Some 2-pyrazinone derivatives and their use as inhibitors of neutrophile elastase

• US 8,466,284 B2
• Filed: 11/05/2008
• Issued: 06/18/2013
• Est. Priority Date: 11/06/2007
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Chapman, David, Lindsj, Martin, Lundkvist, Michael, Nikitidis, Antonios, Ainge, Debra, Pavey, John, Lnn, Hans, Munck AF Rosenschld, Magnus
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US12/740,136
• Publication Number:
  US 20100280048A1
• Time in Patent Office: 1,686 Days
• Field of Search: 544/408, 548/377.1
• US Class Current: 544/408
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 35/00 Antineoplastic agents
• 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: A61P 9/12 Antihypertensives
• 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 certain novel compounds as listed in the specification and pharmaceutically acceptable salts thereof and particular Forms thereof; together with processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase. The present neutrophil elastase inhibitors include 6-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide:

Claims

1. A compound being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide, or a pharmaceutically acceptable salt or polymorph thereof.

2. A polymorph of a compound according to claim 1 being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form A.

3. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or polymorph thereof as claimed in claim 2 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

4. A compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide.

5. A compound according to claim 2, being a pharmaceutically acceptable salt of 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide.

6. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form A and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 8.0, 15.9 and 17.8°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

7. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form A and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.4, 8.0, 10.7, 15.9, 16.2, 17.6, 17.8, 21.6, 22.8 and 24.9°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

8. A polymorph of a compound according to claim 1 being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form B.

9. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form B and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 18.0, 18.2 and 24.7°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

10. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form B and characterised by having an X-ray powder diffraction pattern comprising specific peaks at 12.5, 14.3, 14.4, 15.7, 17.5, 18.0, 18.2, 18.8, 22.2 and 24.7°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

11. A polymorph of a compound according to claim 1 being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form C.

12. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form C and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.6, 20.1 and 22.9°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

13. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form C and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.6, 8.6, 10.7, 12.1, 16.6, 17.1, 20.1, 20.2, 22.7 and 22.9°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

14. A polymorph of a compound according to claim 1 being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form D.

15. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form D and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.4, 10.6 and 18.2°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

16. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form D and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.4, 10.6, 17.3, 18.2, 18.5, 21.4, 22.8, 23.1, 24.8 and 24.9°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

17. A polymorph of a compound according to claim 1 being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form E.

18. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form E and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 7.4, 10.1 and 19.0°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.

19. A polymorph of a compound according to claim 1, being 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide Form E and characterized by having an X-ray powder diffraction pattern comprising specific peaks at 6.9, 7.4, 10.1, 14.7, 15.0, 15.7, 16.4, 19.0, 19.3 and 22.5°

2θ and

wherein said X-ray powder diffraction pattern is measured using CuK_α

radiation.