Cannabinoid receptor ligands

• US 20040132804A1
• Filed: 11/21/2003
• Published: 07/08/2004
• Est. Priority Date: 11/25/2002
• 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., Chen, Lei
• Granted Patent: US 7,253,189 B2
• Time in Patent Office: Days
• US Class Current: 514/454
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 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 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• 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 323/31 : having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 323/41 : Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07C 323/49 : to sulfur atoms
• CPC Class Codes: C07D 213/71 : to which a second hetero atom is attached
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links

Abstract

A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹, R², L¹, L², M¹, M², n, p, q, A, D, 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 (I):

2. A compound according to claim 1, wherein R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, —

N(R³)₂, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

3. A compound according to claim 2, wherein R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

4. A compound according to claim 1, wherein R² is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, —

N(R³)₂, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

5. A compound according to claim 4, wherein R² is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

6. A compound according to claim 1, wherein R³ is selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

7. A compound according to claim 6, wherein R³ is hydrogen.

8. A compound according to claim 1, wherein X is selected from the group consisting of alkyl, halogen, —

CF₃, —

OCF₃, OH and alkoxy, wherein each X can be the same or different and is independently selected when there is more than one X present.

9. A compound according to claim 1, wherein L¹ is selected from the group consisting of —

C(R²)₂—

, —

C(O)—

, —

S(O)₂—

, —

O—

, —

NR²—

, —

C(O)NH—

, —

NHC(O)—

, —

CF₂— and

—

C(═

N—

OR²)—

.

10. A compound according to claim 9, wherein L¹ is selected from the group consisting of —

C(R²)₂—

, —

C(O)—

, and —

S(O)₂—

.

11. A compound according to claim 1, wherein L² is selected from the group consisting of a covalent bond, —

C(R²)₂—

, —

C(═

N—

OR²)—

, S(O)₂—

, —

C(O)—

, —

O—

, —

N(R²)—

, —

C(O)NH— and

—

NHC(O)—

.

12. A compound according to claim 11, wherein L² is selected from the group consisting of a covalpnt bond, —

C(R²)₂—

, —

S(O)₂—

, and —

C(O)—

.

13. A compound according to claim 1, wherein M¹ is a moiety selected from the group consisting of aryl and heteroaryl, wherein said aryl or heteroaryl can be optionally substituted with D.

14. A compound according to claim 13, wherein M¹ is a moiety selected from the group consisting of phenyl, indolyl, benzofuranyl, dihydrobenzofuranyl, furanyl, thienyl, and pyridinyl.

15. A compound according to claim 1, wherein M² is a moiety selected from the group consisting of aryl and heteroaryl, wherein said aryl or heteroaryl can be optionally substituted with A.

16. A compound according to claim 15, wherein M² is a moiety selected from the group consisting of phenyl, furanyl, thienyl, quinolinyl, and pyridinyl.

17. A compound according to claim 1, wherein n is 0-2.

18. A compound according to claim 1 wherein p is 0-2.

19. A compound according to claim 1, wherein q is 0-2.

20. A compound according to claim 1, wherein t is 0-2.

21. A compound according to claim 1, wherein A, which can be the same or different when q>

1, is independently selected from the group consisting of —

NR⁴R⁵, —

Cl, —

F, —

CF₃, —

OCF₃, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, and —

S(O)₂R², wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

22. A compound according to claim 21, wherein A, which can be the same or different when q>

1, is independently selected from the group consisting of NR⁴R⁵, —

Cl, —

F, —

CF₃, —

OCF₃, and substituted or unsubstituted alkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2.

23. A compound according to claim 1, wherein D, which can be the same or different when p>

1, is independently selected from the group consisting of —

Br, —

Cl, —

F, —

CF₃, —

OH, —

OCF₂H, —

OCF₃, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, —

O-cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and —

S(O)₂R², wherein the term “

substituted”

means being substituted with (X)_n, and n is 0-2.

24. A compound according to claim 23, wherein D, which can be the same or different when p>

1, is independently selected from the group consisting of —

Cl, —

F, —

CF₃, —

OCF₂H, —

OCF₃, substituted or unsubstituted alkyl, cycloalkyl, and heteroaryl, wherein the term “

substituted”

means being substituted with (X)_n, and n is 0-2.

25. A compound according to claim 24, wherein Y represents —

S(O)₂—

or —

C(O)—

.

26. A compound according to claim 25, wherein Z represents a covalent bond or —

S(O)₂—

.

27. A compound according to claim 1, wherein Z is a covalent bond, R² is H, n is O, and R¹, L¹, L², M¹, M², q, p, A, D and Y are as defined in the following table:

28. The compound according to claim 1 represented by structural formula IA:

29. The compound according to claim 28, wherein:

R¹ is selected from the group consisting of —

CF₃ and —

CH₃;

Y is —

S(O)₂—

;

X is selected from the group consisting of alkyl, halogen, —

CF₃, —

OH, —

OCF₃, and alkoxy;

L₁ is selected from the group consisting of —

S(O)₂— and

—

CH₂—

,

L₂ is —

S(O)₂—

;

D is selected from the group consisting of —

OCF₃, —

Cl, and cyclopropyl; and

M² is selected from the group consisting of pyridyl and 2-fluorophenyl.

30. The compound according to claim 29, wherein,

R¹ is —

CF₃;

X is selected from the group consisting of alkyl, halogen, —

CF₃, —

OH, —

OCF₃, and alkoxy;

Y is —

S(O)₂—

;

L₁ is —

S(O)₂—

;

L₂ is —

S(O)₂—

;

D is selected from the group consisting of —

OCF₃, —

Cl, and cyclopropyl; and

M² is selected from the group consisting of pyridyl and 2-fluorophenyl.

31. The compound according to claim 1 represented by structural formula IB:

32. The compound according to claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2;

R³ is hydrogen;

L¹ is selected from the group consisting of —

C(R²)₂—

, —

C(O)—

, and —

S(O)₂—

;

L² is selected from the group consisting of a covalent bond, —

C(R²)₂—

, —

S(O)₂—

, and —

C(O)—

;

X is selected from the group consisting of halogen, —

CF₃, —

OH, and —

OCF₃, wherein each X can be the same or different and is independently selected when there are more than one X present;

Y represents —

S(O)₂—

or —

C(O)—

;

M², which can be optionally substituted with A, is a moiety selected from the group consisting of phenyl, furanyl, thienyl, quinolinyl and pyridinyl;

n is 0-2;

p is 0-2; and

q is 0-2.

33. The compound according to claim 32, wherein,

R¹ is —

CF₃;

X is selected from the group consisting of halo, —

CF₃, —

OH, and —

OCF₃, wherein each X can be the same or different and is independently selected when there is more than one X present;

Y is —

S(O₂)—

;

L₁ is —

S(O)₂—

;

L₂ is —

S(O)₂—

; and

M² is selected from the group consisting of pyridyl and 2-fluorophenyl.

34. The compound according to claim 1 represented by structural formula IC:

35. The compound according to claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein:

R¹ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl, wherein the term “

substituted”

means being substituted with (X)_t, and t is 0-2;

R³ is hydrogen;

R⁴ is hydrogen or alkyl;

L¹ is selected from the group consisting of —

C(R²)₂—

, —

C(O)—

, and —

S(O)₂—

;

L² is selected from the group consisting of a covalent bond, —

C(R²)₂—

, —

S(O)₂—

, and —

C(O)—

;

X is selected from the group consisting of halogen, —

CF₃, —

OH, and —

OCF₃, wherein each X can be the same or different and is independently selected when there are more than one X present;

Y represents —

S(O)₂—

or —

C(O)—

;

M², which can be optionally substituted with A, is a moiety selected from the group consisting of phenyl, furanyl, thienyl, quinolinyl and pyridinyl;

n is 0-2;

p is 0-2; and

q is 0-2.

36. The compound according to claim 35 wherein,

R¹ is —

CF₃;

X is selected from the group consisting of halo, —

CF₃, —

OH, and —

OCF₃, wherein each X can be the same or different and is independently selected when there is more than one X present;

Y is —

S(O)₂—

;

L₁ is —

S(O)₂—

;

L₂ is —

S(O)₂—

; and

M² is selected from the group consisting of pyridyl and 2-fluorophenyl.

37. The compound according to claim 1, wherein said compound is selected from the group consisting of:

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

39. The pharmaceutical composition according to claim 38, further comprising one or more pharmaceutically acceptable carriers.

40. A method of preparing the pharmaceutical composition of claim 38, said method comprising contacting one or more compounds of formula I with one or more pharmaceutically acceptable carriers.

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

42. 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.

43. The method of treating cancer, inflammatory diseases, immunomodulatory diseases, or respiratory diseases according to claim 42, wherein the amount of compound 1 that is administered is a therapeutically effective amount.

44. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 42, 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, neuropathic pain, 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.

45. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 44, further comprising co-administering or combining the compound of claim 1 with one or more second agents which can be the same or different from each other, and are independently selected from the group consisting of DMARDS, NSAIDS, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs;

and other anti-inflammatory agents.

46. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, 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.

47. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, wherein said NSAIDS can be the same or different and are independently selected from the group consisting of piroxicam, naproxen, indomethacin and ibuprofen.

48. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, wherein said COX-1 inhibitor is Piroxicam.

49. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, wherein said COX-2 selective inhibitor is refecoxib or celecoxib.

50. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, wherein said immunosuppressives can be the same or different and are independently selected from the group consisting of steroids, cyclosporine, Tacrolimus and rapamycin.

51. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, 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.

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

53. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, 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.

54. The method of treating cancer, inflammatory diseases, immunomodulatory diseases or respiratory diseases according to claim 45, wherein said administration is oral or subcutaneous.

55. 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.

56. A kit comprising a pharmaceutical composition for use in treating cancer, inflammatory diseases, immunomodulatory diseases, and respiratory diseases, wherein said composition comprises one or more compounds according to claim 1 and one or more pharmaceutically acceptable carriers.