Cannabinoid receptor agonists

• US 20040044051A1
• Filed: 06/17/2003
• Published: 03/04/2004
• Est. Priority Date: 06/19/2002
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Shih, Neng-Yang, Tong, Ling, Shankar, Bandarpalle B., Kozlowski, Joseph A.
• Granted Patent: US 7,217,732 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/30 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 213/643 : 2-Phenoxypyridines; Derivatives thereof
• CPC Class Codes: C07D 213/71 : to which a second hetero atom is attached
• CPC Class Codes: C07D 307/64 : Sulfur atoms
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links

Abstract

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:

R¹, R², R³, R⁴, R⁵, R⁶, L¹, L², M, n, p, X, Y and Z are as described in the specification; pharmaceutical compositions thereof, methods of making said pharmaceutical compositions; and methods of use thereof.

Claims

1. A compound represented by the structural formula:

2. A compound according to claim 1, wherein L¹ is —

S(O₂)—

, —

CH₂—

or —

CH(OH)—

.

3. A compound according to claim 1, wherein L² is —

S(O₂)—

4. A compound according to claim 1, wherein Y is —

S(O₂)—

or —

C(O)—

.

5. A compound according to claim 1, wherein R¹ is CH₃ or CF₃.

6. A compound according to claim 1, wherein R⁵ and R⁶, which can be the same or different, are H or CH₃.

7. A compound according to claim 1, wherein n is 0.

8. A compound according to claim 1, wherein X is Cl.

9. A compound according to claim 1, wherein M is selected from the group consisting of indolyl, benzofuranyl, dihydrobenzofuranyl, furanyl, thienyl, pyridinyl, aryl and pyridinyl-N-oxide.

10. A compound according to claim 1, wherein Z is a covalent bond, n is 0, R² is H, and R¹, R⁴, R⁵, R⁶, M, L¹, L², p, Y and X are defined in the following table:

11. The compound according to claim 1 having the following formula:

12. The compound according to claim 1 having the following formula:

13. The compound according to claim 1 having the following formula:

14. The compound according to claim 1 having the following formula:

15. The compound according to claim 1 having the following formula:

16. The compound according to claim 1 having the following formula:

17. The compound according to claim 1 having the following formula:

18. The compound according to claim 1 having the following formula:

19. The compound according to claim 1 having the following formula:

20. The compound according to claim 1 having the following formula:

21. The compound according to claim 1 having the following formula:

22. The compound according to claim 1 having the following formula:

23. The compound according to claim 1 having the following formula:

24. The compound according to claim 1 having the following formula:

25. The compound according to claim 1 having the following formula:

26. The compound according to claim 1 having the following formula:

27. The compound according to claim 1 having the following formula:

28. The compound according to claim 1 having the following formula:

29. The compound according to claim 1 having the following formula:

30. The compound according to claim 1 wherein said alkyl is in the various definitions of lower alkyl.

31. A pharmaceutical composition comprising one or more compounds according to claim 1.

32. The pharmaceutical composition according to claim 31, further comprising one or more pharmaceutically acceptable carriers.

33. A method of preparing the pharmaceutical composition of claim 32, said method comprising contacting said one or more compounds of formula I with said one or more pharmaceutically acceptable carriers.

34. A method of stimulating cannabinoid CB₂ receptors in a patient comprising administering to a patient having CB₂ receptors a CB₂ receptor stimulating amount of one or more compounds according to claim 1.

35. A method of treating cancer, inflammatory diseases, immunomodulatory diseases, or respiratory diseases comprising administering to a patient in need of such treatment one or more compounds according to claim 1.

36. The method of treating cancer, inflammatory diseases, immunomodulatory diseases, or respiratory diseases according to claim 35, wherein the amount of compound 1 that is administered is a therapeutically effective amount.

37. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 35, wherein said cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases are one or more diseases selected from the group consisting of cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn'"'"'s disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis.

38. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 35, further comprising co-administering or combining the compound of claim 1 with one or more second agents which can be the same or different, and are independently selected from the group consisting of DMARDS, NSAIDS, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, and BRMs.

39. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said DMARDS can be the same or different and are independently selected from the group consisting of methotrexate, azathioptrine leflunomide, pencillinamine, gold salts, mycophenolate mofetil, and cyclophosphamide.

40. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said NSAIDS can be the same or different and are independently selected from the group consisting of piroxicam, naproxen, indomethacin and ibuprofen.

41. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said COX-1 inhibitor is Piroxicam.

42. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said COX-2 selective inhibitor is refecoxib or celecoxib.

43. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said immunosuppressives can be the same or different and are independently selected from the group consisting of steroids, cyclosporine, Tacrolimus or rapamycin.

44. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said BRMs can be the same or different and are independently selected from the group consisting of etanercept, infliximab, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, and anti-adhesion molecules.

45. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 38, wherein said anti-inflammatory agents can be the same or different and are independently selected from the group consisting of p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, and Thalidomide.

46. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 35, further comprising co-administering or combining the compound of claim 1 with a second agent selected from the group consisting of Anaprox, Arava, Arthrotec, Azulfidine, Aspirin, Cataflam, Celestone Soluspan, Clinoril, Cortone Acetate, Cuprimine, Daypro, Decadron, Depen, Depo-Medrol, Disalcid, Dolobid, Naprosyn, Gengraf, Hydrocortone, Imuran, Indocin, Lodine, Motrin, Myochrysine, Nalfon, Naprelan, Neoral, Orudis, Oruvail, Pediapred, Plaquenil, Prelone, Relafen, Solu-Medrol, Tolectin, Trilisate and Volataren.

47. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 35, wherein said administration is oral or subcutaneous.

48. A method of treating multiple sclerosis comprising co-administering or combining with the compound of claim 1 one or more additional agents which may be the same or different and are independently selected from the group consisting of Interferon B1a, Interferon B1b and glatiramer acetate.

49. A kit for treating cancer, inflammatory diseases, immunomodulatory diseases, and respiratory diseases comprising in one or more containers an active compound for stimulating cannabinoid CB₂ receptors in a patient which comprises in one or more containers, one or more compounds according to claim 1 in one or more pharmaceutically acceptable carriers.