Isoxazolines as inhibitors of fatty acid amide hydrolase

• US 8,765,735 B2
• Filed: 05/18/2010
• Issued: 07/01/2014
• Est. Priority Date: 05/18/2009
• Status: Expired due to Fees

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Behnke, Mark L., Castro, Alfredo C., Chan, Lawrence K., Evans, Catherine A., Grenier, Louis, Grogan, Michael J., Liu, Tao, Peluso, Stephane, Snyder, Daniel A., Tibbitts, Thomas T., Leblanc, Yves
• Primary Examiner(s): Pagonakis, Anna
• Application Number:
  US12/782,658
• Publication Number:
  US 20110034437A1
• Time in Patent Office: 1,505 Days
• Field of Search: None
• US Class Current: 514/212.02
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

The present invention provides isoxazoline FAAH inhibitors of the formula (I):

• • or pharmaceutically acceptable forms thereof, wherein each of G, R^a, R^b, R^c, and R^d are as defined herein.

The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.

The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein R^a and R^b are both —

H.

3. The compound according to claim 1, wherein the compound is of the formula:

4. The compound according to 3, wherein t is 0, v is 0 and W²⁵ and W²⁶ are substituted with a fused C₆ aryl ring, and wherein W²⁷ and W²⁸ are, independently, CH₂, CHR¹⁵, or C(R¹⁵)₂.

5. The compound according to claim 4, wherein the compound is of the formula:

6. The compound according to claim 5, wherein W²⁷ and W²⁸ are both CH₂ groups.

7. The compound according to claim 6, wherein the compound is of the formula:

8. The compound according to claim 1, wherein G is —

OR^e.

9. The compound according to claim 8, wherein R^e is 5-14 membered heteroaryl.

10. The compound according to claim 9, wherein R^e is a 6-membered heteroaryl.

11. The compound according to claim 10, wherein R^e is a pyridinyl group.

12. The compound according to claim 11, wherein R^e is a monosubstituted pyridinyl group.

13. The compound according to claim 11, wherein R^e is a 3-pyridinyl group.

14. The compound according to claim 11, wherein R^e is a pyridinyl group of the formula:

15. The compound according to claim 14, wherein R^h is selected from the group consisting of fluoro, bromo, chloro, iodo, —

CN, —

NO₂, —

OH, —

ORⁱ, —

SRⁱ, N(R^k)₂, —

N(R^k)₃⁺X⁻

, —

C(═

O)Rⁱ, —

CO₂Rⁱ, —

CO₂H, —

OC(═

O)Rⁱ, —

OCO₂Rⁱ, —

C(═

O)N(R^k)₂, —

OC(═

O)N(R^k)₂, —

NR^kC(═

O)Rⁱ, —

NR^kCO₂Rⁱ, —

NR^kC(═

O)N(R^k)₂, —

C(═

O)NR^kSO₂Rⁱ, —

NR^kSO₂Rⁱ, —

SO₂N(R^k)₂, —

SO₂Rⁱ, C_1-10 alkyl, C₆ aryl, and 5-6 membered heteroaryl, wherein each alkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 or 4 R^m groups; and

wherein is a counterion.

16. The compound according to claim 15, wherein R^h is selected from the group consisting of —

C(═

O)Rⁱ, —

CO₂H, —

SO₂Rⁱ, and 5-membered heteroaryl independently substituted with 0 or 1 R^m groups.

17. The compound according to claim 16, wherein the 5-membered heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.

18. The compound according to claim 14, wherein the pyridinyl group is a 3-pyridinyl group of the formulae:

19. The compound according to claim 8, wherein G is —

OR^e selected from the group consisting of;

20. The compound according to claim 1, wherein the compound is substantially enantiomerically pure.

21. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.

22. The compound according to claim 19, wherein G is —

OR^e selected from the group consisting of;

23. The compound according to claim 1, wherein the compound is:

24. The compound according to claim 1, wherein the compound is:

25. The compound according to claim 1, wherein the compound is:

26. The compound according to claim 1, wherein the compound is:

27. The compound according to claim 1, wherein the compound is:

28. The pharmaceutical composition according to claim 21, wherein the compound is:

29. The pharmaceutical composition according to claim 21, wherein the compound is:

30. The pharmaceutical composition according to claim 21, wherein the compound is: