Cannabinoid receptor ligands

• US 20030232859A1
• Filed: 08/07/2002
• Published: 12/18/2003
• Est. Priority Date: 02/08/2001
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Shih, Neng-Yang, Lavey, Brian J., Tong, Ling, Shankar, Bandarpalle B., Kozlowski, Joseph A., Wolin, Ronald L., Wong, Michael K., Rizvi, Razia K., Spitler, James M.
• Granted Patent: US 7,067,539 B2
• Time in Patent Office: Days
• US Class Current: 514/332
• 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 11/08 Bronchodilators
• 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 19/10 for osteoporosis
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 Otologicals
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• 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 5/14 : of the thyroid hormones, e.g. T3, T4
• 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: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 31/24 : Tetrahydroxylic alcohols, e.g. pentaerythritol
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 317/36 : with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/41 : Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07C 323/65 : containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 213/71 : to which a second hetero atom is attached
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/36 : Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 233/42 : Sulfur atoms
• CPC Class Codes: C07D 233/84 : Sulfur atoms
• CPC Class Codes: C07D 239/38 : One sulfur atom
• CPC Class Codes: C07D 307/64 : Sulfur atoms
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention relates to compounds of the formula

a prodrug thereof, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound or of said prodrug; which exhibit anti-inflammatory and immunodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds and methods of using the compounds for the treatment of various diseases and conditions.

Claims

1. A compound of the formula

2. A compound according to claim 1 wherein

L¹ is —

SO₂—

, —

CH₂—

, —

CHCH₃—

, —

C(O)—

, —

C═

NOR⁵—

, —

C(CH₃)₂—

, —

CHOH—

, —

O—

, —

S—

or —

S(O)—

;

L² is —

SO₂—

, —

C(O)—

, —

CH₂—

, —

CH(CH₃)—

, —

C(CH₃)₂—

,

—

NH—

, —

O—

, —

NHSO₂—

, —

NHC(O)—

, or

R¹ is H, —

CH₃NH₂, —

CH₂CF₃, —

NHC₃H₇, —

NHC₂H₆, —

NHC₄H₉, C₁-C₆ alkyl, —

CF₃, —

CH(CH₂)₂, thiophenyl, morpholinyl, cyclopropyl, benzyl, naphthyl, —

C(CH₃)₃, NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentyl or N(CH₃)₂;

R² is H or CH₃;

R³ is OH;

R⁴ is furanyl, pyridyl, pyrimidyl, thiophenyl, quinolyl, t-butoxy, alkoxyl, cyclohexyl, phenyl, tolyl, C₃H₇, pyrimdyl, methoxyphenyl, morpholinylphenyl or CH₃;

with the proviso that when R⁴ is t-butoxy, L² must be —

C(O)—

, —

CH₂—

, —

CHCH₃—

, —

C(CH₃)₂—

or

all of the above optionally substituted with one to three X, wherein X can be the same or different and are independently selected when the are more than one X present;

R⁵ and R⁶ are independently H or CH₃;

Y is a covalent bond, —

SO₂—

or —

C(O)—

;

Z is a covalent bond;

or

R¹, Y, R² and Z taken together with the nitrogen atom form a morpholinyl group.

3. The compound according to claim 2 wherein

X is halogen, OH, or cyclopropyl;

R³ is OH;

R⁵ and R⁶ are independently H or CH₃;

X is H, halogen, CF₃, OCH₃, OH, OCF₃, OCF₂H, CH₃ or C₁-C₆cycloalkyl;

Y is a covalent bond;

Z is —

SO₂—

or —

C(O)—

;

L¹ is —

SO₂—

or —

CH₂—

;

L² is —

SO₂—

;

R¹ is CH₃ or CF₃; and

R⁴ is phenyl, pyrimidyl or pyridyl, said phenyl, pyrimidyl or pyridyl groups optionally substituted with one to three substituents selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CF₃ and halogen, wherein said substituents can be the same or different and are independently selected when there are more than one subsituent.

4. The compound according to claim 3 wherein the phenyl in R⁴ is substituted with OCH₃ or halogen.

5. The compound according to claim 4 wherein the halogen is selected from fluorine and chlorine.

6. The compound according to claim 1 of the formula

7. The compound according to claim 1 of the formula

8. The compound according to claim 1 of the formula

9. The compound according to claim 1 of the formula

10. The compound according to claim 1 of the formula

11. The compound according to claim 1 of the formula

12. The compound according to claim 1 of the formula

13. The compound according to claim 1 of the formula

14. The compound according to claim 1 of the formula

15. The compound according to claim 1 of the formula

16. The compound according to claim 1 of the formula

17. The compound according to claim 1 of the formula

18. The compound according to claim 1 of the formula

19. The compound according to claim 1 of the formula

20. The compound according to claim 1 of the formula

21. The compound according to claim 1 of the formula

22. The compound according to claim 1 of the formula

23. The compound according to claim 1 of the formula

24. The compound according to claim 1 of the formula

25. The compound according to claim 1 of the formula

26. The compound according to claim 1 of the formula

27. The compound according to claim 1 of the formula

28. The compound according to claim 1 of the formula

29. The compound according to claim 1 of the formula

30. A pharmaceutical composition comprising one or more compounds according to claim 1 and one or more pharmaceutically acceptable carriers.

31. A pharmaceutical composition comprising one or more compounds according to claim 7 and one or more pharmaceutically acceptable carriers.

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

33. 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.

34. A method of treating cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scieroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, 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), bronchitis, colitis, coronary artery disease, melanoma, transplant rejection, graft versus host disease, Hashimoto'"'"'s thyroiditis, Graves disease, myasthenia gravis or Goodpasture'"'"'s syndrome comprising administering to a patient in need of such treatment a compound according to claim 1.

35. The method of claim 32 wherein the condition or disease treated is selected from rheumatoid arthritis, multiple sclerosis, seasonal allergic rhinitis and chronic obstructive pulmonary disease.

36. A pharmaceutical composition made by combining one or more compounds of claim 1 and one or more pharmaceutically acceptable carriers.

37. A process for making a pharmaceutical composition comprising combining one or more compounds of claim 1 and one or more pharmaceutically acceptable carriers.

38. A method of treating rheumatoid arthritis which comprises co-administration one or more compounds selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and one or more compounds of claim 1.

39. A method of treating rheumatoid arthritis which comprises co-administration one or more compounds selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-60 compound, a PDE IV inhibitor or other classes of compounds indicated for the treatment of rheumatoid arthritis and one or more compounds of claim 7.

40. The method of claim 38 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

41. The method of claim 39 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

42. A composition for treating rheumatoid arthritis which comprises one or more compounds selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and one or more compounds of claim 1.

43. A composition for treating rheumatoid arthritis which comprises one or more compounds selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and one or more compounds of claim 7.

44. The composition of claim 42 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

45. The composition of claim 43 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

46. A method of treating multiple sclerosis which comprises co-administration one or more compounds selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and one or more compounds of claim 1.

47. A method of treating multiple sclerosis which comprises co-administration one or more compounds selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and one or more compounds of claim 7.

48. A composition for treating multiple sclerosis which comprises one or more compounds selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and one or more compounds of claim 1.

49. A composition for treating multiple sclerosis which comprises one or more compounds selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and one or more compounds of claim 7.

50. A method of treating psoriasis which comprises co-administration of one or more compounds selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of psoriasis and one or more compounds of claim 1.

51. A method of treating psoriasis which comprises co-administration of one or more compounds selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of psoriasis and one or more compounds of claim 7.

52. The method of claim 50 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine orcyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

53. The method of claim 51 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

54. A composition for treating psoriasis which comprises one or more compounds selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of psoriasis and one or more compounds of claim 1.

55. A composition for treating psoriasis which comprises one or more compounds selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α

compound or other classes of compounds indicated for the treatment of psoriasis and one or more compounds of claim 7.

56. The composition of claim 54 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.

57. The composition of claim 55 wherein the immunosuppressive is methotrexate, leflunimide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is Enbrel or Remicade.