Immunophilin ligands

• US 6,251,932 B1
• Filed: 09/25/1998
• Issued: 06/26/2001
• Est. Priority Date: 09/25/1998
• Status: Expired due to Fees

• Current Assignee: Asta Medica Aktiengesellschaft (Rag-Stiftung)
• Original Assignee: Asta Medica Aktiengesellschaft (Rag-Stiftung)
• Inventors: Bang, Holger, Reichelt, Dietmar, Kutscher, Berhard, Deppe, Holger, Brune, Kay, Poppe, Hildegard, Quinkert, Gerhard, Szelényi, István
• Primary Examiner(s): Gerstl, Robert
• Application Number:
  US09/161,037
• Time in Patent Office: 1,005 Days
• Field of Search: 548/455, 514/414
• US Class Current: 514/414
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention relates to an immunophilin ligand of Formula I and having antiasthmatic, antiallergic, antirheumatic, immunosuppressant, antipsoriatic and neuroprotectant properties,

Claims

1. An immunophilin ligand of Formula I:

wherein

R₁, R₂ and R₅ 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 residue having 1-4 heteroatoms, or mono- or polysubstituted with a phenyl ring, or

R₁ is an amine group of an amino acid methyl ester from the group of histidine, leucine, valine, serine, threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, —

NH₂,-lysine, —

Z-NH-lysine, -(21-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine, asparagine, citrulline, homocitrulline, ornithine, thiazolecarboxylic acid, proline, 2-indolinecarboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, and 8-aminooctanoic acid; and

R₂ 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 residue having 1-4 heteroatoms, or mono- or polysubstituted with a phenyl ring,

R₃ is H, F, OR₄, Br, NHR₄,

R₄ is hydrogen, a C_3-7 cycloalkyl, C_1-6 alkyl, or carboxy C_1-6 alkyl residue 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,

B is CH₂

D is CH

B-D is CH═

C

X is O, S, H₂

Y is S, C, and when X is ═

H₂ then a single bond; and

Z is S, O, NR₅,

provided that when B is CH₂ then D is CH, and when B is CH, then D is C, and its pharmaceutically acceptable salts.

2. The immunophilic ligand of claim 1, wherein said heteroatoms are independently of each other N, S and O.

3. The immunophilic ligand of claim 2, wherein in at least one of R₁, R₂ and R₅ independently of each other the alkyl group in said alkoxy group, and in R₂ 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.

4. The immunophilic ligand of claim 1, wherein either of said phenyl rings in at least one of R₁, R₂ and R₅ is 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 group esterified with a straight chain or branched C_1-6 alkanol.

5. The immunophilic ligand of claim 4, wherein in at least one of R₁, R₂ and R₅ independently of each other said substituent is substituted with one or more of a benzyl, benzoyl, acetyl group.

6. The immunophilic ligand of claim 4, wherein in R₂ said substituent is substituted with a mono-, bi- or tricyclic aminoaryl or amino-heteroaryl group having 1-4 heteroatoms, or by a carboxy C_1-12 alkyl, carboxycyclopentyl, carboxycyclohexyl or benzoyl group which can be mono- or polysubstituted by a halogen, methoxy, amino, carbamoyl, trifluoromethyl, carboxyl group, or with a carboxyl residue esterified with straight-chain or branched C_1-6 alkanol.

7. The immunophilic ligand of claim 6, wherein said heteroatoms are independently of each other is N, S and O.

8. The immunophilic ligand of claim 1, wherein in R₄ the alkyl group in said carboxy C_1-6 alkyl group is substituted with a mono-, bi- or tricyclic carbonylaryl or carbonylheteroaryl group having 1-4 heteroatoms.

9. The immunophilic ligand of claim 8, wherein said heteroatoms are independently of each other N, S and O.

10. The immunophilic ligand of claim 8, wherein the aryl or heteroaryl group is 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.

11. The immunophilic ligand of claim 10, wherein said substituent is substituted with one or more of a benzyl, benzoyl, acetyl group.

12. An immunophilic ligand of claim 1, which comprises the compounds:

(2S)-1-[((2S)-1-(4-acetylamino)phenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2R)-1-[((2S)-1-(4-acetylamino)phenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-metboxyethyl)indoline-2-carbamide;

(2S)-1-[((2R)-1-(4-acetylamino)phenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2R)-1-[((2R)-1-(4-acetylamino)phenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2R,S)-1-[((2R,S)-1-(4-acetylaminophenylsulfonyl)indolin-2-yl) carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-aminophenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-aminophenylsulfonyl)prolyl)carbonyl]-N-(2-methoxy ethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-aminophenylsulfonyl)pipecolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-methylphenylsulfonyl)prolyl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[(8-quinolinylsulfonyl)]-N-(2-methoxyethyl)indolinecarbamide;

1-[(2S)-1-(4-acetylaminophenylsulfonyl)indolin-2-yl)carbonyl]-N-leucine;

(S)-N-{(2S)-1-[4-(acetylamino)phenylsulfonyl]indolin-2-yl}carbonyl-N-(benzyloxycarbonyl)lysine methyl ester;

methyl (E)-({(2S)-1-[4-(acetylamino)phenylsulfonyl]indolin-2-yl}carbonyl)-4-(aminophenyl)acrylate;

(2S)-1-[((2S)-1-(1-naphthalenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(2-naphthalenylsulfonyl)indolin-2-yl)carbonyl]-N-(2-methoxyethyl)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-methylphenylsulfonyl)indolin-2-yl)carbonyl]-N³-(N-propylimidazole)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-methylphenylsulfonyl)indolin-2-yl)carbonyl]-N²-(N-ethylmorpholine)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-methylphenylsulfonyl)indolin-2-yl)carbonyl]-N²-(ethyl-2-pyridine)indoline-2-carbamide;

(2S)-1-[((2S)-1-(4-methylphenylsulfonyl)indolin-2-yl)carbonyl]-(4-pyridine) indoline-2-carbamide;

methyl (2R)-[4-acetylamino)phenylsulfonyl]indoline-2-carboxylate;

(2R)-[4-(acetylamino)phenylsulfonyl]indoline-2-carboxylic acid;

methyl (2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulfonyl]indolin-2-yl}carbonyl)indoline-2-carboxylate; and

(2RS)-1-({(2RS)-1-[4-(acetylamino)phenylsulfonyl]indolin-2-yl}carbonyl) indoline-2-carboxylic acid.

13. A process for preparing a pharmacological dosage form of a drug which comprises admixing a compound of claim 1 or of claim 12 to at least one of a pharmacological carrier and excipient.

14. A pharmacological dosage form prepared by the process of claim 13, which comprises a coated or uncoated tablet, capsule, solution, ampoule, suppository, patch, or inhalable liquid or powder preparation.

15. A process for treating a patient in need therefor with a drug prepared by the process of claim 13 in a dosage form for a treatment requiring the administration of an antirheumatic, antiasthmatic, antiallergic, antipsoriatic, neuroprotectant, antiinflammatory, or immunosuppressant drug, with or without combination with another like drug.

16. The process of claim 15, wherein said immunosuppressant action is for the treatment of an immunological, autoimmune, or neurodegenerative disorder, or for the prevention of rejection reactions in transplantation, and said antiinflammatory is for the treatment of an inflammation in asthma, rhinitis, psoriasis, rheumatism, and ulcerative colitis.

17. The immunophilic ligand of claim 1, which comprises the compound in a carrier-immobilized form for binding pathogenic immunophilins from fluids, in particular body fluids.

18. A process for preparing an immunophilin ligand of claim 1, which comprises contacting a carboxylic acid derivative of Formula II

wherein R₃, A, B, D, X and Y are the same as in claim 1, with an amine, alkanol, halogen compound or tosylate of Formula III

wherein R₁ and Z are the same as in claim 1, to provide an amide, ester or ether of Formula IV

wherein R₁, R₃, A, B, D, X, Y and Z are the same as in claim 1, then contacting the compound of Formula IV with an acid to provide the compound of Formula V

wherein R₁, R₃, A, B, D, X, Y and Z are the same as in claim 1, then contacting the compound of Formula V with a sulfochloride of Formula VI

wherein R₂ is the same as in claim 1, to provide the target compound of Formula I.

19. A process for preparing an immunophilin ligand of claim 1, which comprises contacting a carboxylic acid derivative of formula VII

wherein R₃, A, B, D, X and Y are the same as in claim 1, with a sulfonyl chloride of Formula VI

wherein R₂ is the same as in claim 1, to provide a sulfonamide of Formula VIII

wherein R₂, R₃, A, B, D, X and Y are the same as in claim 1, and in a continuing reaction with a compound of Formula III

wherein R₁, and Z are the same as in claim 1, or with a compound of Formula V

wherein R₁, R₃, X, Y, Z, A, B and D are the same as in claim 1, to provide the target compound of Formula I.