (s, 3H); 4.63 (dd, J~ = 15.2, J2 = 5.3, 1 H); 6.88-7.31 (m, 4H);
7.52-7.70 (dd, J~ = 8.9, J2 = 8.9, 4H); 7.93 (s, 1 H).
EA: cal. for C~8H~8N205S x'/4 H20 (374.42): C 57.74 H 4.84 N 7.48;
found: C 56.82 H 4.99 N 7.15.
Example 21 (2R~[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid M.p.: 198-202°C.
'TLC: DCM/MeOH 95:5; 1 % HoAc; Rf 0.20.
'~I NMR (270 MHz, CDCI3): 2.08 (s, 3H); 2.97-3.34 (m, 2H); 3.78 (s, 3H); 4.86-4.92 (dd, J = 15.5, 5.4, 1 H); 6.95-7.36 (m, 4H);
7.67-7.78 (dd, J = 9.0, 9.0, 4H); 10.33 (s, 1 H); 12.97 (s, 1 H).
Example 22 Methyl (2RSr1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate M.p.: 213-215°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.31.
'H NMR (270 MHz, DMSO): 2.07 (s, 3H); 3.02-3.46 (m, 4H); 3.76 (s, 3H); 5.18-5.69 (m, 2H); 6.95-7.40 (m, 7H); 7.71 (s, 4H); 10.33 (s, 1 H).
EA: cal. for C2~H25N306S x 1 H20 (537.59): C 60.32 H 5.09 N 7.82;
found: C 60.13 H 4.89 N 7.62.
Example 23 (2RS~1-({(2RS~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)indoline-2-carboxylic acid M.p.: 190-192°C.
TLC: DCM/MeOH 95:5; Rf 0.23.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, DMSO): 2.07 (s, 3H); 3.03-3.70 (m, 4H); 5.05-5.70 (m, 2H); 6.96-7.53 (m, 7H); 7.72 (4H); 7.95-8.09 (m, 1 H);
10.35 (s, 1 H).
EA: cal. for C26HZSNsOsS x 1/2 H20 (514.56): C 60.69 H 4.70 N 8.17;
found: C 60.64 H 4.81 N 8.03.
The listed examples 1-23 proved to be surprisingly strongly binding immunophilin modulators which are suitable and able as the carrier-immobilized formula [sic] to bind pathogenic immunophilins from fluids, in particular body fluids.
To find strongly binding Cyp B or FKBP ligands of the formula I, the immobilized ligands were subjected to an SDS-PAGE with cell homogenate. Carrier-immobilized ligands which have a particular affinity for the immunophilins bind these specifically with a high affinity.
The compounds of formula (I) according to the invention are distinguished by immunophilin binding and inhibit its peptidyl-prolyl cis-trans isomerase (PPlase) activity. For the initial screening (1 Nmol/l of substance), the inhibition of human cyclophilin B is determined in the PPlase test. This PPlase activity is tested for according to an enzyme test which is customary worldwide: G. Fischer, H. Bang, C. Mech, Biomsd. Biochim.
Acfa, 43, 1101-1111; G. Fischer, H. Bang, A. Schellenberger, Biochim.
Biophys. Acfa, 791, 87-97, 7984; D.H. Rich et al., J. Med. Chem. 38, 4164 4170, 9995).
The compounds of the general formula I according to the invention are preincubated at 4°C for 15 min together with 10 nmol of Cyp B. The enzyme reaction is started using the test peptide Suc-Ala-Ala-Pro-Phe-Nan after addition of chymotrypsin and HEPES buffer. The change in extinction at 390 nm is then monitored and analysed. The photometrically determined change in extinction results from two subreactions: a) the rapid chymo-tryptic cleavage of the trans peptide; b) the non-enzymatic cis-trans isomerization, which is catalysed by cyclophilins. The corresponding PPlase activity of the compounds of the general formula according to the invention are [sic] shown in Table 1:
REPLACEMENT PAGE (RULE 26) Table 1:
Compound [10 Nmol) Inhibition [%) Example 1: 40 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: 40 (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 40 (2S)-1-[((2R~1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 60 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 20-4.0 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 40 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 40 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 40-60 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 40-60 (ZS)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 20-40 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide Example 11 40 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-leucine REPLACEMENT PAGE (RULE 26) Example 12 60 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 0-20 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)acrylate Example 14 20 (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 20 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 20-40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-Nz-(N-ethylmorpholine)indoline-2-carbamide Example 18 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-, N2-(ethyl-2-pyridine)indoline-2-carbamide Example 19 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 0-20 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 0-20 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 30 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate Example 23 0-20 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)indoline-2-carboxylic acid REPLACEMENT PAGE (RULE 26) The formation of the supramolecule from CsA-Cyp B-calcineurin (Ca2+-dependent phosphatase) appears to be responsible for the known immunosuppressant effects of CsA. For the investigation on the interaction with this supramolecule from CsA-Cyp B or CsA-Cyp B-calcineurin with cell homogenates of a human T-cell line, the compounds of the general formula I according to the invention were incubated with 3H-CsA
(100 nmol). After gel filtration on Superose 12, the radioactivity of the eluted fractions was measured and compared with the untreated control.
The corresponding displacement of 3H-CsA by the compounds of the general formula I according to the invention from the supramolecule Cyp B-CsA and Cyp-CsA-calcineurin is shown in Table 2:
Table 2:
DisplacementDisplacement Compound [10 Nmol] from Cyp-CsAfrom Cyp-CsA-in [%] CaN in [%]
Example 1: 30 -85 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: -gp (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 -gg (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 10 -73 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenyl-sulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxy-ethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 6 50 -59 (2S)-1-[((2S)-1-(4-Arninophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 45 -65 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 42 -81 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)-pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 39 -64 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 15 -54 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxy-ethyl)indolinecarbamide Example 11 8 12 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indoliri-2-yl)carbonyl]-N-leucine Example 12 27 14 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 1 g Methyl (E)-({(2S)-1-[4-(Acetylamino)phenyl-sulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)-acrylate Example 14 -51 (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 -48 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 16 41 -46 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 39 -52 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide Example 18 34 -53 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide Example 19 42 -49 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 ~ 4 18 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]-indoline-2-carboxylate Example 21 3 5 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 2 8 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenyl-sulphonyl]indolin-2-yl)carbonyl)indoline-2-carboxylate ~xample 23 4 ~ 12 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenyl-sulphonyl]indolin-2-yl)carbonyl)indoline-2-carboxylic acid The II-2 [sic] proliferation test is based on the incorporation of 3H-thymidine in T cells stimulated with OKT-3 (human anti-CD-3-antibodies) and is carried out in the following manner:
100,000 T cells are inoculated into microtitre plates in 150 NI of culture medium per well, stimulated by addition of OKT-3 (1 Ng/ml) and incubated for 45 h in each case with one of the compounds of the general formula I
according to the invention. After this incubation time, 10 NI of the 3H-thymidine solution (0.5. NCi) are pipetted into each well. The mixture is REPLACEMENT PAGE (RULE 26) then incubated in a 5% C02 atmosphere at 37°C for 6 h. After harvesting the cells, the radioactivity is quantified in a [i-counter. The corresponding CD3-induced inhibition of proliferation by the compounds of the general formula I according to the invention are [sic] shown in Table 3:
REPLACEMENT PAGE (RULE 26) Table 3:
CD3-induced Compound [10 Nmol] inhibition of proliferation in [%]
Example 1: 83 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: 85 (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 84 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 85 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 85 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 84 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 7g (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 71 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 75 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 59 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide REPLACEMENT PAGE (RULE 26) Example 11 61 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-leucine Example 12 ~ 7g (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 46 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)acrylate Example 14 4g (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 56 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 54 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yi)-carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 57 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide Example 18 5g (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-NZ-(ethyl-2-pyridine)indoline-2-carbamide Example 19 64 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 I 15 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 12 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 43 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate REPLACEMENT PAGE (RULE 26) Example 23 ~ 46 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)indoline-2-carboxylic acid Like CsA, FK 506 or rapamycin, the compounds of the general formula I
according to the invention show the blockade of cytokines such as TNF-a, GM-CSF, IL-2, IL-4 and IL-5, which cause the allergically induced inflammations in the case of disease, in animal experiments.
For the determination of the inhibition of cell division by the compounds of the general formula I according to the invention, 50,000 human tumor cells were cultured for 48 h in the presence of the compounds of the general formula I according to the invention, provided with 10 NI of yellow tetrazolium salt solution (MTT) and incubated in a C02 atmosphere at 37°C
for a further 4 h. The resulting violet coloration was analysed photo-metrically at 570 nm. After addition of 100 NI of SDS solution each, the colouration was quantified photometrically after overnight incubation. it was not possible to establish a general cytotoxicity of the compounds of the general formula I according to the invention.
REPLACEMENT PAGE (RULE 26)
A class of substance which binds immunophilins surprisingly specifically, inhibits IL-2-dependent proliferation, and also inhibits the release of TNF-a and GM-CSF and surprisingly blocks a Ca++-dependent signal transmission pathway is represented by the compounds of the formula I according to the invention. This class of compounds and their pharmaceutically acceptable salts has [sic] a high affinity for immunophilins such as CypA, CypB, CypC
and FKBP12. Moreover, substances of the formula I inhibit various cytokine syntheses, as ~nrell as a Ca++-dependent signal transmission pathway.
-(hose compounds of the formula I which contain asymmetric carbon atoms and therefore as a rule occur as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid. However, the possibility also exists of. employing optically active starting substances to begin with, corresponding optically active or diastereoisomeric compounds then being obtained as the final product.
The invention thus comprises compounds of the formula I which contain an asymmetric carbon atom, the R form, the S form and R, S mixtures, and, the case of a number of asymmetric carbon atoms, the diastereoisomeric forms.
Depending on the process conditions and starting substances, the compounds of the formula I can be obtained as free compounds or in the form of their salts. The salts obtained can be converted into the free bases or acids in a manner known per se, for example using acids, alkali or ion exchangers.
The compounds of the formula I liberated in this way can be converted into the corresponding physiologically tolerable acid addition salts using inorganic or organic acids or bases.
Both the free bases and their salts are biologically active. The compounds of the formula I can be administered in free form or as a salt with a physio-REPLACEMENT PAGE (RULE 26) logically tolerable acid or base. Administration can be carried out orally, parenterally, intravenously, transdermally or by inhalation.
The invention further relates to pharmaceutical preparations which contain at least one compound of the formula I or its salts with physiologically tolerable inorganic or organic acids or bases and, if appropriate, pharma ceutically utilizable excipients and auxiliaries.
Suitable administration forms are, for example, tablets or coated tablets, capsules, solutions or ampoules, suppositories, patches or powder preparations which can be employed in inhalers.
The dose of the abovementioned pharmaceutical preparations depends on the condition of the patient and on the administration form. The daily dose of active compound is between 0.01 and 100 mg per kg of body weight per day.
Examples of compounds of the formula I which may be mentioned are:
Example 1 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl~
2U carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2 (2R~1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide Example 3 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl~
carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 (2R,S~1-[((2R,S~1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 7 (2S~1-[((2Sr1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide Example 11 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl~
carbonyl]-N-leucine Example 12 (S~Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl)carbonyl)-4-(aminophenyl)acrylate Example 14 (2S)-1-[((2S~1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 (2S~1-[((2Sr1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 (2S~1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-NZ-(N-ethylmorpholine)indoline-2-carbamide Example 18 (2S}-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) _g_ Example 19 (2S}-1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(-4-pyridine)indoline-2-carbamide Example 20 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 (2R~[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate Example 23 (2RS~1-({(2RS~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)indoline-2-carboxylic acid REPLACEMENT PAGE (RULE 26) 1 ' According to the present invention, the compounds of the formula I can be prepared by the following processes.
1 St process:
B
A N.D.Y.ON + N'Z'R, A N.D.Y.Z.R
'~ R~ ~ ~~ ~ --Boc X III BoC X
II IV
d~ ;O
A B + O S~Rx A 8 .D. .Z, -~ .D. .Z
R' H X Rt ~ R3 N Y ~fl~
or VIII O=S_-O X
V I
In the first process, the compounds of the formula I according to the invention, in which R~, Rz, R3, A, B, D, X, Y and Z have the meaning mentioned, are prepared by reacting a carboxylic acid derivative of the formula II, in which R3, A, B, D, X, Y and Z have the meaning mentioned, with an amine, alkanol, halogen compound or tosylate III to give an amide, ester or ether IV, in which R~, R3, A, B, D, X, Y and Z have the meaning mentioned, reacting this derivative IV, after deprotection with acid, to give an intermediate V, in which R~, R3, A, B, D, X, Y and Z have the meaning mentioned, and reacting in a continuing reaction with a compound VI, in which R2 has the meaning mentioned, or with a compound VIII (see 2~d process), in which R2, R3, A, B, D, X, Y and Z has [sic] the meaning mentioned, to give the target compound I.
REPLACEMENT PAGE (RULE 26) 2"d process:
a. , o A B + O ~S\~ 8 + N.Z.R, B
~O.y.ON~ ~D. .OH ~ A .D. _Z, N Y ~ y H X
VI O=S_O X or R' O;S X
V ~' O
YII VOI I
In the second process, the compounds of the formula I according to the invention, in which R~, R2, R3, A, B, D, X, Y and Z have the meaning mentioned, are prepared by reacting a carboxylic acid derivative of the formula VII, in which R3, A, B, D, X, Y and Z have the meaning mentioned, with a sulphonyl chloride VI, in which R2 have [sic] the meaning mentioned, and reacting in a continuing reaction with a compound III, in which R~ has the meaning mentioned, or with a compound V, in which R~, R3, A, B, D, X, Y and Z has [sicJ the meaning mentioned, to give the target compound I.
for the preparation of the physiologically tolerable salts, the compounds of '35 the formula I are reacted in a known manner with inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, malefic acid, lactic acid or embonic acid, or with inorganically [sic]
or inorganic [sicJ bases.
Pharmaceutical preparations contain at least one compound of the general formula I or its salts with physiologically tolerable inorganic or organic acids or bases and, if appropriate, pharmaceutically utilizable excipients and auxiliaries.
The compounds of the formula I can be administered orally, parenterally, intravenously, transdermally or by inhalation, in free form or as a salt with a physiologically tolerable acid or base.
Suitable administration forms are, for example, tablets or coated tablets, capsules, solutions or ampoules, suppositories, patches or powder preparations which can be employed in inhalers.
REPLACEMENT PAGE (RULE 26) The dose of these abovementioned pharmaceutical preparations depends on the condition of the patient and on the administration form. The daily dose of active compound is between 0.01 and 100 mg per kg of body weight.
The compounds of formula (I) according to the invention are distinguished by immunophilin binding and inhibit its isomerase activity. This prolyl isomerase activity is tested according to an enzyme test which is customary worldwide: G. Fischer, H. Bang, A. Schellenberger, Biochim.
8iophys. Acta, 791, 87-97, 1984; D.H. Rich et al., J. Med. Chem. 38, 4164-4170, 1995).
Without the peptidyl cis-trans isomerase activity of the immunophilins being affected in each case, such compounds surprisingly specifically inhibit the TNF-a, GM-CSF, IL-2, IL-4 and IL-5 proliferation of mast cells, macrophages and activated T cells. The compounds according to the invention can be employed, like cyclosporin A (Sandimrnun~, CsA), FK 506 or rapamycin (Tacrolimus) as immunosuppressants (R.Y. Galne et al., Br.
Med. J. 282, 934-936, 1981 ), for the treatment of autoimmune disorders (R.H. Wiener et al., Hepatology 7, 1025, Abst. 9, 1987; L. Fry, J:
Autoimmun. 5, 231-240, 1992, G.J. Feutren, J. Autoimmun. 5, 183-195, 1992, EP 610,743), allergic inflammations (P. Zabel et al., Lancet 343, 1984), [lacuna] antiasthmatics (C. Bachert, Atemw.-Lungenkrkh. 20, 59, 1994), [lacuna] insulin-dependent diabetes mellitus (C.R. Stiller, Science, 223, 1362-1367, 1984), sepsis, as a neuroprotectant or for neuroregeneration in multiple sclerosis, Alzheimer's and Parkinson's disease (US 5 614 547, JP 08 333 334, Nature Medicine, 3, 4, 1997), antirheumatics, psoriasis (SANDORMA, 4, 1995) and also in combination with known immunophilin ligands such as CsA, FK 506 or rapamycin (M.J. Wyvratt, N.H. Sigal, Perspectives in Drug Discovery and Design, Immunosuppression, 2, 1, 1994; WO 92121313, US 5 330 993).
The invention is illustrated in greater detail below with the aid of working examples. The abbreviations used here are:
AcOEt ethyl acetate Boc tert-butyloxycarbonyl (Boc)20 tert-butyloxycarbonyl [sic] anhydride REPLACEMENT PAGE (RULE 26) CN calcineurin CsA cyclosporin A
Cyp cyclophilin DMAP N,N-dimethylaminopyridine EA elementary analysis EE ethyl acetate [sic]
FKBP FK 506 binding protein HPLC high-pressure liquid chromatography in OPV in an oil pump vacuum soln solution MeOH methanol PPlase peptidyl-proline cis-trans isomerase in RE in a rotary evaporator in vac. in vacuo RT room temperature rac racemic ent enantio -tFA trifluoroacetic acid Z benzyloxycarbonyl REPLACEMENT PAGE (RULE 26) General procedure stage fsicl for the preparation of carboxamides of the general formula IV:
[lacuna] (3.3 mmol) of the Boc-protected carboxylic acid, 1 eq (3.3 mmol) of the appropriate amine and 1.5 eq (4.9 mmol) of 2-chloro-1-methyl pyridinium iodide and 2.5 eq (8.1 mmol, 1.13 ml) of TEA were dissolved or suspended together in DCM, and the mixture was stirred for 30 min and refluxed for 6 h. The solvent was distilled off on a rotary evaporator and the residue was taken up in AcOEt. This suspension was washed twice each with aqueous KHS04 soln, with aqueous NaOH soln and once with aqueous, satd NaCI soln, dried over Na2S04 and purified by chromatography on silica gel using AcOEt/hexane or using CH2C12/MeOH
mixtures.
General procedure for the preparation of sulphonamides of the general formula VIII:
100 mmol of the amino acid was [sic] suspended in water and treated with 300 mmol of NaOH and with 110 mmol of sulphonyl chloride and the mixture was heated at 90°C for 4 h. After cooling, it is [sic]
acidified with aqueous 2N HCI, and the precipitated product was filtered off with suction and dried at 40°C.
General procedure for the preparation of compounds of the general formula I:
4.7 mmol of Boc-protected carboxamides [sic] of the general formula IV
were stirred at room temp. for 2 h in DCM/TFA 4:1. The solvt and excess TFA were removed in vac. The oily residue was stirred at 35°C for 24 h in 120 ml of DCM with a (7 mmol) sulphonamide [sic] of the general formula VI, with 11.7 mmol of TEA and 7.7 mmol of Mukaiyama reagent. The solvent was distilled off on a rotary evaporator and the residue was taken up in AcOEt. This suspension was washed twice each with aqueous KHS04 soln, with aqueous NaOH soln and once with aqueous satd NaCI
soln, dried over Na2S04 and purified by chromatography on silica gel using AcOEt/hexane or using CH2CI2/MeOH mixtures.
The following compounds of the general formula I were prepared according to these general procedures:
REPLACEMENT PAGE (RULE 26) Example 1 (2S)-1-[((2Sr1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.01 (s, 3H); 3.08 (s, 3H); 3.09-3.83 (m, 8H); 4.70-5.45 (m, 2H); 6.93-7.41 (m, 7H); 7.62-8.16 (m, 5H); 8.45-8.73 (m, 1 H); 10.44 (s, 1 H).
EA: cal. for C29H3oN406S C 61.91 H 5.37 N 9.96;
found: C 60.42 H 5.15 N 9.64.
Example 2 (2R)-1-[((2S~1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 223-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.09 (s, 3H); 3.10-3.70 (m, 8H); 4.77-5.51 (m, 2H); 6.89-7.39 (m, 7H); 7.60-8.21 (m, 5H); 8.31-8.59 (m, 1 H); 10.39 (s, 1 H).
MS (ESI+): cal. for C29H3oN406S, M = 562.65: found: M+ = 563.72.
example 3 (2S~1-[((2R)-1-(4-Acetylamino)phenylsulphonyf)indolin-2-yl)-carbonyl)-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.02 (s, 3H); 3.00 (s, 3H); 3.15-3.80 (m, 8H); 4.72-5.40 (m, 2H); 6.98-7.44 (m, 7H); 7.66-8.22 (m, 5H); 8.48-8.70 (m, 1 H); 10.52 (s, 1 H).
MS (ESI+): cal. for C29H3oN406S, M = 562.65; found: M' = 563.71.
Example 4 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 221-225°C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.08 (s, 3H); 3.00 (s, 3H); 3.11-3.76 (m, 8H); 4.72-5.39 (m, 2H); 6.88-7.47 (m, 7H); 7.62-8.17 (m, 5H); 8.41-8.68 (m, 1 H); 10.43 (s, 1 H).
MS (ESI''): cal. for CZ9H3oN40sS M = 562.65 found: M+ = 563.7.
REPLACEMENT PAGE (RULE 26) Example 5 (2R,S~1-[((2R,S~1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 220-225C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H); 3.10 (s, 3H); 3.06-3.75 (m, 8H); 4.72-5.40 (m, 2H); 6.91-7.41 (m, 7H);
7.68-8.26 (m, 5H); 8.46-8.79 (m, 1 H); 10.41 (s, 1 H).
EA: cal. for C29H3oN406S x'/. H20 (567.15) C 61.41 H 5.42 N 9.87;
found: C 61.23 H 5.51 N 9.63.
Example 6 (2S~1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.16.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.02-3.8 (m, 8H); 4.72-5.35 (m, 2H); 6.15 (s, NH2); 6.91-7.41 (m, 7H); 7.68-8.26 (m, 5H); 8.3-8.7 (m, 1 H).
Example 7 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.12.
'H NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (m, 6H); 4.5 (m, 1 H); 5.1 (m, 1 H); 6.05 (s, NH2);
7.0-7.65 (m, 7H); 8.2 (m, 1 H).
Example 8 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)-4-piperidinyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide [sic]
TLC: DCM/MeOH 95:5; Rf 0.14.
'H NMR (270 MHz, (Ds) DMSO): 1.55 (m, 2H); 1.85 (m, 2H); 2.03 (s, 3H); 2.3-2.4 (m, 2H); 2.85-3.65 (m, 6H); 4.1 (m, 1 H); 5.15 (m, 1 H); 6.05 (s, NH2); 7.0-7.65 (m, 8H); 8.4 (m, 1 H).
Example 9 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.42.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (m, 6H); 4.54 (m, 1 H); 5.1 (m, 1 H); 7.0-7.75 (m, 8H); 8.25 (m, 1 H).
Example 10 (2S~1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide TLC: DCM/MeOH 95:5; Rf 0.46.
'H NMR (270 MHz, (D6) DMSO): 3.08 (s, 3H); 3.09-3.83 (m, 4H); 6.15 (m, 1 H); 6.65-8.65 (m, 10H); 9.15 (s, 1 H).
Example 11 1-[(2Sr1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-leucine MS (ESI+): cal. for C23H2~N405S, M = 471.56; found: M+ = 471.9, M++Na+ = 495.3 Example 12 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester M.p.: 189-192°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.3.
'H NMR (270 MHz, DMSO): 1.2-1.45 (m, 4H); 1.6-1.76 (m, 2H); 2.08 (s, 3H); 2.78-3.21 (m, 5H); 3.63 (s, 3H); 4.25 (m, 1 H); 4.8-4.92 (m, 1 H); 5.02 (s, 2H); 6.93-7.45 (m, 9H); 7.65-7.75 (m, 4H); 8.40 (m, 1 H); 10.33 (s, 1 H) EA: cal. for C32H36N4O8S (636.83) C 60.36 H 5.70 N 8.8;
found: C 60.27 H 5.93 N 8.92.
Example 13 Methyl (E)-(f(2S~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonylr4-(aminophenyl)acrylate M.p.: 167-171 °C (AcOEt) TLC: DCM/MeOH 95:5; Rf 0.63.
'H NMR (270 MHz, DMSO): 2.11 (s, 3H); 3.05-3.11 (m, 1 H); 3.27-3.36 (m, 1 H); 3.71 (s, 3H); 4.95 (dd, J1 = 4.1, J2 = 13, 1 H); 6.68 (d, J = 16.1, 1 H); 7.00-7.83 (m, 12H); 10.37 (s, 1 H); 10.48 (s, 1 H).
EA: cal. for C2~H25N306S x 1 /8 H20 (521.83): C 62.14 H 4.87 N 8.01;
found: C 62.28 H 5.10 N 7.72.
REPLACEMENT PAGE (RULE 26) Example 14 (2S)-1-[((2S~1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H); 3.10 (s, 3H); 3.0-3.7 (m, 8H); 4.8-5.2 (m, 2H); 6.93-7.41 (m, 7H); 7.7-8.4 (m, 9H).
Example 15 (2S~1-[((2S~1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide M.p.: 224-227C (dec.) (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.35.
'H NMR (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.06 (s, 3H); 3.1-3.8 (m, 8H); 4.75-5.5 (m, 2H); 6.93-7.41 (m, 7H); 7.7-8.4 (m, 9H).
Example 16 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.26.
'H NMR (270 MHz, (Ds) DMSO): 1.95 (m, 2H); 2.3 (s, 3H); 3.~1 (m, 2H); 4.05 (m, 2H); 4.64 (m, 1 H); 5.1 (m, 1 H); fi.9-7.85 (m, 15H); 8.2 (m, 1 H).
Example 17 (2S)-1-[((2S~1-(4-Methylphenyisulphonyl)indolin-2-yl)carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.24.
'H NMR (270 MHz, (D6) DMSO): 1.5-1.7 (m, 4H); 1.9 (m, 4H); 2.25 (s, 3H); 2.75 (m, 2H); 3.65 (m, 2H); 4.72-5.35 (m, 2H); 6.91-7.71 (m, 12H); 8.4 (m, 1 H).
Example 18 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.19.
'H NMR (270 MHz, (D6) DMSO): 2.2 (s, 3H); 2.6 (m, 2H); 3.4 (m, 2H);
4.72-5.35 (m, 2H); 6.85-7.9 (m, 12H); 8.4 (m, 1 H).
Example 19 (2S~1-[((2S~1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl)-(4-pyridine)indoline-2-carbamide TLC: DCM/MeOH 95:5; Rf 0.24.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, (D6) DMSO): 2.4 (s, 3H); 3.25 (m, 2H); 4.72-5.35 (m, 2H); 6.85-8.1 (m, 16H); 8.4 (m, 1 H).
Example 20 Methyl (2Rr[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate M.p.: 172-176°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.44.
'H NMR (270 MHz, (D6) DMSO): 2.22 (s, 3H); 3.0-3.22 (m, 2H); 3.83 (s, 3H); 4.63 (dd, J~ = 15.2, J2 = 5.3, 1 H); 6.88-7.31 (m, 4H);
7.52-7.70 (dd, J~ = 8.9, J2 = 8.9, 4H); 7.93 (s, 1 H).
EA: cal. for C~8H~8N205S x'/4 H20 (374.42): C 57.74 H 4.84 N 7.48;
found: C 56.82 H 4.99 N 7.15.
Example 21 (2R~[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid M.p.: 198-202°C.
'TLC: DCM/MeOH 95:5; 1 % HoAc; Rf 0.20.
'~I NMR (270 MHz, CDCI3): 2.08 (s, 3H); 2.97-3.34 (m, 2H); 3.78 (s, 3H); 4.86-4.92 (dd, J = 15.5, 5.4, 1 H); 6.95-7.36 (m, 4H);
7.67-7.78 (dd, J = 9.0, 9.0, 4H); 10.33 (s, 1 H); 12.97 (s, 1 H).
Example 22 Methyl (2RSr1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate M.p.: 213-215°C (AcOEt/PE).
TLC: DCM/MeOH 95:5; Rf 0.31.
'H NMR (270 MHz, DMSO): 2.07 (s, 3H); 3.02-3.46 (m, 4H); 3.76 (s, 3H); 5.18-5.69 (m, 2H); 6.95-7.40 (m, 7H); 7.71 (s, 4H); 10.33 (s, 1 H).
EA: cal. for C2~H25N306S x 1 H20 (537.59): C 60.32 H 5.09 N 7.82;
found: C 60.13 H 4.89 N 7.62.
Example 23 (2RS~1-({(2RS~1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)indoline-2-carboxylic acid M.p.: 190-192°C.
TLC: DCM/MeOH 95:5; Rf 0.23.
REPLACEMENT PAGE (RULE 26) 'H NMR (270 MHz, DMSO): 2.07 (s, 3H); 3.03-3.70 (m, 4H); 5.05-5.70 (m, 2H); 6.96-7.53 (m, 7H); 7.72 (4H); 7.95-8.09 (m, 1 H);
10.35 (s, 1 H).
EA: cal. for C26HZSNsOsS x 1/2 H20 (514.56): C 60.69 H 4.70 N 8.17;
found: C 60.64 H 4.81 N 8.03.
The listed examples 1-23 proved to be surprisingly strongly binding immunophilin modulators which are suitable and able as the carrier-immobilized formula [sic] to bind pathogenic immunophilins from fluids, in particular body fluids.
To find strongly binding Cyp B or FKBP ligands of the formula I, the immobilized ligands were subjected to an SDS-PAGE with cell homogenate. Carrier-immobilized ligands which have a particular affinity for the immunophilins bind these specifically with a high affinity.
The compounds of formula (I) according to the invention are distinguished by immunophilin binding and inhibit its peptidyl-prolyl cis-trans isomerase (PPlase) activity. For the initial screening (1 Nmol/l of substance), the inhibition of human cyclophilin B is determined in the PPlase test. This PPlase activity is tested for according to an enzyme test which is customary worldwide: G. Fischer, H. Bang, C. Mech, Biomsd. Biochim.
Acfa, 43, 1101-1111; G. Fischer, H. Bang, A. Schellenberger, Biochim.
Biophys. Acfa, 791, 87-97, 7984; D.H. Rich et al., J. Med. Chem. 38, 4164 4170, 9995).
The compounds of the general formula I according to the invention are preincubated at 4°C for 15 min together with 10 nmol of Cyp B. The enzyme reaction is started using the test peptide Suc-Ala-Ala-Pro-Phe-Nan after addition of chymotrypsin and HEPES buffer. The change in extinction at 390 nm is then monitored and analysed. The photometrically determined change in extinction results from two subreactions: a) the rapid chymo-tryptic cleavage of the trans peptide; b) the non-enzymatic cis-trans isomerization, which is catalysed by cyclophilins. The corresponding PPlase activity of the compounds of the general formula according to the invention are [sic] shown in Table 1:
REPLACEMENT PAGE (RULE 26) Table 1:
Compound [10 Nmol) Inhibition [%) Example 1: 40 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: 40 (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 40 (2S)-1-[((2R~1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 60 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 20-4.0 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 40 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 40 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 40-60 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 40-60 (ZS)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 20-40 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide Example 11 40 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-leucine REPLACEMENT PAGE (RULE 26) Example 12 60 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 0-20 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)acrylate Example 14 20 (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 20 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 20-40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-Nz-(N-ethylmorpholine)indoline-2-carbamide Example 18 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-, N2-(ethyl-2-pyridine)indoline-2-carbamide Example 19 40 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 0-20 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 0-20 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 30 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate Example 23 0-20 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)indoline-2-carboxylic acid REPLACEMENT PAGE (RULE 26) The formation of the supramolecule from CsA-Cyp B-calcineurin (Ca2+-dependent phosphatase) appears to be responsible for the known immunosuppressant effects of CsA. For the investigation on the interaction with this supramolecule from CsA-Cyp B or CsA-Cyp B-calcineurin with cell homogenates of a human T-cell line, the compounds of the general formula I according to the invention were incubated with 3H-CsA
(100 nmol). After gel filtration on Superose 12, the radioactivity of the eluted fractions was measured and compared with the untreated control.
The corresponding displacement of 3H-CsA by the compounds of the general formula I according to the invention from the supramolecule Cyp B-CsA and Cyp-CsA-calcineurin is shown in Table 2:
Table 2:
DisplacementDisplacement Compound [10 Nmol] from Cyp-CsAfrom Cyp-CsA-in [%] CaN in [%]
Example 1: 30 -85 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: -gp (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 -gg (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)-indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 10 -73 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenyl-sulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxy-ethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 6 50 -59 (2S)-1-[((2S)-1-(4-Arninophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 45 -65 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 42 -81 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)-pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 39 -64 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 15 -54 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxy-ethyl)indolinecarbamide Example 11 8 12 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indoliri-2-yl)carbonyl]-N-leucine Example 12 27 14 (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 1 g Methyl (E)-({(2S)-1-[4-(Acetylamino)phenyl-sulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)-acrylate Example 14 -51 (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 -48 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide REPLACEMENT PAGE (RULE 26) Example 16 41 -46 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 39 -52 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide Example 18 34 -53 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide Example 19 42 -49 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 ~ 4 18 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]-indoline-2-carboxylate Example 21 3 5 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 2 8 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenyl-sulphonyl]indolin-2-yl)carbonyl)indoline-2-carboxylate ~xample 23 4 ~ 12 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenyl-sulphonyl]indolin-2-yl)carbonyl)indoline-2-carboxylic acid The II-2 [sic] proliferation test is based on the incorporation of 3H-thymidine in T cells stimulated with OKT-3 (human anti-CD-3-antibodies) and is carried out in the following manner:
100,000 T cells are inoculated into microtitre plates in 150 NI of culture medium per well, stimulated by addition of OKT-3 (1 Ng/ml) and incubated for 45 h in each case with one of the compounds of the general formula I
according to the invention. After this incubation time, 10 NI of the 3H-thymidine solution (0.5. NCi) are pipetted into each well. The mixture is REPLACEMENT PAGE (RULE 26) then incubated in a 5% C02 atmosphere at 37°C for 6 h. After harvesting the cells, the radioactivity is quantified in a [i-counter. The corresponding CD3-induced inhibition of proliferation by the compounds of the general formula I according to the invention are [sic] shown in Table 3:
REPLACEMENT PAGE (RULE 26) Table 3:
CD3-induced Compound [10 Nmol] inhibition of proliferation in [%]
Example 1: 83 (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 2: 85 (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 3 84 (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 4 85 (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 5 85 (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 6 84 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 7 7g (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 8 71 (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 9 75 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 10 59 (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indoline-carbamide REPLACEMENT PAGE (RULE 26) Example 11 61 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-leucine Example 12 ~ 7g (S)-Na {(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl-NE (benzyloxycarbonyl)lysine methyl ester Example 13 46 Methyl (E)-({(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)acrylate Example 14 4g (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 15 56 (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide Example 16 54 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yi)-carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide Example 17 57 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide Example 18 5g (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-NZ-(ethyl-2-pyridine)indoline-2-carbamide Example 19 64 (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)-carbonyl]-(4-pyridine)indoline-2-carbamide Example 20 I 15 Methyl (2R)-[4-(acetylamino)phenylsulphonyl]indoline-2-carboxylate Example 21 12 (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid Example 22 43 Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]-indolin-2-yl}carbonyl)indoline-2-carboxylate REPLACEMENT PAGE (RULE 26) Example 23 ~ 46 (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)indoline-2-carboxylic acid Like CsA, FK 506 or rapamycin, the compounds of the general formula I
according to the invention show the blockade of cytokines such as TNF-a, GM-CSF, IL-2, IL-4 and IL-5, which cause the allergically induced inflammations in the case of disease, in animal experiments.
For the determination of the inhibition of cell division by the compounds of the general formula I according to the invention, 50,000 human tumor cells were cultured for 48 h in the presence of the compounds of the general formula I according to the invention, provided with 10 NI of yellow tetrazolium salt solution (MTT) and incubated in a C02 atmosphere at 37°C
for a further 4 h. The resulting violet coloration was analysed photo-metrically at 570 nm. After addition of 100 NI of SDS solution each, the colouration was quantified photometrically after overnight incubation. it was not possible to establish a general cytotoxicity of the compounds of the general formula I according to the invention.
REPLACEMENT PAGE (RULE 26)
Claims (32)
1. Novel specific immunophilin ligands of the formula I
in which the radicals R1, R2, R3, R4 [sic], X, Y, Z, A, B and D have the following meaning:
R1 [lacuna] hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl;
R1 can additionally be the amine radical of the following amino acid methyl esters: histidine, leucine, valine, serine(Bzl), threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, .epsilon.-NH2-lysine, .epsilon.-Z-NH-lysine, .epsilon.-(2Cl-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine(Tos), asparagine, citrulline, homocitrulline, ornithine, thiazolecarboxylic acid, proline, 2-indolinecarboxylic acid, octa-hydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid;
R2 = hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna]
amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aryl- or heteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C1-C12)-alkyl, carboxycyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols;
R2 = amino-(C1-C12)-alkyl or amino-(C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aminoaryl- or aminoheteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C1-C12)-alkyl, carboxy-cyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols;
R3 = H, F, OR4, Br, NHR4;
R4 = hydrogen, (C3-C7)-cycloalkyl, (C1-C6)-alkyl or carboxy-(C1-C6)-alkyl, where the alkyl group can be straight-chain or branched and can be substituted by a mono- bi- or tricyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, preferably N, S and O, where aryl or heteroaryl itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl;
A = without a ring, aromatic, non-aromatic, aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O;
B = CH2;
D = CH;
B-D = CH=C;
X = O, S, H2;
Y = S, C, single bond;
Z = S, O, NR5;
R5 = hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring can itself be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
in which the radicals R1, R2, R3, R4 [sic], X, Y, Z, A, B and D have the following meaning:
R1 [lacuna] hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl;
R1 can additionally be the amine radical of the following amino acid methyl esters: histidine, leucine, valine, serine(Bzl), threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, .epsilon.-NH2-lysine, .epsilon.-Z-NH-lysine, .epsilon.-(2Cl-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine(Tos), asparagine, citrulline, homocitrulline, ornithine, thiazolecarboxylic acid, proline, 2-indolinecarboxylic acid, octa-hydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctanoic acid;
R2 = hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna]
amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aryl- or heteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C1-C12)-alkyl, carboxycyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols;
R2 = amino-(C1-C12)-alkyl or amino-(C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan and imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl, or can be substituted by mono- bi- or tricyclic aminoaryl- or aminoheteroaryl having 1-4 heteroatoms, preferably N, S and O, or by carboxy-(C1-C12)-alkyl, carboxy-cyclopentane, carboxycyclohexane or benzoyl which can be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, or carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols;
R3 = H, F, OR4, Br, NHR4;
R4 = hydrogen, (C3-C7)-cycloalkyl, (C1-C6)-alkyl or carboxy-(C1-C6)-alkyl, where the alkyl group can be straight-chain or branched and can be substituted by a mono- bi- or tricyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, preferably N, S and O, where aryl or heteroaryl itself can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which themselves are in turn substituted by benzyl, benzoyl or acetyl;
A = without a ring, aromatic, non-aromatic, aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic having 1-2 heteroatoms, preferably N, S, O;
B = CH2;
D = CH;
B-D = CH=C;
X = O, S, H2;
Y = S, C, single bond;
Z = S, O, NR5;
R5 = hydrogen, (C1-C12)-alkyl or (C2-C6)-alkyloxy groups, where the alkyl group is straight-chain or branched and can be substituted by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S and O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, or can be mono- or polysubstituted by a phenyl ring, where this phenyl ring can itself be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C1-C6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups [lacuna] amino groups, which themselves are in turn substituted by benzyl, benzoyl [lacuna] acetyl.
2. (2S)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
3. (2R)-1-[((2S)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
4. (2S)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
5. (2R)-1-[((2R)-1-(4-Acetylamino)phenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
6. (2R,S)-1-[((2R,S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)-carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
7. (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
8. (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
9. (2S)-1-[((2S)-1-(4-Aminophenylsulphonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
10. (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
11. (2S)-1-[(8-Quinolinylsulphonyl)]-N-(2-methoxyethyl)indolinecarbamide
12. 1-[(2S)-1-(4-Acetylaminophenylsulphonyl)indolin-2-yl)carbonyl]-N-leucine
13. (S)-N.alpha.{(2S)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl-N.epsilon.-(benzyloxycarbonyl)lysine methyl ester
14. Methyl (E)-({(2S)-1-[4-(acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)-4-(aminophenyl)acrylate
15. (2S)-1-[((2S)-1-(1-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
16. (2S)-1-[((2S)-1-(2-Naphthalenylsulphonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide
17. (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N3-(N-propylimidazole)indoline-2-carbamide
18. (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(N-ethylmorpholine)indoline-2-carbamide
19. (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-N2-(ethyl-2-pyridine)indoline-2-carbamide
20. (2S)-1-[((2S)-1-(4-Methylphenylsulphonyl)indolin-2-yl)carbonyl]-(-4-pyridine)indoline-2-carbamide
21. Methyl (2R)-[4-acetylamino)phenylsulphonyl]indoline-2-carboxylate
22. (2R)-[4-(Acetylamino)phenylsulphonyl]indoline-2-carboxylic acid
23. Methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulphonyl]indolin-2-yl}carbonyl)indoline-2-carboxylate
24. (2RS)-1-({(2RS)-1-[4-(Acetylamino)phenylsulphonyl]indolin-2-yl}-carbonyl)indoline-2-carboxylic acid
25. Use of the compounds according to one of Claims 1 to 24 for the production of a finished medicament.
26. Uses of the compounds of the general formula I according to Claims 1 to 24 for the production of a medicament having antiasthmatic, antipsoriatic and immunosuppressant action for the treatment of immunologically [sic], autoimmune and neurodegenerative disorders, as well as diseases accompanied by inflammation, such as asthma, rhinitis, psoriasis, rheumatism, prevention of rejection reactions in transplantation and ulcerative collitis [sic] or in combination with therapeutically known antiasthmatics, antirheumatics or immunosuppressants.
27. Carrier-immobilized forms, comprising compounds according to one of Claims 1 to 24 for use in binding pathogenic immunophilins from fluids, in particular body fluids.
28. Medicaments comprising at least one compound according to one of Claims 1 to 24 in addition to customary excipients and/or diluents or auxiliaries.
29. Process for the production of a medicament, characterized in that a compound according to one of Claims 1 to 24 is processed to give pharmaceutical preparations using customary pharmaceutical excipients or diluents and other auxiliaries and brought into a therapeutically utilizable form.
30. Medicaments according to Claims 1 to 29 in the form of tablets or coated tablets, capsules, solutions or ampoules, suppositories, patches or liquid or powder preparations which can be employed in inhalers.
31. Process for the preparation of novel specific immunophilin ligands of the formula I according to Claim 1, in which R1, R2, R3, X, Y, Z, A, B
and D have the meaning mentioned in Claim 1, characterized in that a carboxylic acid derivative of the formula II, in which R3, A, B, D, X
and Y have the meaning mentioned, is reacted with an amine, alkanol, halogen compound or tosylate III, in which R1 and Z have the meaning mentioned, to give an amide, ester or ether IV, in which R1, R3, A, B, D, X, Y and Z have the meaning mentioned, the derivative IV is reacted with an acid to give a compound V, in which R1, R3, A, B, D, X, Y and Z have the meaning mentioned, then this compound V is reacted with a sulphonyl chloride VI, in which R2 has the meaning mentioned to give the target compound I.
and D have the meaning mentioned in Claim 1, characterized in that a carboxylic acid derivative of the formula II, in which R3, A, B, D, X
and Y have the meaning mentioned, is reacted with an amine, alkanol, halogen compound or tosylate III, in which R1 and Z have the meaning mentioned, to give an amide, ester or ether IV, in which R1, R3, A, B, D, X, Y and Z have the meaning mentioned, the derivative IV is reacted with an acid to give a compound V, in which R1, R3, A, B, D, X, Y and Z have the meaning mentioned, then this compound V is reacted with a sulphonyl chloride VI, in which R2 has the meaning mentioned to give the target compound I.
32. Process for the preparation of novel specific immunophilin ligands of the formula I according to Claim 1, in which R1, R2, R3, X, Y, Z, A, B
and D have the meaning mentioned in Claim 1, characterized in that a carboxylic acid derivative of the formula II [sic], in which R3, A, B, D, X and Y have the meaning mentioned, is reacted with a sulphonyl chloride VI, in which R2 has the meaning mentioned, to give a sulphonamide of the formula VIII, in which R2, R3, A, B, D, X
and Y have the meaning mentioned, and in a continuing reaction reacted with a compound III, in which R1 and Z have the meaning mentioned, or with a compound V, in which R1, R3, X, Y, Z, A, B and D have the meaning mentioned, to give the target compound I.
and D have the meaning mentioned in Claim 1, characterized in that a carboxylic acid derivative of the formula II [sic], in which R3, A, B, D, X and Y have the meaning mentioned, is reacted with a sulphonyl chloride VI, in which R2 has the meaning mentioned, to give a sulphonamide of the formula VIII, in which R2, R3, A, B, D, X
and Y have the meaning mentioned, and in a continuing reaction reacted with a compound III, in which R1 and Z have the meaning mentioned, or with a compound V, in which R1, R3, X, Y, Z, A, B and D have the meaning mentioned, to give the target compound I.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742263.2 | 1997-09-25 | ||
| DE19742263A DE19742263A1 (en) | 1997-09-25 | 1997-09-25 | New specific immunophilin ligands as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, anti-psoriatic, neuroprotective |
| PCT/EP1998/005300 WO1999015501A1 (en) | 1997-09-25 | 1998-08-20 | Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents |
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|---|---|
| CA2304451A1 true CA2304451A1 (en) | 1999-04-01 |
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| CA002304451A Abandoned CA2304451A1 (en) | 1997-09-25 | 1998-08-20 | Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents |
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| Country | Link |
|---|---|
| EP (1) | EP1017673A1 (en) |
| JP (1) | JP2001517653A (en) |
| KR (1) | KR20010040253A (en) |
| AU (1) | AU9345098A (en) |
| BR (1) | BR9813226A (en) |
| CA (1) | CA2304451A1 (en) |
| DE (1) | DE19742263A1 (en) |
| HU (1) | HUP0004294A3 (en) |
| IL (1) | IL133246A0 (en) |
| NO (1) | NO20001510L (en) |
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| WO1999062880A1 (en) | 1998-06-03 | 1999-12-09 | Gpi Nil Holdings, Inc. | N-linked sulfonamides of n-heterocyclic carboxylic acids or carboxylic acid isosteres |
| US6300341B1 (en) | 1998-09-30 | 2001-10-09 | The Procter & Gamble Co. | 2-substituted heterocyclic sulfonamides |
| US6417189B1 (en) | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
| US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
| ATE319712T1 (en) | 1999-12-21 | 2006-03-15 | Mgi Gp Inc | HYDANTOIN DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE THEREOF |
| CN101006054A (en) * | 2004-06-18 | 2007-07-25 | 比奥里波克斯公司 | Indoles useful in the treatment of inflammation |
| ES2315877T3 (en) | 2004-06-18 | 2009-04-01 | Biolipox Ab | USEFUL INDOLES IN THE TREATMENT OF INFLAMMATIONS. |
| CA2571710A1 (en) | 2004-06-24 | 2006-11-02 | Nicholas Valiante | Small molecule immunopotentiators and assays for their detection |
| US8097623B2 (en) | 2005-01-19 | 2012-01-17 | Biolipox Ab | Indoles useful in the treatment of inflammation |
| WO2013138600A1 (en) * | 2012-03-16 | 2013-09-19 | Rosen Eliot M | Radioprotector compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5192773A (en) * | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| MX9202466A (en) * | 1991-05-24 | 1994-06-30 | Vertex Pharma | NOVELTY IMMUNOSUPPRESSIVE COMPOUNDS. |
| US5385918A (en) * | 1993-02-09 | 1995-01-31 | Miles Inc. | Aminomethylene-peptides as immunosuppressants |
| US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
| US5614547A (en) * | 1995-06-07 | 1997-03-25 | Guilford Pharmaceuticals Inc. | Small molecule inhibitors of rotamase enzyme |
| KR100266467B1 (en) * | 1995-09-27 | 2000-10-02 | 우에노 도시오 | Sulfonamide derivatives |
| DE19542189A1 (en) * | 1995-11-13 | 1997-05-15 | Hoechst Ag | New cyclic alpha-imino:hydroxamic acid derivatives |
| DE19616509A1 (en) * | 1996-04-25 | 1998-01-15 | Asta Medica Ag | New specific immunophilin ligands as anti-asthmatics, immunosuppressants |
-
1997
- 1997-09-25 DE DE19742263A patent/DE19742263A1/en not_active Withdrawn
-
1998
- 1998-08-20 HU HU0004294A patent/HUP0004294A3/en unknown
- 1998-08-20 BR BR9813226-1A patent/BR9813226A/en not_active IP Right Cessation
- 1998-08-20 AU AU93450/98A patent/AU9345098A/en not_active Abandoned
- 1998-08-20 EP EP98946392A patent/EP1017673A1/en not_active Withdrawn
- 1998-08-20 WO PCT/EP1998/005300 patent/WO1999015501A1/en not_active Application Discontinuation
- 1998-08-20 KR KR1020007003191A patent/KR20010040253A/en not_active Application Discontinuation
- 1998-08-20 JP JP2000512810A patent/JP2001517653A/en active Pending
- 1998-08-20 CA CA002304451A patent/CA2304451A1/en not_active Abandoned
- 1998-08-20 IL IL13324698A patent/IL133246A0/en unknown
- 1998-08-27 ZA ZA987819A patent/ZA987819B/en unknown
-
2000
- 2000-03-23 NO NO20001510A patent/NO20001510L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BR9813226A (en) | 2000-08-29 |
| NO20001510L (en) | 2000-05-22 |
| NO20001510D0 (en) | 2000-03-23 |
| DE19742263A1 (en) | 1999-04-01 |
| ZA987819B (en) | 1999-04-07 |
| EP1017673A1 (en) | 2000-07-12 |
| WO1999015501A1 (en) | 1999-04-01 |
| AU9345098A (en) | 1999-04-12 |
| JP2001517653A (en) | 2001-10-09 |
| HUP0004294A2 (en) | 2001-05-28 |
| HUP0004294A3 (en) | 2001-11-28 |
| KR20010040253A (en) | 2001-05-15 |
| IL133246A0 (en) | 2001-04-30 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |