Novel 2-Pyridone Compounds

• US 20110082155A1
• Filed: 10/01/2010
• Published: 04/07/2011
• Est. Priority Date: 10/02/2009
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Meigh, Jon, Bergstrom, Lena Kristina, Sjö, Peter Olof, Murugan, Andiappan, Ashton, Mark David, Lindsjö, Martin, Kristoffersson, Anna
• Granted Patent: US 8,436,024 B2
• Time in Patent Office: Days
• US Class Current: 514/255.05
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

The invention provides compounds of formula

wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, L, X and Y are as defined in the specification; together with processes and intermediates for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase.

Claims

1. A compound of formula (I):

2. A compound according to claim 1, wherein X represents CH.

3. A compound according to claim 1, wherein R³ represents a phenyl group substituted in the 3-(meta) position with trifluoromethyl.

4. A compound according to claim 1, wherein R⁴, R⁵, and R⁶ each independently represent C₁-C₄ alkyl.

5. A compound according to claim 1, wherein R⁴ and R⁵ joined together such that the group NR⁴R⁵ together represents a 5- or 6-membered cyclic ammonium group;

and R⁶ represents C₁-C₄ alkyl.

6. A compound according to claim 1, wherein R⁷ represents a 4-cyanophenyl group.

7. A compound according to claim 1 wherein R¹ represents methyl.

8. A compound of formula (I) as defined in claim 1 selected from:

1-{2-[({5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]ethyl}-1-methylpyrrolidinium Y;

1-{4-[({5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]butyl}-1-methylpyrrolidinium Y;

2-[({5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]-N,N,N-trimethylethanaminium Y;

4-[({5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]-N,N,N-trimethylbutan-1-aminium Y;

1-{3-[({5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-[1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-yl}carbonyl)amino]propyl}-1-methylpyrrolidinium Y;

3-[({6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazin-2-yl}carbonyl)amino]-N,N,N-trimethylpropan-1-aminium Y; and

3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamido)-N,N,N-trimethylpropan-1-aminium Y;

wherein Y represents a pharmaceutically acceptable anion.

9. A compound of formula (I) as defined in claim 1 which is 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamido)-N,N,N-trimethylpropan-1-aminium Y;

wherein Y represents a pharmaceutically acceptable anion.

10. A compound of formula (I) as defined in claim 1 which is 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamido)-N,N,N-trimethylpropan-1-aminium benzenesulfonate.

11. A compound of formula (I) as defined in claim 1 which is 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamido)-N,N,N-trimethylpropan-1-aminium benzenesulfonate Form B.

12. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as claimed in claim 1.

14. A combination product comprising a compound according to claim 1 and another therapeutic agent, for use in the treatment of an inflammatory disease, wherein the compound according to claim 1 and the other therapeutic agent are administered concurrently or sequentially or as a combined preparation.

15. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises:

reacting a compound of the formula (II);

16. A compound of the formula (II):

17. A compound of the formula (VHF), or a salt thereof: