CYTOKINE INHIBITORS

• US 20090118292A1
• Filed: 11/02/2007
• Published: 05/07/2009
• Est. Priority Date: 11/02/2007
• Status: Active Grant

• Current Assignee: Hutchison Medipharma Enterprises Limited
• Original Assignee: Hutchison Medipharma Enterprises Limited
• Inventors: Su, Wei-Guo, Cai, Yu, Duan, Jeff, Deng, Wei
• Granted Patent: US 7,868,001 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 487/04 Ortho-condensed systems

Abstract

A compound of Formula I:

Each variable is defined in the specification. This invention relates to a method of decreasing a level of a cytokine (e.g., TNFα or interlukine such as IL-1β) in a subject with a compound of Formula I. It also relates to a method of treating a disorder mediated by an overproduction of a cytokine with such a compound.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein A is deleted, CH₂, or

3. The compound of claim 2, wherein B is

4. The compound of claim 3, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

5. The compound of claim 4, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

6. The compound of claim 2, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

7. The compound of claim 6, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

8. The compound of claim 1, wherein the compound is

2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(2-morpholinoethyl)urea;

1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(2-methoxyethyl)urea;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyethanamine;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-morpholinoethanamine;

2-(3-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N,N-dimethylmethanamine;

2-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methylamino)ethanol;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)ethanamine;

2-(3-(5-((4-fluorophenoxy)methyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl acetate;

2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methanol;

2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

N-methyl-2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-amine;

ethyl 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxylate;

ethyl 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetate;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxylic acid;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide;

2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetic acid;

2-(3-(5-(methylthiomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(methylsulfonylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine;

2-(3-(2-methoxyethoxy)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(2-methoxyethoxy)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(2-methoxyethoxy)-5-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2-(3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[1,2-b]pyridazine;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazol-5-yl)methanol;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylic acid;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin-2-yl)-1,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2,2,2-trifluoroethyl)-1,2,4-oxadiazole-5-carboxamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)acetamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2,2,2-trifluoroacetamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-chloroacetamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-chlorobenzamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-nitrobenzenesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-cyanobenzamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-bromobenzamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-fluorobenzenesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-chlorobenzenesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-methylbenzenesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-fluorobenzenesulfonamide;

N-(2-(diethylamino)ethyl)-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide;

N-butyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide;

2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide;

N-cyclopentyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide;

2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(2-methoxyethyl)acetamide;

2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-1-morpholinoethanone;

N-cyclopropyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(2-morpholinoethyl)-1,2,4-oxadiazole-5-carboxamide;

N-ethyl-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide;

N-cyclopentyl-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)(morpholino)methanone;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(2-methoxyethyl)-1,2,4-oxadiazole-5-carboxamide;

N-(2-(dimethylamino)ethyl)-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide;

(4-ethylpiperazin-1-yl)(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methanone;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(thiophen-2-ylmethyl)-1,2,4-oxadiazole-5-carboxamide;

N-(2-hydroxyethyl)-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N,N-dimethyl-1,2,4-oxadiazole-5-carboxamide;

(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)(pyrrolidin-1-yl)methanone;

3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide;

2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

(2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(pyrrolidin-1-yl)methanone;

N-(2-hydroxyethyl)-2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

ethyl 2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinate;

N-cyclopropyl-2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide;

(2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(morpholino)methanone;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-((2-methoxyethylamino)methyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide;

N-(3-(5-((2-(dimethylamino)ethylamino)methyl)-1,2,4-oxadiazol-3-yl)-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide;

N-(3-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide;

2-(3-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

N1-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)ethane-1,2-diamine;

N1-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-N2,N2-dimethylethane-1,2-diamine;

2-(3-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine;

2,2,2-trifluoro-N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide;

ethyl 2-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl-amino)-2-oxoacetate;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyacetamide;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopentanecarboxamide;

ethyl 3-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl-amino)-3-oxopropanoate;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide;

N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4- oxadiazol-5-yl)methyl)isobutyramide;

3-((3-(imidazo[1,2-b]pyridazin-2-yl)benzylamino)methyl)benzonitrile;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-4-chlorobenzamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-2-methoxyacetamide;

N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-cyanobenzenesulfonamide;

1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(thiophen-2-ylmethyl)urea;

3-bromo-N-((3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)methyl)benzamide;

4-chloro-N-((3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)methyl)benzamide;

N-((3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)methyl)butyramide;

N-((3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)methyl)cyclopropanecarboxamide;

N-((3-(3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)(4-(methylsulfonyl)phenyl)methanamine;

2-methoxy-N-((3-(3-(2-methylimidazo[2,1-b]thiazol-6-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)ethanamine;

N-((3-(H-imidazo[1,2-a]pyridin-2-yl)phenyl)methyl)-2-methoxyacetamide;

ethyl 2-((3-(H-imidazo[1,2-a]pyridin-2-yl)phenyl)methylamino)nicotinate;

1-((3-(H-imidazo[1,2-a]pyridin-2-yl)phenyl)methyl)-3-(2-chloro-4-fluorophenyl)urea;

or

1-((3-(H-imidazo[1,2-a]pyridin-2-yl)phenyl)methyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea.

37. A process for the preparation of a compound of Formula I as defined in claim 1 or its salt or solvate, the process comprising:

(a) coupling a compound of the following formula;

9. A method of decreasing a level of a cytokine in a subject, the method comprising administering to a subject with an effective amount of a compound of Formula I:

10. The method of claim 9, wherein the cytokine is TNFα

or interleukin.

11. The method of claim 10, wherein the interleukin is IL-1β

, IL-2, or IL-6.

12. The method of claim 11, wherein A is deleted, CH₂, or

13. The method of claim 12, wherein B is

14. The method of claim 13, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

15. The method of claim 14, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

16. The method of claim 12, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

17. The method of claim 16, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

18. A method of treating a disorder mediated by an overproduction of a cytokine, the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I.

19. The method of claim 18, wherein the cytokine is TNFα

or interleukin.

20. The method of claim 19, wherein the interleukin is IL-1β

, IL-2, or IL-6.

21. The method of claim 20, wherein A is deleted, CH₂, or

22. The method of claim 21, wherein B is

23. The method of claim 22, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

24. The method of claim 23, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

25. The method of claim 21, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

26. The method of claim 25, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

27. The method of claim 18, wherein the disorder is an inflammatory disease, an autoimmune disease, cancer, diabetes, allergy or atherosclerosis.

28. The method of claim 27, wherein the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, or septic shock.

29. The method of claim 28, wherein the inflammatory bowel disease is ulcerative colitis or Crohn'"'"'s disease.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I:

31. The pharmaceutical composition of claim 30, wherein A is deleted, CH₂, or

32. The pharmaceutical composition of claim 31, wherein B is

33. The pharmaceutical composition of claim 32, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CONR^c′

, or NR^c′

CONR^d′

.

34. The pharmaceutical composition of claim 33, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.

35. The pharmaceutical composition of claim 31, wherein X is deleted, (CR^a′

R^b′

)_m, CO, COO, NR^c′

, CON^c′

, or NR^c′

CONR^d′

.

36. The pharmaceutical composition of claim 35, wherein X is CH₂, NH, CO, COO, CONH, or NHCONH.