Gyrase inhibitors and uses thereof

• US 20040235886A1
• Filed: 01/29/2004
• Published: 11/25/2004
• Est. Priority Date: 01/31/2003
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Deininger, David D., Stamos, Dean, Wang, Tiansheng, Perola, Emanuele, Grillot, Anne-Laure, Charifson, Paul S., LeTiran, Arnaud, Liao, Yusheng, Drumm, Joseph, Ronkin, Steven M.
• Granted Patent: US 7,495,014 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

The present invention relates to compounds which inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordingly, the present invention also relates to methods for treating bacterial infections in mammals.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein Ring A is selected from the following optionally substituted rings:

3. The compound according to claim 2, wherein Ring A is an optionally substituted ring selected from rings a, f, l, s, w, y, or z:

4. The compound according to claim 1, wherein:

R¹ is selected from an optionally substituted phenyl or 5-6 membered heteroaryl ring having 1-2 nitrogens.

5. The compound according to claim 4, wherein R¹ is an optionally substituted ring selected from pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl.

6. The compound according to claim 5, wherein R¹ is substituted with 0-2 groups independently selected from halogen, oxo, R′

, CO₂R′

, OR′

, N(R′

)₂, SR′

, C(O)N(R′

)₂, NR′

C(O)R′

, SO₂R′

, SO₂N(R′

)₂, or NR′

SO₂R′

.

7. The compound according to claim 6, wherein R² is selected from methyl, ethyl, isopropyl, or cyclopropyl.

8. The compound according to claim 1, wherein said compound is of formula II-a:

9. The compound according to claim 1, wherein said compound is of formula III:

10. The compound according to claim 9, wherein said compound is of formula III-a:

11. The compound according to claim 10, wherein:

R′

is hydrogen or C_1-4 aliphatic, and wherein;

R′

is optionally substituted with phenyl or pyridyl.

12. The compound according to claim 1, wherein said compound is of formula IV:

13. The compound according to claim 12, wherein Ar is an optionally substituted 5-6 membered saturated ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

14. The compound according to claim 12, wherein Ar is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

15. The compound according to claim 12, wherein Ar is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

16. The compound according to claim 12, wherein Ar is optionally substituted phenyl.

17. The compound according to claim 1, wherein said compound is of formula V:

18. The compound according to claim 17, wherein said compound is of formula VI:

19. The compound according to any one of claims 8, 11, 12, or 17 wherein R² is ethyl.

21. A composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

22. The composition according to claim 21, additionally comprising an additional therapeutic agent selected from an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin an anti-vascular hyperproliferation compound, or an agent which increases the susceptibility of bacterial organisms to antibiotics.

23. A method of inhibiting gyrase activity in a biological sample or in a patient, comprising the step of contacting said biological sample with:

a) a composition according to claim 21;

or

b) a compound according to claim 1.

24. A method of inhibiting TopoIV activity in a biological sample or in a patient, comprising the step of contacting said biological sample with:

a) a composition according to claim 21;

or

b) a compound according to claim 1.

25. A method of inhibiting gyrase and TopoIV activity in a biological sample or in a patient, comprising the step of contacting said biological sample with:

a) a composition according to claim 21;

or

b) a compound according to claim 1.

26. A method of decreasing bacterial quantity in a patient, comprising the step of administering to said patient:

a) a composition according to claim 21;

or

b) a compound according to claim 1.

27. A method of treating, preventing, or lessening the severity of, a bacterial infection in a patient, comprising the step of administering to said patient:

a) a composition according to claim 21;

or

b) a compound according to claim 1.

28. The method according to claim 27, wherein the bacterial infection to be treated is characterized by the presence of one or more of the following:

Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae, Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis, Chlamydia pneumoniae, Legionella pneumophila, Staphylococcus epidermidis, Mycobacterium tuberculosis, or Helcoibacter pylori.

29. The method according to claim 28, wherein the bacterial infection to be treated is selected from one or more of the following:

a urinary tract infection, a respiratory infection, pneumonia, prostatitis, a skin or soft tissue infection, an intra-abdominal infection, a blood stream infection, or an infection of febrile neutropenic patients.

30. The method according to claim 29, further comprising the step of administering to said patient an additional therapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.

31. The method according to claim 28, further comprising the step of administering to said patient an agent that increases the susceptibility of bacterial organisms to antibiotics.

20. A compound selected from the group consisting of: