IL-8 RECEPTOR ANTAGONISTS

• US 20110059937A1
• Filed: 11/12/2010
• Published: 03/10/2011
• Est. Priority Date: 04/21/2006
• Status: Abandoned Application

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Busch-Petersen, Jakob
• Application Number:
  US12/944,902
• Publication Number:
  US 20110059937A1
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/06 Antimalarials
• 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 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 209/02 : condensed with one carbocyclic ring
• CPC Class Codes: C07D 211/54 : Sulfur atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

This invention relates to novel compounds and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Claims

1. A compound according to Formula (I):

2. A compound according to claim 1 wherein X is halogen.

3. A compound according to claim 1 wherein X is chlorine.

4. A compound according to claim 1 wherein R2 is phenyl optionally substituted, independently once or twice, by a substituent selected from the group consisting of C_1-3alkyl, halogen, OCF₃ and phenyloxy.

5. A compound according to claim 4 wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl.

6. A compound according to claim 1 wherein R2 is 3-fluoro-2-methylphenyl or 2-chloro-3-fluorophenyl.

7. A compound according to claim 1 wherein R2 is pyridyl, optionally substituted once by halogen.

8. A compound according to claim 7 wherein R2 is 2-chloro-3-pyridyl.

9. A compound according to claim 1 wherein n is 0.

10. A compound according to claim 1 wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety.

11. A compound according to claim 1 wherein n is 1, and R1 is a pyrrolidin-3-yl or a ethyl-1-pyrrolidinylcarboxylate moiety.

12. A compound according to claim 1 wherein R1 is 3-exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl or 3-exo-8-azabicyclo[3.2.1]oct-3-yl.

13. A compound according to claim 1 wherein the pharmaceutically acceptable salt is a hydrochloride salt.

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

15. A compound according to claim 1 selected from the group consisting of

N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-(2-ethylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2-ethylphenyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2-ethylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-[2-(phenyloxy)phenyl]urea;

ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]-phenyl}sulfonyl)-1-piperidinecarboxylate;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-(2-chloro-3-fluorophenyl)-N′

-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea;

ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2,3-dichlorophenyl)urea;

or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1 selected from the group consisting of:

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′

-[2-(phenyloxy)phenyl]urea;

ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]phenyl}sulfonyl)-1-piperidinecarboxylate;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-(2-chloro-3-fluorophenyl)-N′

-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea;

ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;

N-(2-chloro-3-fluorophenyl)-N′

-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2,3-dichlorophenyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′

-(2,3-dichlorophenyl)urea;

or a pharmaceutically acceptable salt thereof.

31. A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 α

or β

receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound according to claim 1.

17. A method of synthesizing a compound according to Formula (I):

18. The process according to claim 17 wherein the compound of Formula (I) is

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-[2-(phenyloxy)phenyl]urea;

or

N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

or a pharmaceutically acceptable salt thereof.

19. The process according to claim 17 wherein the compound of Formula (I) is

N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2-ethylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea;

or

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea;

or a pharmaceutically acceptable salt thereof.

20. The process according to claim 17 wherein the compound of Formula (I) is

N-(2-chloro-3-fluorophenyl)-N′

-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea;

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea, or

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′

-(3-fluoro-2-methylphenyl)urea,

or a pharmaceutically acceptable salt thereof.

21. The process according to claim 17 wherein the compound of Formula (I) is

N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′

-(3-fluoro-2-methylphenyl)urea, or

N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′

-(3-fluoro-2-methylphenyl)urea,

or a pharmaceutically acceptable salt thereof.

22. The process according to claim 17 wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety.

23. The process according to claim 17 wherein R2 is phenyl optionally substituted, independently once or twice, by a substituent selected from the group consisting of C_1-3alkyl, halogen, OCF₃ and phenyloxy.

24. The process according to claim 17 wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl.

25. The process according to claim 17 wherein n=0 and R1 is a 3-azetidinyl, 4-piperidinyl, 3-piperidinyl, 3-pyrrolidinyl or ethyl-1-pyrrolidinylcarboxylate.

26. The process according to claim 17 wherein R1 is an optionally substituted piperidine-3-yl.

27. The process according to claim 26 wherein X is halogen.

28. The process according to claim 27 wherein R2 is a phenyl substituted, once or twice, independently, by a substituent selected from the group consisting of C_1-3alkyl, halogen, CF₃, OCF₃, phenyloxy and benzyloxy.

29. A compound which is

N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

or

N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

or a pharmaceutically acceptable salt thereof.

30. A compound selected from the group consisting of: