Patent ID: 6258815
Filing Date: 2001-07-10
Classification: A61K,A61P,C07D,C07K

Abstract:
Specific immunophilin ligands of the formula ##STR4##in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, Y, A, B and D are defined as follows:R.sub.1 is hydrogen, a (C.sub.1 -C.sub.12)-alkyl group or a (C.sub.2 -C.sub.6)-alkoxy group, where the alkyl group is linear or branched and is unsubstituted or substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, or monosubstituted or polysubstituted by a phenyl ring, said phenyl ring being unsubstituted or monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, tri-fluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl; orR.sub.1 is the amine radical of the methyl esters of the following amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecolic acid, piperidine-4-carboxylic acid, piperidine-3-carboxylic 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, proline, indoline-2-carboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid and 8-aminooctanoic acid;R.sub.2 is hydrogen, a (C.sub.1 -C.sub.12)-alkyl group or a (C.sub.2 -C.sub.6)-alkoxy group, where the alkyl group is linear or branched and is unsubstituted or substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, or monosubstituted or polysubstituted by a phenyl ring, said phenyl ring being unsubstiututed or monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, tri-fluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl;R.sub.3 is hydrogen, butoxycarbonyl, carboxybenzyl, mono-, bi-, or tri-cyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, where said aryl or heteroaryl is unsubstituted, or monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl; or R.sub.3 is carboxy-(C.sub.1 -C.sub.6)-alkyl, where the alkyl group is linear or branched and is unsubstituted or substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, or monosubstituted or polysubstituted by a phenyl ring, where said phenyl ring is unsubstituted or is monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl; orR.sub.3 is the acid radical of an amino acid selected from the group consisting of histidine, leucine, valine, serine (Bzl), threonine, pipecolic acid, piperidine-4-carboxylic acid, piperidine-3-carboxylic acid, .epsilon.-NH.sub.2 -lysine, .epsilon.-Z-NH-lysine, .epsilon.-(2Cl-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Tos), asparagine, citrulline, homocitrulline, ornithine, proline, indoline-2-carboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid and 8-amino-octanoic acid, where the N terminus of the amino acids is unsubstituted or substituted by butoxycarbonyl, carboxybenzyl or the acid radical of mono-, bi- or tri-cyclic arylcarboxylic or heteroarylcarboxylic acids having 1-4 heteroatoms, or by carboxy-(C.sub.1 -C.sub.12)-alkyl, carboxycyclopentane, carboxycyclohexane or benzoyl, which may be unsubstituted or monosubstituted or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups or carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols;R.sub.4 is H, F or OR.sub.5 ;R.sub.5 is hydrogen, (C.sub.3 -C.sub.7)-cycloalkyl, (C.sub.1 -C.sub.6)-alkyl or carboxy-(C.sub.1 -C.sub.6)-alkyl, where the alkyl group is linear or branched and is unsubstituted or substituted by a mono-, bi- or tri-cyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, where aryl or heteroaryl itself is unsubstituted or is monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl;A is an aromatic or non-aromatic carbon ring;B is CH.sub.2 and D is CH; orB--D is CH.dbd.C;X is O, S or H.sub.2 ; andY is C or a single bond;with the proviso that when R.sub.1, R.sub.2 and R.sub.3 are all lower alkyl groups or hydrogen, B--D is CH.dbd.C.