Novel Specific Caspase-10 Inhibitors

• US 20080255173A1
• Filed: 11/02/2005
• Published: 10/16/2008
• Est. Priority Date: 12/01/2004
• Status: Active Grant

• Current Assignee: Merck Patent Gesellschaft Mit Beschränkter Haftung
• Original Assignee: Merck Patent Gesellschaft Mit Beschränkter Haftung
• Inventors: Convard, Thierry, Descours, Denis, Vidal, Catherine, Lecomte, Marc, Lardy, Claude, Yvon, Stephane, Denuault, Marie Noelle
• Granted Patent: US 7,829,721 B2
• Time in Patent Office: Days
• US Class Current: 514/277
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 57/38 polycyclic
• CPC Class Codes: C07C 57/58 containing six-membered aromatic rings
• CPC Class Codes: C07C 59/64 containing six-membered aromatic rings

Abstract

The invention relates to compounds of the general formula (I), and to their use as caspase-10 inhibitors, especially for the treatment of diabetic retinopathy.

Claims

1. Use of the compounds of the general formula (I):

2. Use according to claim 1, such that, in formula (I), R3 is in the para position relative to the phenyl nucleus.

3. Use according to claim 1, such that, in formula (I), R2 is in the para position relative to the phenyl nucleus.

4. Use according to claim 1, such that, in formula (I), m=0, 1 or 2.

5. Use according to claim 1, such that, in formula (I), n=0 or 1.

6. Use according to claim 1, such that, in formula (I), X, Y and Z each represent a —

CH═

group.

7. Use according to claim 1, such that, in formula (I), only one from among X, Y and Z represents a nitrogen atom, the other two representing a —

CH═

group.

8. Use according to claim 1, such that, in formula (I), R1 represents a —

COOH, —

COOalkyl, —

CH₂COOH, —

CH₂COOH, —

CH₂CN or —

CH₂OH group.

9. Use according to claim 1, such that, in formula (I), R1 represents a —

COOH group.

10. Use according to claim 1, such that, in formula (I), each of the R2, which may be identical or different, independently represents a halogen atom or a group chosen from —

Oalkyl, -perhaloalkyl, —

NO₂ and —

NHCOalkyl.

11. Use according to claim 1, such that, in formula (I), R2 represents a halogen atom.

12. Use according to claim 1, such that, in formula (I), each of the R3, which may be identical or different, independently represents a halogen atom or an -alkyl, —

SO₂alkyl, -alkylalkyl″

, —

Oalkyl, perhaloalkyl or —

Operhaloalkyl group.

13. Use according to claim 1, such that, in formula (I), m=1, R3 is in the para position relative to the phenyl nucleus, and represents a halogen atom or an -alkyl, -perhaloalkyl or —

Oalkyl group.

14. Use according to claim 1, such that the compound of the formula (I) is chosen from the following compounds:

(4′

-methylbiphenyl-2-yl)acetic acid

[4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

[4′

-(dimethylamino)biphenyl-2-yl]acetic acid

(2-pyridin-3-ylphenyl)acetic acid

(2-pyridin-4-ylphenyl)acetic acid

[4-chloro-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

[4-chloro-4′

-(dimethylamino)biphenyl-2-yl]acetic acid

(5-chloro-2-pyridin-3-ylphenyl)acetic acid

(5-chloro-2-pyridin-4-ylphenyl)acetic acid

(5-methoxy-2-pyridin-3-ylphenyl)acetic acid

(5-methoxy-2-pyridin-4-ylphenyl)acetic acid

(4-chloro-4′

-methylbiphenyl-2-yl)acetic acid

(4-chloro-4′

-fluorobiphenyl-2-yl)acetic acid

(4,4′

-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-chloro-4′

-methoxybiphenyl-2-yl)acetic acid

(4′

-tert-butyl-4-chlorobiphenyl-2-yl)acetic acid

(3′

,4-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethoxy)biphenyl-2-yl]acetic acid

[4,4′

-bis(trifluoromethyl)biphenyl-2-yl]acetic acid

(2′

-propoxybiphenyl-2-yl)acetic acid

(5′

-chloro-2′

-ethoxybiphenyl-2-yl)acetic acid

ethyl [4′

-(trifluoromethyl)biphenyl-2-yl]acetate

[4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-fluorobiphenyl-2-yl)acetic acid

(4-fluoro-4′

-methylbiphenyl-2-yl)acetic acid

(4,4′

-difluorobiphenyl-2-yl)acetic acid

(4-fluoro-4′

-methoxybiphenyl-2-yl)acetic acid

[4-fluoro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-fluoro-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

(4′

-chloro-4-fluorobiphenyl-2-yl)acetic acid

[4′

-(dimethylamino)-4-fluorobiphenyl-2-yl]acetic acid

(4-methoxybiphenyl-2-yl)acetic acid

(4-methoxy-4′

-methylbiphenyl-2-yl)acetic acid

(4′

-fluoro-4-methoxybiphenyl-2-yl)acetic acid

(4,4′

-dimethoxybiphenyl-2-yl)acetic acid

[4-methoxy-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-methoxy-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

[4′

-(dimethylamino)-4-methoxybiphenyl-2-yl]acetic acid

(5-fluoro-2-pyridin-3-ylphenyl)acetic acid

(5-fluoro-2-pyridin-4-ylphenyl)acetic acid

(4′

-methyl-4-nitrobiphenyl-2-yl)acetic acid

(4′

-methoxy-4-nitrobiphenyl-2-yl)acetic acid

(4′

-chloro-4-nitrobiphenyl-2-yl)acetic acid

[4-nitro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-methoxybiphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-chlorobiphenyl-2-yl]acetic acid

[4-(acetylamino)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-methylbiphenyl-2-yl]acetic acid

2-(4-chlorobiphenyl-2-yl)ethanol

2-(4′

-chlorobiphenyl-2-yl)ethanol

3-(4-chlorobiphenyl-2-yl)propanenitrile

3-(4-chlorobiphenyl-2-yl)propanoic acid

and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts.

15. Use according to claim 1, such that the compound of the formula (I) is chosen from the following compounds:

(4-chloro-4′

-methylbiphenyl-2-yl)acetic acid

(4,4′

-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-chloro-4′

-methoxybiphenyl-2-yl)acetic acid

and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts.

16. Use according to claim 1, such that the retinopathy is diabetic retinopathy.

17. Use of a compound of the formula (I) as defined according to claim 1, for the preparation of a medicament for specifically inhibiting caspase-10 in a patient in need thereof.

18. Use according to claim 17, for which the said medicament is suitable for the prevention and/or treatment of microvascular complications of diabetes.

19. Compound of the general formula (II):

20. Compound according to claim 19, such that, in formula (II), X, Y, Z, R1, R2, R3 and/or m are as defined above.

21. Compound according to claim 19, chosen from the following compounds:

[4-chloro-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

[4-chloro-4′

-(dimethylamino)biphenyl-2-yl]acetic acid

(5-chloro-2-pyridin-3-ylphenyl)acetic acid

(5-chloro-2-pyridin-4-ylphenyl)acetic acid

(5-methoxy-2-pyridin-3-ylphenyl)acetic acid

(5-methoxy-2-pyridin-4-ylphenyl)acetic acid

(4-chloro-4′

-methylbiphenyl-2-yl)acetic acid

(4-chloro-4′

-fluorobiphenyl-2-yl)acetic acid

(4,4′

-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-chloro-4′

-methoxybiphenyl-2-yl)acetic acid

(4′

-tert-butyl-4-chlorobiphenyl-2-yl)acetic acid

(3′

,4-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethoxy)biphenyl-2-yl]acetic acid

[4,4′

-bis(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-fluorobiphenyl-2-yl)acetic acid

(4-fluoro-4′

-methylbiphenyl-2-yl)acetic acid

(4,4′

-difluorobiphenyl-2-yl)acetic acid

(4-fluoro-4′

-methoxybiphenyl-2-yl)acetic acid

[4-fluoro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-fluoro-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

(4′

-chloro-4-fluorobiphenyl-2-yl)acetic acid

[4′

-(dimethylamino)-4-fluorobiphenyl-2-yl]acetic acid

(4-methoxybiphenyl-2-yl)acetic acid

(4-methoxy-4′

-methylbiphenyl-2-yl)acetic acid

(4′

-fluoro-4-methoxybiphenyl-2-yl)acetic acid

(4,4′

-dimethoxybiphenyl-2-yl)acetic acid

[4-methoxy-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-methoxy-4′

-(methylsulfonyl)biphenyl-2-yl]acetic acid

[4′

-(dimethylamino)-4-methoxybiphenyl-2-yl]acetic acid

(5-fluoro-2-pyridin-3-ylphenyl)acetic acid

(5-fluoro-2-pyridin-4-ylphenyl)acetic acid

(4′

-methyl-4-nitrobiphenyl-2-yl)acetic acid

(4′

-methoxy-4-nitrobiphenyl-2-yl)acetic acid

(4′

-chloro-4-nitrobiphenyl-2-yl)acetic acid

[4-nitro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-methoxybiphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-chlorobiphenyl-2-yl]acetic acid

[4-(acetylamino)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

[4-(acetylamino)-4′

-methylbiphenyl-2-yl]acetic acid

2-(4-chlorobiphenyl-2-yl)ethanol

2-(4′

-chlorobiphenyl-2-yl)ethanol

3-(4-chlorobiphenyl-2-yl)propanenitrile

3-(4-chlorobiphenyl-2-yl) propanoic acid

and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts.

22. Compound according to claim 19, chosen from the following compounds:

(4-chloro-4′

-methylbiphenyl-2-yl)acetic acid

(4,4′

-dichlorobiphenyl-2-yl)acetic acid

[4-chloro-4′

-(trifluoromethyl)biphenyl-2-yl]acetic acid

(4-chloro-4′

-methoxybiphenyl-2-yl)acetic acid

and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts.

23. Pharmaceutical composition comprising a compound of the general formula (II) as defined according to claim 19 and a pharmaceutically acceptable excipient.

24. Process for the preparation of a compound of the formula (II) according to claim 19, comprising the step of preparing a corresponding compound of the formula (II′

);

25. Process according to claim 24, such that the coupling reaction is performed using a palladium catalyst.

26. Process according to claim 24, also comprising the step of isolating and/or purifying the product of the formula (II).