Immunophilin ligands

Details Immunophilin ligands Immunophilin ligands

1998-09-25

2001-06-26

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S455000

Reexamination Certificate

active

06251932

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel specific immunophilin ligands with antiasthmatic, antiallergic, antirheumatic, immunosuppressant, antipsoriatic and neuroprotectant properties.
BACKGROUND
Cyclosporin A (CsA) and FK 506 are immunosuppressant natural substances derived from fungi which inhibit the Ca
2+
-dependent 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 trans-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 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 substance mixtures (G. Quinkert, H. Bang and D. Reichert,
Helv. Chim. Acta
1996, 79, 1260). The structure published there is an indoline-2-carboxamide which at 10 &mgr;mol exhibited an inhibition of IL-2 proliferation of 77% and at 1 &mgr;mol an inhibition of IL-2 proliferation of 12%. New measurements at a concentration of 10 &mgr;mol showed an IL-2-dependent inhibition of proliferation of 29%.
A substance class which likewise contains indolinecarboxylic acid as a central unit and exhibits immunosuppressant properties as well as antiasthmatic properties was described in German patent No. 1,961,6509.1.
DESCRIPTION OF THE INVENTION
It is an object of the present invention is to provide novel immunophilic ligands having useful pharmacological properties and providing processes for their targeted synthesis.
It has been found that the novel immunophilin ligand of Formula I surprisingly satisfies the aforementioned object of the present invention. The compounds of Formula I are
wherein
R
1
, R
2
and R
5
are independently of each other hydrogen, C
1-12
alkyl or C
2-6
alkoxy groups in which the alkyl group is straight-chain or branched and can be substituted with a mono- or bicyclic heteroaryl group having 1-4 heteroatoms suitably independently of each other N, S, and O, or mono- or polysubstituted with a phenyl ring, or
R
1
is an amine group of an amino acid methyl ester from the group of histidine, leucine, valine, serine, threonine, pipecolic acid, 4-piperidine-carboxylic acid, 3-piperidinecarboxylic acid, —NH
2
-lysine, —Z-NH-lysine, -(21-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine, asparagine, citrulline, homocitrulline, ornithine, thiazole-carboxylic acid, proline, 2-indolinecarboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, and 8-aminooctanoic acid; and
R
2
is an amino C
1-12
alkyl, or an amino C
2-6
alkoxy group wherein the alkyl group is straight-chain or branched and can be substituted with a mono- or bicyclic heteroaryl group having 1-4heteroatoms suitably independently of each other N, S, and O, or mono- or polysubstituted with a phenyl ring,
R
3
is H, F, OR
4
, Br, NHR
4
R
4
is hydrogen, a C
3-7
cycloalkyl, C
1-6
alkyl, or carboxy C
1-6
alkyl group wherein the alkyl group is straight-chain or branched,
A is without a ring, or an aromatic, non-aromatic, or aromatic heterocyclic or non-aromatic heterocyclic having 1-2 heteroatoms, suitably independently of each other N, S and O,
B is CH
D is CH
B—D is CH═C
X is O, S, H
Y is S, C, and when X is═H
2
then a single bond; and
Z is S, O, NR
5
.
At least in one of R
1
, R
2
and R
5
independently of each other the alkyl group in said alkoxy group, and in R
2
in said amino C
2-6
alkoxy group, is substituted with a morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazine, thiophene, furan or imidazole group.
Either of said phenyl rings in at least one of R
1
, R
2
and R
5
can be independently of each other mono- or polysubstituted with the substituent halogen, C
1-6
alkyl, C
3-7
cycloalkyl, carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino, carboxyl, or carboxyl residue esterified with a straight chain or branched C
1-6
alkanol. In at least one of R
1
, R
2
and R
5
independently of each other the aforementioned substituent is suitably substituted with one or more of a benzyl, benzoyl, acetyl group.
In R
2
the aforesaid substituent can also be substituted with a mono-, bi- or tricyclic aminoaryl or aminoheteroaryl group having 1-4 heteroatoms suitably independently of each other N, S, and O, or by a carboxy C
1-12
alky, carboxycyclopentyl, carboxycyclohexyl or benzoyl group which can be mono- or polysubstituted by a halogen, methoxy, amino, carbamoyl, trifluoromethyl, carboxyl residue, or with a carboxyl group esterified with straight-chain or branched C
1-6
alkanol.
In R
4
the alkyl group in the carboxy C
1-6
alkyl group can be substituted with a mono-, bi- or tricyclic carbonylaryl or carbonylheteroaryl residue having 1-4 heteroatoms suitably independently of each other N, S and O.
In R
2
the aryl or heteroaryl group can be mono- or polysubstituted with the substituent halogen, C
1-6
alkyl, C
3-7
cycloalkyl carbamoyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy, amino, carboxyl, or carboxyl group esterified with a straight chain or branched C
1-6
alkanol, and the aforementioned substituent can also be substituted with one or more of a benzyl, benzoyl, acetyl group.
The invention furthermore relates to the pharmaceutically acceptable salts of the compounds of Formula I, the processes for the preparation of the compounds of Formula I, and processes for their pharmacological use.
This class of compounds and their pharmaceutically acceptable salts have a high affinity for immunophilins such as CypA, CypB, CypC and FKBP12. Moreover, substances of Formula I inhibit various cytokine syntheses, as well as a Ca
++
-dependent signal transmission pathway.
Those compounds

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