Cannabinoid receptor ligands

• US 7,067,539 B2
• Filed: 08/07/2002
• Issued: 06/27/2006
• Est. Priority Date: 02/08/2001
• Status: Expired due to Fees

• 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.
• Primary Examiner(s): Saeed, Kamal A.
• Assistant Examiner(s): Coppins, Janet L
• Application Number:
  US10/214,897
• Publication Number:
  US 20030232859A1
• Time in Patent Office: 1,420 Days
• Field of Search: 546/294, 546/290, 546/329, 546/255, 514/347, 514/345, 514/354, 514/335
• US Class Current: 514/347
• 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—

, —

S—

or —

S(O)—

;

L² is —

SO₂—

;

R¹ is H, —

CH₃NH₂, —

CH₂CF₃, —

NHC₃H₇, —

NHC₂H₆, —

NHC₄H₉, C₁–

C₆alkyl, —

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 pyridyl 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–

C₆ cycloalkyl;

Y is a covalent bond;

Z is —

SO₂—

or —

C(O)—

;

L¹ is —

SO₂—

;

L² is —

SO₂—

;

R¹ is CH₃ or CF₃; and

R⁴ is pyridyl, and said pyridyl group is 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 is more than one substituent.

4. The compound according to claim 1 of the formula

5. The compound according to claim 1 of the formula

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

14. A pharmaceutical composition comprising one or more compounds according to claim 5 and one or more pharmaceutically acceptable carriers.

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

16. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-α

compound, and one or more compounds of claim 1.

17. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-α

compound, and one or more compounds of claim 5.

18. The composition of claim 16 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is etanercept or infliximab.

19. The composition of claim 17 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is etanercept or infliximab.

20. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 1.

21. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 5.

22. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-α

compound, and one or more compounds of claim 1.

23. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-α

compound, and one or more compounds of claim 5.

24. The composition of claim 22 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is etanercept or infliximab.

25. The composition of claim 23 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β

-methasone and the anti-TNF-α

compound is etanercept or infliximab.

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. The compound according to claim 1 of the formula

31. compound according to claim 1 of the formula