FATTY ACID AMIDE HYDROLASE INHIBITORS

• US 20110201574A1
• Filed: 02/01/2011
• Published: 08/18/2011
• Est. Priority Date: 02/03/2010
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: AUSTAD, Brian C., Lo, Ching Kam, Grogan, Michael J., Yu, Lin-Chen, Liu, Tao, Grenier, Louis, Martinot, Theodore A.
• Granted Patent: US 9,034,849 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/36 Opioid-abuse
• 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 3/00 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 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: 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: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/05 : Cyclic compounds having at least one ring containing boron but no carbon in the ring

Abstract

The present invention provides fatty acid amide hydrolase inhibitors, solid forms thereof, compositions thereof, and methods of making and using the same.

Claims

1. A solid form comprising a crystalline compound of formula 1:

2. The solid form of claim 1, wherein the solid form is substantially free of a compound of formula IMP-1, formula IMP-2, formula IMP-3, or formula IMP-4:

3. The solid form of claim 2, wherein the solid form is substantially free of amorphous Compound 1.

4. The solid form of claim 2, wherein solid form is substantially free of the compound of formula IMP-1.

5. The solid form of claim 4, wherein the solid form has less than about 0.05% a/a of the compound of formula IMP-1.

6. The solid form of claim 2, wherein the solid form is substantially free of the compound of formula IMP-2.

7. The solid form of claim 6, wherein the solid form has less than about 0.05% a/a of the compound of formula IMP-2.

8. The solid form of claim 2, wherein the solid form is substantially free of the compound of formula IMP-3.

9. The solid form of claim 8, wherein the solid form has less than about 0.05% a/a of the compound of formula IMP-3.

10. The solid form of claim 2, wherein the solid form is substantially free of the compound of formula IMP-4.

11. The solid form of claim 10, wherein the solid form has less than about 0.05% a/a of the compound of formula IMP-4.

12. The solid form of claim 1, wherein the crystalline compound of formula 1 is a Form A crystal form of compound 1.

13. The solid form of claim 12, wherein the solid form is substantially free of other crystal forms of compound 1.

14. The solid form of claim 1 having an X-ray power diffraction pattern having peaks located at 1, 2, 3, 4, 5, 6, or all of the following approximate peak positions:

9.68±

0.10, 17.26±

0.10, 21.60±

0.10, 24.68±

0.10, 25.48±

0.10, 27.73±

0.10 and 29.08±

0.10 degrees 2θ

.

15. The solid form of claim 1 having an X-ray powder diffraction pattern comprising peaks at approximately 17.26, 21.60, and 27.73 degrees 2θ

.

16. The solid form of claim 15 having an X-ray powder diffraction pattern further comprising peaks at approximately 24.68 and 25.48 degrees 2θ

.

17. The solid form of claim 16 having an X-ray powder diffraction pattern further comprising peaks at approximately 9.68 and 29.08 degrees 2θ

.

18. The solid form of claim 1 having an X-ray powder diffraction pattern that is substantially similar to the XRPD pattern presented in FIG. 1, FIG. 19A, FIG. 22, of FIG. 23.

19. The solid form of claim 1, which has unit cell parameters consistent with the following approximate unit cell parameters:

a=5.45 Å

;

b=5.16 ↑

;

c=36.12 Å

;

α

=90°

;

β

=90°

;

γ

=90°

;

V=1016.5 Å

³, and Z=4.

20. The solid form of claim 1, having one or more transition temperatures selected from 128±

5°

C. and about 244±

2°

C. as determined by differential scanning calorimetry.

21. The solid form of claim 1, having a differential scanning calorimetry thermogram that is substantially similar to the differential scanning calorimetry thermogram presented in FIG. 2.

22. The solid form of claim 1, wherein the solid form is substantially free of one or more anhydrides of Compound 1.

23. The solid form of claim 22, wherein the one or more anhydrides is Compound 2:

35. A pharmaceutical composition comprising the solid form of claim 1 and a pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising the solid form of claim 2 and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising the solid form of claim 12 and a pharmaceutically acceptable excipient.

58. A method of treating an FAAH-mediated condition comprising administering to a subject in need thereof a therapeutically effective amount of a solid form of claim 1.

59. The method according to claim 58, 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.

60. The method according to claim 59, 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 withdrawal 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.

61. The method according to claim 58, wherein the FAAH-mediated condition is an inflammatory condition or an immune disorder.

62. The method according to claim 61, wherein the inflammatory condition or immune disorder is a gastrointestinal disorder.

63. The method according to claim 61, wherein the inflammatory condition or immune disorder is a skin condition.

64. The method according to claim 58, 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.

65. The method according to claim 58, wherein the FAAH-mediated condition is a metabolic disorder selected from a wasting condition or an obesity-related condition or complication thereof.

66. The method according to claim 58, wherein the FAAH-mediated condition is a cardiac disorder selected from hypertension, circulatory shock, myocardial reperfusion injury and atherosclerosis.

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

24. A solid form comprising a crystalline compound of formula 2:

25. The solid form according to claim 24, wherein the solid form is substantially free a compound of formula IMP-1, formula IMP-2, formula IMP-3, or formula IMP-4:

26. The solid form of claim 25, wherein the solid form is substantially free of amorphous Compound 2.

27. The solid form of claim 24, which is the Form I crystal form of Compound 2, wherein the solid form is substantially free of other crystalline forms of Compound 2.

28. The solid form of claim 24, wherein the solid form is substantially free of Compound 1 or other anhydrides thereof.

29. The solid form of claim 24 having an X-ray powder diffraction pattern comprising peaks at approximately 6.32, 12.69, and 26.77 degrees 2θ

.

30. The solid form of claim 29 having an X-ray powder diffraction pattern further comprising peaks at approximately 6.32, 12.69, and 26.77 degrees 2θ

.

31. The solid form of claim 24 having an X-ray powder diffraction pattern having at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, or all of the following approximate XRPD pattern peaks:

6.3, 9.6, 11.2, 11.5, 12.7, 13.1, 14.7, 15.2, 16.9, 17.3, 17.4, 17.7, 18.0, 18.6, 19.0, 19.4, 20.4, 20.8, 21.6, 22.5, 22.7, 23.0, 23.4, 24.5, 24.7, 25.1, 25.5, 26.8, 27.7, 28.3, 29.0 degrees 2θ

.

32. The solid form of claim 24 having an X-ray powder diffraction pattern that is substantially similar to the XRPD pattern presented in FIG. 8, FIG. 28, or FIG. 29.

33. The solid form of claim 24 having a differential scanning calorimetry thermogram that is substantially similar to the differential scanning calorimetry thermogram presented in FIG.

34. The solid form of claim 24 having one or more transition temperatures selected from about 112±

5°

C. and about 241±

2°

C. as determined by differential scanning calorimetry.

38. A pharmaceutical composition comprising the solid form of claim 24 and a pharmaceutically acceptable excipient.

39. A method of preparing Compound 1:

40. The method according to claim 39 wherein the method further comprises crystallizing Compound 1 of step (b) to provide crystalline Compound 1.

41. The method according to claim 40 wherein the crystallizing step comprises crystallizing Compound 1 from a polar solution comprising water, a polar apolar solvent or a mixture thereof.

42. The method according to claim 40 wherein the crystallizing step comprises crystallizing Compound 1 from a mixture of water and acetone.

43. The method according to claim 40 wherein the crystalline Compound 1 is further washed with a non-polar solution.

44. The method according to claim 43 wherein the non-polar solution comprises hexanes, heptanes or a mixture thereof.

45. The method according to claim 39 wherein E-1 is E-1b:

46. The method according to claim 39 wherein E-2 is E-2a:

47. The method according to claim 39, wherein E-3 is E-3a:

48. The method according to claim 39 wherein the coupling step comprises a palladium catalyst.

49. The method according to claim 48 wherein the palladium catalyst is selected from Pd(PPh₃)₄, Pd(OAc)₂, Pd₂(dba)₃, Pd(dppf)₂Cl₂, and PdCl₂(PPh₃)₂.

50. The method according to claim 39 wherein the coupling step comprises a base.

51. The method according to claim 50 wherein the base is selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium acetate, sodium acetate, potassium phosphate, lithium hydroxide, sodium hydroxide and magnesium hydroxide.

52. The method according to claim 39 wherein the boronation reagent is a boronate ester.

53. The method according to claim 52, wherein the boronate ester is selected from trimethyl borate, triethyl borate, triallyl borate, triisopropyl borate, Tributyl borate, Tri-tert-butyl borate, Tripentyl borate, Trihexyl borate, Tritolyl borate, Tribenzyl borate, Triphenyl borate, Trimethylene borate, Triethanolamine borate, Trimethallyl borate, 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-Methoxy-4,4,6-trimethyl-1,3,2-dioxaborinane, 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-Isopropoxy-4,4,6-trimethyl-1,3,2-dioxaborinane, 2-(2-dimethylaminoethoxy)-4-methyl-1,3,2-dioxaborinane, 2-butoxy-4,4,6-trimethylL-1,3,2-dioxaborinane, tris(2,2,2-trifluoroethyl)borate, tris(1-isopropyl-2-methylpropyl)borate, and 2,2′

-(2-methyl-2,4-pentanediyldioxy)bis(4,4,6-trimethyl-1,3,2-dioxaborinane).

54. The method according to claim 39, wherein the metal reagent is an alkyl lithium reagent.

55. The method according to claim 54, wherein the alkyl lithium reagent is n-butyllithium or hexyllithium.

56. The method according to claim 39, wherein the method step (b) further comprises the steps of dehydrating Compound 1 in order to provide an anhydride of Compound 1 followed by hydrolyzing the anhydride of Compound 1 in order to provide Compound 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

57. The method according to claim 56, wherein the anhydride of Compound 1 is Compound 2: