Heterocyclic compounds and methods of making and using thereof

• US 20050119269A1
• Filed: 10/28/2004
• Published: 06/02/2005
• Est. Priority Date: 10/28/2003
• Status: Active Grant

• Current Assignee: Dr. Reddy's Laboratories Ltd.
• Original Assignee: Reddy US Therapeutics, Inc.
• Inventors: Sharma, Vedula Manohar, Venkateswarlu, Akella, Rao, Yeleswarapu Koteswar, Pillarisetti, Ram, Pal, Manojit
• Granted Patent: US 7,456,288 B2
• Time in Patent Office: Days
• US Class Current: 514/251
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• 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: C04B 35/632 Organic additives
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 239/88 Oxygen atoms
• CPC Class Codes: C07D 239/90 with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 311/30 not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds of formula (I), and methods and/or compositions comprising compounds that are effective in modulating inflammatory responses, such as those resulting from AGE and glycated protein accumulation are provided. Methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto are also provided.

Claims

1. A compound of general formula (I)

2. The compound of claim 1, wherein any of R¹, R², R³, and R⁴ independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O═

) group, a thio(S═

) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

16. A method of treatment or prophylaxis of a disease that is mediated by an inflammation response or smooth muscle cell proliferation in a human or animal, comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

17. The method of claim 16, wherein the inflammation response includes a diabetic vascular complication, wherein the diabetic vascular complication comprises diabetic retinopathy, microangiopathies, renal insufficiency, or Alzheimer'"'"'s disease.

18. The method of claim 16, wherein the inflammation response results from a glycated protein or an advanced glycation end product accumulation.

19. The method of claim 18, wherein the glycated protein or the advanced glycation end product accumulation is mediated by a pro-inflammatory cytokine.

20. The method of claim 19, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a, or MCP-1.

21. The method of claim 16, wherein the smooth muscle cell proliferation is inhibited by inducing the expression of perlecan.

22. The method of claim 16, wherein the smooth muscle cell proliferation is mediated by a pro-inflammatory cytokine.

23. The method of claim 22, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a, or MCP-1.

24. A method of treatment or prophylaxis of undesired inflammation in a human or animal comprising administering to the human or animal with the undesired inflammation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

25. A method of treatment or prophylaxis of undesired smooth muscle cell proliferation in a human or animal comprising administering to the human or animal with the undesired smooth muscle cell proliferation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

26. A method for treatment or prophylaxis of a disease or disorder mediated by a cell adhesion molecule, comprising administering to a patient in need thereof a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

27. The method of claim 26, wherein the disease or disorder mediated by cell adhesion molecules is an inflammatory disorder or a cardiovascular disease.

28. The method of claim 27, wherein the inflammatory disorder is rheumatoid arthritis, osteoarthrites, asthama, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, or multiple sclerosis.

29. The method of claim 27, wherein the cardiovascular disease is athresclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nepropathy, or diabetic retinopathy.

30. The method of claim 26, wherein the cell adhesion molecule is VCAM-1.

31. The method of claim 26, further comprising administering a therapeutically or prophylactically effective amount of at least one other medication comprising a platelet aggregation inhibitor, an antithrombotic agent, a, calcium channel blocker, an angiotension converting enzyme inhibitor, a β

blocker, a non-steroid antiinflamatory agent, a COX II inhibitor, a corticosteroid, a TNF-a modulating agent, a HMGCoA reductose inhibitor, a PPAR-? agonist, an HDL elevator, or a retinoid.

32. The method of claim 31, wherein the at least one other medication is aspirin, dilteazem, nefidipine, captopril, enalopril, propanalol, ibuprofen, indomethacin, sulindac, rofecoxib, celecoxib, etanercept, or infliximab.

33. A method of treatment or prophylaxis of cancer in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

34. A method according to claim 33, wherein the cancer comprises melanoma, prostate cancer, leukemia, lymphoma, non-small lung cancer, cancer of the central nervous system, breast cancer, colon cancer, ovarian cancer, or renal cancer.

35. A method for inhibiting smooth muscle cell proliferation in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

36. A method for inhibiting an inflammatory response in an endothelial cell in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

37. A method for treating or preventing organ transplant vasculopathy in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

38. The method of claim 37, wherein the organ is a liver, a kidney, a heart, a lung, a pancreas, a pancreatic islet, and skin.

39. The method of claim 37, further comprising administering a therapeutically or prophylactically effective amount of an immunosuppressive agent.

40. The method of claim 39, wherein the immunosuppressive agent is CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, Zenapax.

41. The method of claim 39, wherein the administering is oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.

42. The method of claim 39, wherein the immunosuppressive agent is administered before the composition.

43. The method of claim 39, wherein the immunosuppressive agent is administered after the composition.

44. The method of claim 39, wherein the immunosuppressive agent is administered simultaneously with the composition.

45. A method for treating or preventing restenosis in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

46. A method for treating or preventing atherosclerosis in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

47. A method for treating a disease mediated by inflammation in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

48. The method of claim 47, wherein the disease mediated by inflammation is an autoimmune disease.

49. The method of claim 48, wherein the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison'"'"'s disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet'"'"'s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn'"'"'s disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves'"'"' disease, Guillain-Barré

, Hashimoto'"'"'s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, mé

niè

re'"'"'s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud'"'"'s phenomenon, Reiter'"'"'s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjö

gren'"'"'s syndrome, stiff-man syndrome, systematic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, or Wegener'"'"'s granulomatosis.

50. A method for treating or preventing metastases in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

51. A method of modulating Perlecan activity in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

52. A method for modulating Heparanase in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

53. A stent coated with a composition comprising a compound according to claim 1.

54. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent, excipient, or solvate.

55. The pharmaceutical composition of claim 54, in the form of a tablet, capsule, powder, syrup, solution, suspension.

56. A medical device coated with a composition comprising a compound according to claim 1.

57. The medical device of claim 56, wherein the medical device is a shunt, a colostomy bag attachment device, an ear drainage tube, a lead for a pace maker and implantable defibrillator, a suture, a staple, an anastornosis device, a vertebral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a screw, a plate, a clip, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device, and a vascular support.

58. A method for treatment or prophylaxis of cardiovascular disease in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

59. The method of claim 58, wherein the cardiovascular disease is athresclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nepropathy, or diabetic retinopathy.

3. A compound of general formula (II)

4. The compound of claim 3, wherein any of R¹, R², R³, and R⁴ independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O═

) group, a thio(S═

) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

5. A compound of general formula (III)

6. The compound of claim 5, wherein any of R¹, R², R³, and R⁴ independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O═

) group, a thio(S═

) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

7. The compound of claim 5, wherein one or both of R′

and R″

independently are substituted with a halogen, a hydroxyl group, a nitro group, an amino group, or an alkyloxy group.

8. The compound of claim 5, wherein one or both of R′

and R″

independently are substituted with a heterocyclyl group comprising a morphonyl group, a thiomorphoine, or a piperzine.

9. The compound of formula (III) as claimed in claim 5, wherein the compound is:

10. A compound of general formula (IV)

11. The compound of claim 10, wherein any of R¹, R², R³, and R⁴ independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O═

) group, a thio(S═

) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

12. The compound of formula (IV) as claimed in claim 10, wherein the compound is:

13. A compound of general formula (V)

14. The compound of claim 13, wherein any of R¹, R², R³, and R⁴ independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O═

) group, a thio(S═

) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

15. The compound of formula (V) as claimed in claim 13, wherein the compound is: