Inhibitors of fatty acid amide hydrolase

• US 8,802,119 B2
• Filed: 08/19/2013
• Issued: 08/12/2014
• Est. Priority Date: 04/07/2009
• Status: Expired due to Fees

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Castro, Alfredo C., Evans, Catherine A., Grenier, Louis, Grogan, Michael J.
• Primary Examiner(s): Andres, Janet L
• Assistant Examiner(s): Rozof, Timothy R
• Application Number:
  US13/970,495
• Publication Number:
  US 20130338107A1
• Time in Patent Office: 358 Days
• Field of Search: None
• US Class Current: 424/401
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

Provided herein are compounds of formula (I): or pharmaceutically acceptable salts, solvates or prodrugs thereof or mixtures thereof, wherein Z¹, Z², X¹, X², X³, R¹, R² R³, R⁴, m and n are defined herein. Also provided are pharmaceutically acceptable compositions that include a compound of formula I and a pharmaceutically acceptable excipient. Also provided are methods for treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the present invention.

Claims

1. A method of treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

2. The method of claim 1, wherein X² is NR⁸ and X¹ is CR⁶R⁷.

3. The method of claim 2, wherein R⁸ is selected from C_1-6 alkyl, —

C(O)R²⁰, —

C(O)OR²¹, —

C(O)NR²²R²³, —

S(O)₂R²⁴, and —

(CH₂)_p—

R²⁵.

4. The method of claim 2, wherein R⁸ is —

C(O)R²⁰, and R²⁰ is selected from C_1-6 alkyl, C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —

(CH₂)_q—

R²⁸.

5. The method of claim 4, wherein R²⁰ is —

(CH₂)_q—

R²⁸, and R²⁸ is selected from C_3-10 carbocyclyl, C_6-10 aryl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl.

6. The method of claim 4, wherein R²⁰ is —

(CH₂)_q—

R²⁸, and R²⁸ is —

NR³²R³³.

7. The method of claim 6, wherein R³² and R³³ each independently is selected from hydrogen, C_1-6 alkyl, and C_7-12 aralkyl.

8. The method of claim 2, wherein R⁸ is —

C(O)OR²¹.

9. The method of claim 8, wherein R²¹ is selected from C_1-6 alkyl and —

(CH₂)_q—

R²⁸.

10. The method of claim 9, wherein R²⁸ is selected from C_6-10 aryl and 5-10 membered heteroaryl.

11. The method of claim 2, wherein R⁸ is —

C(O)NR²²R²³.

12. The method of claim 11, wherein R²² and R²³ each independently is selected from hydrogen, C_1-6 alkyl, and —

(CH₂)_r—

R²⁹.

13. The method of claim 12, wherein R²⁹ is selected from C_6-10 aryl and 5-10 membered heteroaryl.

14. The method of claim 2, wherein R⁸ is —

S(O)₂R²⁴.

15. The method of claim 14, wherein R²⁴ is selected from C_1-6 alkyl, C_6-10 aryl, 5-10 membered heteroaryl, and —

(CH₂)_t—

R³⁰.

16. The method of claim 2, wherein R⁸ is —

(CH₂)_p—

R²⁵.

17. The method of claim 16, wherein R²⁵ is selected from C_6-10 aryl and 5-10 membered heteroaryl.

18. The method claim 1, wherein n is 1.

19. The method of claim 18, wherein X³ is CR¹²R¹³.

20. The method of claim 19, wherein R¹² is hydrogen and R¹³ is H.

21. The method of claim 1, wherein n is 0.

22. The method of claim 1, wherein R⁶ is hydrogen and R⁷ is hydrogen.

23. The method of claim 1, wherein is a double bond and m is 0.

24. The method of claim 1, wherein is a single bond and m is 1.

25. The method of claim 24, wherein R² is hydrogen.

26. The method of claim 1, wherein R¹ is hydrogen.

27. The method of claim 1, wherein R³ is hydrogen and R⁴ is hydrogen.

28. The method of claim 1, wherein Z¹ is —

OR¹⁴ and Z² is —

OR¹⁵.

29. The method of claim 28, wherein R¹⁴ is hydrogen and R¹⁵ is hydrogen.

30. The method of claim 1, wherein the compound is of the formula III:

31. The method of claim 30, wherein the compound is of the formulae IIIa or IIIb:

32. The method of claim 1, wherein the compound is of the formula VIII:

33. The method of claim 32, wherein the compound is of the formulae VIIIa or VIIIb:

34. The method of claim 1, wherein the compound is of the formula VI:

35. The method of claim 34, wherein the compound is of the formulae VIa or VIb:

36. The method of claim 1, wherein the compound of the formula IV:

37. The method of claim 36, wherein the compound is of the formulae IVa or IVb:

38. The method of claim 1, wherein the compound is of the formula VII:

39. The method of claim 38, wherein the compound is of the formulae VIIa or VIIb:

40. The method of claim 1, wherein the compound is selected from:

41. The method of claim 1, wherein the FAAH-mediated disorder is a pain disorder.

43. The method of claim 41, wherein the pain disorder is neuropathic pain.

44. The method of claim 41, wherein the pain disorder is arthritic pain.

48. The method of claim 1, wherein the FAAH-mediated disorder is an inflammatory disorder.

49. The method of claim 48, wherein the inflammatory disorder is irritable bowel disease.

50. The method of claim 43, wherein the neuropathic pain is diabetic retinopathy;

sciatica;

non-specific lower back pain;

multiple sclerosis pain;

fibromyalgia;

HIV-related neuropathy;

neuralgia;

or pain resulting from physical trauma, amputation, cancer, chemotherapy, surgery, invasive medical procedures, toxins, burns, infection, chronic inflammatory condition, peripheral nerve disorder, nerve crush, nerve stretch, incomplete nerve transsection, mononeuropathy, polyneuropathy, dorsal root ganglion compression, inflammation of the spinal cord, contusion, tumor or hemisection of the spinal cord, tumor of the brainstem, thalamus, or cortex, or trauma to the brainstem, thalamus, or cortex.

51. The method of claim 41, wherein the pain disorder is a non-inflammatory pain.

52. The method of claim 51, wherein the non-inflammatory pain is peripheral neuropathic pain, central pain, deafferentation pain, chronic noiceptive pain, phantom pain, pain felt by psychiatric patients, or wandering pain.

53. The method of claim 48, wherein the inflammatory disorder is inflammation affecting blood vessels, joints, gastrointestinal tract, skin, multiple organs and tissues;

inflammation associated with vascular disease, migraine headache, tension headache, arteritis, thyroiditis, asplastic anemia, Hodgkin'"'"'s disease, scleroderma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet'"'"'s syndrome, polymyostis, gingivitis, hypersensitivity, conjunctivitis, multiple sclerosis, or ischemia;

neuroinflammation associated with brain disorders;

chronic inflammation associated with cranial radiation injury;

inflammation associated with trauma;

or inflammation that is acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomenbranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, supporative, toxic, traumatic, or ulcerative.

42. The method of 41, wherein the pain disorder is selected from neuropathic pain, central pain, deafferentiation pain, chronic pain, stimulus of nociceptive receptors, acute pain, non-inflammatory pain, inflammatory pain, pain associated with cancer, preoperative pain, arthritic pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back and neck pain, and toothache.

45. The method of claim 42, wherein the arthritic pain is osteoarthritic pain.

46. The method of claim 42, wherein the arthritic pain is rheumatoid arthritic pain.

47. The method of claim 42, wherein the inflammatory pain is associated with an inflammatory disorder.