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Claims
1. Novel specific immunophilin ligands of the formula I
<IMG>
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-
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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
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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,
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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
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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
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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,
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<IMG>
is reacted with an amine, alkanol, halogen compound or tosylate III,
in which R1 and Z have the meaning mentioned,
<IMG>
to give an amide, ester or ether IV, in which R1, R3, A, B, D, X, Y and
Z have the meaning mentioned,
<IMG>
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,
<IMG>
then this compound V is reacted with a sulphonyl chloride VI, in which
R2 has the meaning mentioned
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<IMG>
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,
<IMG>
is reacted with a sulphonyl chloride VI, in which R2 has the meaning
mentioned,
<IMG>
to give a sulphonamide of the formula VIII, in which R2, R3, A, B, D, X
and Y have the meaning mentioned,
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<IMG>
and in a continuing reaction reacted with a compound III, in which R1
and Z have the meaning mentioned, or
<IMG>
with a compound V, in which R1, R3, X, Y, Z, A, B and D have the
meaning mentioned,
<IMG>
to give the target compound I.
