INHIBITORS OF FATTY ACID AMIDE HYDROLASE

• US 20110230440A1
• Filed: 03/16/2011
• Published: 09/22/2011
• Est. Priority Date: 10/10/2006
• Status: Active Grant

• Current Assignee: Alfredo C. Castro, Catherine A. Evans, Daniel A. Snyder, Julian Adams, Louis Grenier, Mark L. Behnke, Michael J. Grogan, Tao Liu, Thomas T. Tibbitts
• Original Assignee: Alfredo C. Castro, Catherine A. Evans, Daniel A. Snyder, Julian Adams, Louis Grenier, Mark L. Behnke, Michael J. Grogan, Tao Liu, Thomas T. Tibbitts
• Inventors: Behnke, Mark L., Grogan, Michael J., Tibbitts, Thomas T., Snyder, Daniel A., Castro, Alfredo C., Adams, Julian, Liu, Tao, Evans, Catherine A., Grenier, Louis
• Granted Patent: US 8,349,814 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• 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 provide compounds, and pharmaceutical compositions thereof, encompassed by the formulae (I), (II) or (III).

The present invention also provides methods for treating an FAAH mediated disease, disorder or condition by administering a therapeutically effective amount of a provided compound of the formulae (I), (II) or (III), or a pharmaceutical composition thereof, to a patient in need thereof. Additionally, the present invention provides methods for inhibiting FAAH in a patient by administering a therapeutically effective amount of a compound of the formulae (I), (II) or (III), or a pharmaceutical composition thereof, to a patient in need thereof.

Claims

1. A pharmaceutically acceptable composition, comprising a compound of formula III,

2. The composition according to claim 1, wherein both Ring A and Ring B are aromatic.

4. The composition according to claim 1, wherein Ring A is phenyl and the group

5. The composition according to claim 1, wherein X is a bivalent C_1-6 hydrocarbon chain, wherein one, two or three methylene units of X are optionally and independently replaced with one or more —

O—

.

3. The composition according to claim 3, wherein both Ring A and Ring B are phenyl.

6. A method for treating an FAAH-mediated disease, disorder or condition by administering a therapeutically effective amount of a compound of formula I,

7. The method according to claim 6, wherein said compound is of formula II:

8. The method according to claim 6, wherein said compound is of formula III:

9. The method according to claim 6, wherein both Ring A and Ring B are aromatic.

10. The method according to claim 9, wherein both Ring A and Ring B are phenyl.

11. The method according to claim 6, wherein Ring A is phenyl and at least one R¹ group is fluoro in the ortho position relative to the boron atom.

12. The method according to claim 6, wherein Ring A is phenyl and the group

13. The method according to claim 6, wherein X is a covalent bond.

14. The method according to claim 6, wherein X is a bivalent C_1-6 hydrocarbon chain, wherein one, two or three methylene units of X are optionally and independently replaced with one or more —

O—

, —

N═

N—

, —

NR′

—

, —

(C═

NR′

)—

, —

S—

, —

C(═

O)—

, —

S(═

O)—

, —

S(═

O)₂—

or an optionally substituted phenylene moiety.

15. The method according to claim 14, wherein X is a bivalent C_1-6 hydrocarbon chain, wherein one, two or three methylene units of X are optionally and independently replaced with one or more —

O—

.

16. The method according to claim 15, wherein X is a bivalent C_1-6 hydrocarbon chain wherein one methylene unit of X is replaced with —

O—

.

17. The method according to claim 6, wherein the FAAH mediated disease, disorder or condition is a painful syndrome, disease and/or disorder, an inflammatory disorder, an immune disorder, depression, anxiety, a sleep disorder, a feeding behavior, a movement disorder, glaucoma, neuroprotection or cardiovascular disease.

18. The method according to claim 17, wherein the painful syndrome, disease and/or disorder 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.

19. The method according to claim 18, wherein the painful syndrome, disease and/or disorder is neuropathic pain.

20. The method according to claim 17, wherein the inflammatory disorder is inflammation characterized by one or more of the signs of pain from the generation of noxious substances and the stimulation of nerves;

inflammation characterized by heat from vasodilatation;

inflammation characterized by redness from vasodilatation and increased blood flow;

inflammation characterized by swelling from excessive inflow or restricted outflow of fluid;

inflammation characterized by loss of function;

inflammation affecting the blood vessels inflammation affecting the joints;

inflammation affecting the gastrointestinal tract;

inflammation affecting the skin;

inflammation affecting multiple organs and tissues;

inflammation associated with vascular disease;

inflammation associated with migraine headache;

inflammation associated with tension headache;

inflammation associated with psoriasis, irritable bowel disease, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin'"'"'s disease, scierodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet'"'"'s syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, multiple sclerosis, and ischemia;

neuroinflammation associated with the brain disorders;

chronic inflammation associated with cranial radiation injury;

acute inflammatory conditions and chronic inflammatory conditions;

inflammation associated with trauma and non-inflammatory myalgia;

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

21. The method according to claim 20, wherein the inflammatory disorder is inflammation associated with psoriasis or irritable bowel disease.

22. A complex comprising a compound associated with a serine residue of a protein having the formula (I)-complex:

23. The complex according to claim 22, wherein said compound is a compound of formula (II)-complex:

24. The complex according to claim 22, wherein said compound is a compound of formula (III)-complex:

25. The complex according to claim 22, wherein said compound is a compound of formula (III-a)-complex: