NF-kB inhibitors and uses threreof

• US 20030232998A1
• Filed: 05/30/2003
• Published: 12/18/2003
• Est. Priority Date: 05/31/2002
• Status: Active Grant

• Current Assignee: Michigan State University, The Board of Trustees of Michigan State University (Michigan State University)
• Original Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Inventors: Tepe, Jetze J.
• Granted Patent: US 7,345,078 B2
• Time in Patent Office: Days
• US Class Current: 548/322.5
• 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 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 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 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 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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 233/22 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 233/28 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A new class of imidazolines as 4-position acids or esters with very potent anti-inflammatory as well as antimicrobial activity is described. The synthesis of these imidazolines includes a multicomponent reaction applicable to a combinatorial synthetic approach. The combination of these two key characteristics provides an effective therapeutic drug in the treatment of septic shock as well as many other inflammatory (arthritis and asthma) and infectious disorders. The use of this novel class of non-steroidal agents as anti-inflammatory agents (for the treatment of asthma, etc.), antibacterial agents, and antiseptic agents is described. The compounds are also useful in the treatment of tumors (such as cancers). The imidazolines are potent inhibitors of the transcription factor NF-κB as well as potent activity against the Gram (+) bacterium. The compositions are also useful for treating autoimmune diseases and for inhibiting rejection of organ and tissue transplants.

Claims

1. An imidazoline of the formula:

2. The imidazoline of claim 1 wherein R₁ is phenyl.

3. The imidazoline of claim 1 wherein R₄ is benzyl.

4. The imidazoline of claim 1 wherein R₅ is lower alkyl containing 1 to 4 carbon atoms.

5. The imidazoline of claim 4 wherein R₅ is ethyl.

6. The imidazoline of claim 1 wherein R₂ is lower alkyl containing 1 to 4 carbon atoms.

7. The imidazoline of claim 6 wherein R₂ is methyl.

8. The imidazoline of claim 1 wherein R₃ is selected from the group consisting of phenyl and substituted phenyl.

9. The imidazoline of claim 1 wherein (Compound 1) R₁ is phenyl, R₂ is method, R₃ is phenyl, R₄ is benzyl and R₅ is H.

10. The imidazoline of claim 1 wherein (Compound 2) R₁ is phenyl, R₂ is methyl, R₃ is 4-methoxyphenyl, R₄ is benzyl and R₅ is H.

11. The imidazoline of claim 1 wherein (compound 3) wherein R₁ is phenyl, R₂ is methyl, R₃ is phenyl, R₄ is 4-fluorophenyl and R₅ is H.

12. The imidazoline of claim 1 wherein (compound 4) wherein R₁ is phenyl, R₂ is phenyl, R₃ is phenyl, R₄ is benzyl and R₅ is H.

13. The imidazoline of claim 1 wherein (compound 5) wherein R₁ is phenyl, R₂ is 1H-indol-3-ylmethyl, R₃ is phenyl, R₄ is benzyl and R₅ is H.

14. The imidazoline of claim 1 wherein (compound 6) wherein R₁ is phenyl, R₂ is methyl, R₃ is pyridin-4-yl, R₄ is benzyl and R₅ is H.

15. The imidazoline of claim 1 wherein (compound 7) wherein R₁ is phenyl, R₂ is methyl, R₃ is phenyl, R₄ is H and R₅ is H.

16. The imidazoline of claim 1 wherein (compound 8) wherein R₁ is phenyl, R₂ is methyl, R₃ is ethoxycarbonyl, R₄ is H and R₅ is H.

17. The imidazoline of claim 1 wherein (compound 9) wherein R₁ is phenyl, R₂ is methyl, R₃ is pyridin-4-yl, R₄ is benzyl and R₅ is ethyl.

18. The imidazoline of claim 1 wherein (Compound 10) R₁ is phenyl, R₂ is methyl, R₃ is phenyl, R₄ is benzyl and R₅ is ethyl.

19. A process for the preparation of imidazoline of the formula:

20. The process of claim 19 wherein the imidazoline is esterified by reaction with an alcohol.

21. The process of claim 19 wherein the imidazoline is esterified by reaction with the alcohol and sulfonyl dichloride.

22. A method for inhibiting inflammation in a mammal which comprises administering an imidazoline of the formula:

23. The method of claim 22 wherein the mammal is human.

24. The method of claim 22 wherein the mammal is a lower mammal.

25. The method of any one of claims 22, 23 or 24 wherein the administration is orally to the mammal.

26. The method of any one of claims 22, 23 or 24 wherein the administration is topically to the mammal.

27. The method of any one of claims 22, 23 or 24 wherein the administration is by injection into the mammal.

28. The method of any one of claims 22, 23 or 24 wherein the administration is intravenous into the mammal.

29. A method for inhibiting a microorganism which comprises:

administering an effective amount of a compound of the formula;

wherein R₁, R₂, R₃ and R₄ are selected from the group consisting of alkyl, acyl, aryl, arylalkyl, heteroaryl containing 5 to 14 ring members, and heterocyclic containing 5 to 12 ring members; and

R₅ is selected from the group consisting of hydrogen and an alkyl group, all of which are optionally substituted, to inhibit the microorganism.

30. The method of claim 29 wherein the inhibition is in vitro.

31. The method of claim 29 wherein the inflammation is in vivo.

32. The method of claim 29 wherein the administration is to a mammal.

33. The method of claim 32 wherein the mammal is human.

34. The method of any one of claims 29, 30 or 31 wherein the administration is orally to a mammal.

35. The method of any one of claims 29, 30 or 31 wherein the administration is by injection into a mammal.

36. The method of any one of claims 29, 30 or 31 wherein the administration is intravenously into a mammal.

37. The method of any one of claims 29, 30 or 31 wherein the administration is topically to a mammal.

39. The method of claim 37 wherein the inhibition is in vivo.

38. A method of inhibiting degradation of a protein which is NF-κ

B or NF-κ

B kinase which comprises contacting the protein with a compound of the formula;

40. The method of claim 38 wherein the inhibition is in the treatment of cancer.

41. A method for inhibiting inflammation in a mammal which comprises administering a multi-substituted 4-acid or 4-alkyl ester imidazoline to the mammal in an amount sufficient to inhibit the inflammation.

42. A method of inhibiting degradation of a protein which is NF-κ

B or NF-κ

B kinase which comprises contacting the protein with a multi-substituted imidazoline in an amount sufficient to inhibit degradation of the protein.

43. A method of inhibiting a cancer which comprises contacting the cancer with a multi-substituted 4-acid or 4-alkyl ester imidazoline in an amount sufficient to inhibit the cancer.

44. A method for inhibiting a tumor or cancer in a mammal which comprises administering an imidazoline of the formula:

45. The method of claim 44 wherein the mammal is human.

46. The method of claim 44 wherein the mammal is a lower mammal.

47. The method of any one of claims 44, 45 or 46 wherein the administration is orally to the mammal.

48. The method of any one of claims 44, 45 or 46 wherein the administration is topically to the mammal.

49. The method of any one of claims 44, 45 or 46 wherein the administration is by injection into the mammal.

50. The method of any one of claims 44, 45 or 46 wherein the administration is intravenous into the mammal.

51. The method of claim 44 wherein the imidazoline is admixed with a drug which inhibits growth of the tumor or cancer.

52. The method of claim 44 wherein the drug is a platinate.

53. The method of claim 44 wherein the drug is camptothecin.

54. The method of any one of claims 44, 45 or 46.

55. A composition which comprises an imidazoline of the formula

56. The composition of claim 55 wherein the drug is a platinate.

57. The composition of claim 55 wherein the drug is camptothecin.

58. The composition of any one of claims 55, 56 or 57 with a pharmaceutical carrier.

59. An imidazoline of the formula:

60. An imidazoline of the formula

61. A process for the preparation of an amino imidazoline which comprises reacting an imidazoline of the formula:

62. An imidazoline of the formula:

63. A method for inhibiting an immune response to a foreign NF-κ

B activator introduced into a mammal which comprises;

administering an effective amount of an imidazoline of the formula;

wherein R₁, R₂, R₃ and R₄ are each individually selected from the group consisting of alkyl, acyl, aryl, arylalkyl, heteroaryl containing 5 to 14 ring members, and heterocyclic containing 5 to 12 ring members; and

, R₅ is selected from the group consisting of hydrogen and an alkyl group, all of which are optionally substituted, to the mammal so as to thereby inhibit the immune response to the foreign NF-κ

B activator.

64. The method of claim 63 wherein R₁ is phenyl.

65. The method of claim 63 wherein R₄ is benzyl.

66. The method of claim 63 wherein R₅ is lower alkyl containing 1 to 4 carbon atoms.

67. The method of claim 63 wherein R₅ is ethyl.

68. The method of claim 63 wherein R₂ is lower alkyl containing 1 to 4 carbon atoms.

69. The method of claim 63 wherein R₂ is methyl and R₃ is selected from the group consisting of phenyl and substituted phenyl.

70. A method for treating an autoimmune disease in a mammal without bringing on complete immunodeficiency in the mammal which comprises:

administering an effective amount of an imidazoline of the formula;

wherein R₁, R₂, R₃ and R₄ are each individually selected from the group consisting of alkyl, acyl, aryl, arylalkyl, heteroaryl containing 5 to 14 ring members, and heterocyclic containing 5 to 12 ring members; and

, R₅ is selected from the group consisting of hydrogen and an alkyl group, all of which are optionally substituted, to the mammal so as to treat the autoimmune disease.

71. The method of claim 70 wherein R₁ is phenyl.

72. The method of claim 70 wherein R₄ is benzyl.

73. The method of claim 70 wherein R₅ is lower alkyl containing 1 to 4 carbon atoms.

74. The method of claim 70 wherein R₅ is ethyl.

75. The method of claim 70 wherein R₂ is lower alkyl containing 1 to 4 carbon atoms.

76. The method of claim 70 wherein R₂ is methyl and R₃ is selected from the group consisting of phenyl and substituted phenyl.

77. A method for inhibiting rejection of an organ transplanted into a mammal which comprises:

administering an effective amount of an imidazoline of the formula;

wherein R₁, R₂, R₃ and R₄ are each individually selected from the group consisting of alkyl, acyl, aryl, arylalkyl, heteroaryl containing 5 to 14 ring members, and heterocyclic containing 5 to 12 ring members; and

, R₅ is selected from the group consisting of hydrogen and an alkyl group, all of which are optionally substituted, to the mammal so as to inhibit rejection of the organ transplanted into the mammal.

78. The method of claim 77 wherein R₁ is phenyl.

79. The method of claim 77 wherein R₄ is benzyl.

80. The method of claim 77 wherein R₅ is lower alkyl containing 1 to 4 carbon atoms.

81. The method of claim 77 wherein R₅ is ethyl.

82. The method of claim 77 wherein R₂ is lower alkyl containing 1 to 4 carbon atoms.

83. The method of claim 77 wherein R₂ is methyl and R₃ is selected from the group consisting of phenyl and substituted phenyl.

84. A method for inhibiting reactivation of human immunodeficiency virus (HIV) in cells latently infected with the HIV which comprises:

administering an effective amount of an imidazoline of the formula;

wherein R₁, R₂, R₃ and R₄ are each individually selected from the group consisting of alkyl, acyl, aryl, arylalkyl, heteroaryl containing 5 to 14 ring members, and heterocyclic containing 5 to 12 ring members; and

, R₅ is selected from the group consisting of hydrogen and an alkyl group, all of which are optionally substituted, to inhibit the reactivation of the HIV in the latently infected cells.

85. The method of claim 84 wherein R₁ is phenyl.

86. The method of claim 84 wherein R₄ is benzyl.

87. The method of claim 84 wherein R₅ is lower alkyl containing 1 to 4 carbon atoms.

88. The method of claim 84 wherein R₅ is ethyl.

89. The method of claim 84 wherein R₂ is lower alkyl containing 1 to 4 carbon atoms.

90. The method of claim 84 wherein R₂ is methyl and R₃ is selected from the group consisting of phenyl and substituted phenyl.