ISOXAZOLINES AS INHIBITORS OF FATTY ACID AMIDE HYDROLASE

• US 20110028478A1
• Filed: 05/18/2010
• Published: 02/03/2011
• Est. Priority Date: 05/18/2009
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: LeBlanc, Yves, Behnke, Mark L., Grogan, Michael J., Tibbitts, Thomas T., Snyder, Daniel A., Castro, Alfredo C., Peluso, Stephane, Liu, Tao, Chan, Lawrence K., Evans, Catherine A., Grenier, Louis
• Granted Patent: US 9,149,465 B2
• Time in Patent Office: Days
• US Class Current: 514/236.8
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 27/06 Antiglaucoma agents or miotics
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 261/04 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-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 L is a covalent bond or L is a divalent C_1-6 hydrocarbon group, wherein one, two or three methylene units of L are replaced with one or more oxygen atoms.

3. The compound according to claim 2, wherein L is a covalent bond.

4. The compound according to claim 2, wherein L is an unsubstituted divalent C_1-6 hydrocarbon group, wherein one methylene unit of L is replaced with an oxygen atom.

5. The compound claim 2, wherein L is —

O—

.

6. The compound according to claim 1, wherein R^a, R^b, and R^c independently is selected from —

H, C_1-3alkyl and C_1-3 perhaloalkyl.

7. The compound according to claim 6, wherein each R^a, R^b, and R^c is independently selected from —

H, —

CH₃ and —

CF₃.

8. The compound according to claim 7, wherein R^a and R^b are —

H and R^c is selected from —

CH₃ and —

CF₃.

9. The compound according to claim 7, wherein R^b and R^c are —

H and R^a is selected from —

CH₃ and —

CF₃.

10. The compound according to claim 7, wherein each of R^a, R^b, and R^c is —

H.

11. The compound according to claim 1, wherein Z is phenyl.

12. The compound according to claim 11, wherein the compound is of the formula:

13. The compound according to claim 12, wherein R¹⁵ is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

OR¹⁶, —

C(═

O)N(R¹⁸)₂, —

SO₂N(R¹⁸)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups.

14. The compound according to claim 12, wherein z is 1 or 2.

15. The compound according to claim 14, wherein z is 1.

16. The compound according to claim 15, wherein the compound is of the formula:

17. The compound according to claim 16, wherein the compound is of the formula:

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

19. The compound according to claim 17, wherein the compound is formula:

20. The compound according to claim 16, wherein the compound is formula:

21. The compound according to claim 14, wherein z is 2.

22. The compound according to claim 21, wherein the compound is of the formula:

23. The compound according to claim 22, wherein the compound is of the formulae:

24. The compound according to claim 1, wherein G is selected from —

Cl, —

Br, —

I, —

OR^e, —

ONR^fR^e, —

ONR^f(C═

O)R^e, —

ONR^fSO₂R^e, —

ONR^fPO₂R^e, —

ONR^fPO₂OR^e, —

SR^e, —

OSO₂R^e, —

NR^fSO₂R^e, —

OPO₂R^e, —

OPO₂OR^e, —

NR^fPO₂R^e, —

NR^fPO₂OR^e, —

OPO₂NR^fR^e, —

O(C═

O)R^e, —

O(C═

O)OR^e, —

NR^fR^e, —

NR^f(C═

O)R^e, —

NR^f(C═

O)OR^e, —

O(C═

O)NR^fR^e, —

NR^f(C═

NR^f)NR^fR^e, —

O(C═

NR^f)NR^fR^e, —

NR^f(C═

NR^f)OR^e, and —

[N(R^f)₂R^e]⁺X⁻

wherein X⁻

is a counterion.

25. The compound according to claim 24, wherein G is —

OR^e.

26. The compound according to claim 25, wherein R^e is C_6-14 aryl.

27. The compound according to claim 26, wherein R^e is phenyl.

28. The compound according to claim 27, wherein R^e is a monosubstituted phenyl.

29. The compound according to claim 27, wherein R^e is a phenyl group of the formula:

30. The compound according to claim 29, wherein R^h is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

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 X⁻

is a counterion.

31. The compound according to claim 30, wherein R^h is selected from —

C(═

O)Rⁱ, —

CO₂H, —

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

32. The compound according to claim 31, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.

33. The compound according to claim 29, wherein the phenyl group is a monosubstituted phenyl group of any one of the formulae:

34. The compound according to claim 29, wherein the phenyl group is a disubstituted phenyl group of any one of the formulae:

35. The compound according to claim 25, wherein G is —

OR^e selected from;

36. The compound according to claim 25, wherein R^e is 5-14 membered heteroaryl.

37. The compound according to claim 36 wherein R^e is a 6-membered heteroaryl.

38. The compound according to claim 37, wherein R^e is a pyrindinyl group.

39. The compound according to claim 38, wherein R^e is a monosubstituted pyrindinyl group.

40. The compound according to claim 38, wherein R^e is a 3-pyridinyl group.

41. The compound according to claim 38, wherein R^e is a pyrindinyl group of the formula:

42. The compound according to claim 41, wherein R^h is selected from fluoro (—

F), bromo (—

Br), chloro (—

Cl), and iodo (—

I), —

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 X⁻

is a counterion.

43. The compound according to claim 42, wherein R^h is selected from —

C(═

O)Rⁱ, —

CO₂H, —

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

44. The compound according to claim 43, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl.

45. The compound according to claim 41, wherein the pyridinyl group is a 3-pyridinyl group of the formulae:

46. The compound according to claim 25, wherein G is —

OR^e selected from;

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

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

49. A method of treating an FAAH-mediated condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable form thereof.

50. The method according to claim 49, wherein the FAAH-mediated condition is selected from a painful condition, an inflammatory condition, an immune disorder, a disorder of the central nervous system, a metabolic disorder, a cardiac disorder and glaucoma.

51. The method according to claim 50, wherein the FAAH-mediated condition is a painful condition selected from neuropathic pain, central pain, deafferentiation pain, chronic pain, post-operative pain, pre-operative pain, nociceptive pain, acute pain, non-inflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder, pain associated with premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with drawal symptoms from drug addiction, joint pain, arthritic pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache dental/maxillofacial pain and visceral pain.

52. The method according to claim 50, wherein the FAAH-mediated condition is an inflammatory condition or an immune disorder.

53. The method according to claim 52, wherein the inflammatory condition or immune disorder is a gastrointestinal disorder.

54. The method according to claim 52, wherein the inflammatory condition or immune disorder is a skin condition.

55. The method according to claim 50, wherein the FAAH-mediated condition is a disorder of the central nervous system selected from neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer'"'"'s disease and drug addiction

56. The method according to claim 50, wherein the FAAH-mediated condition is a metabolic disorder selected from a wasting condition or an obesity-related condition or complication thereof.

57. The method according to claim 50, wherein the FAAH-mediated condition is a cardiac disorder selected from hypertension, circulatory shock, myocardial reperfusion injury and atherosclerosis.

58. The method according to claim 50, wherein the FAAH-mediated condition is glaucoma.