Imidazoquinoline Compounds

• US 20080213308A1
• Filed: 09/14/2005
• Published: 09/04/2008
• Est. Priority Date: 09/14/2004
• Status: Abandoned Application

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Inventors: Lin, Xiaodong, Xu, Feng, Valiante, Nicholas, Chu, Daniel, Wang, Xiaojing Michael
• Application Number:
  US11/662,984
• Publication Number:
  US 20080213308A1
• Time in Patent Office: Days
• US Class Current: 424/208.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• 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 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides novel compositions comprising imidazoquinoline compounds. Also provided are methods of administering the compositions in an effective amount to enhance the immune response of a subject. Further provided are novel compositions and methods of administering the compositions in combination with (an)other agent(s).

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein R₄ and R₅ are each H.

3. The compound of claim 2, wherein R₁ is —

NR₆R₇.

4. The compound of claim 2, wherein R₁ is —

S(O)_qR₁₀.

5. The compound of claim 2, wherein R₁ is —

C(O)NR₆R₇.

6. The compound of claim 2, wherein R₁ is —

(CH₂)_mCH═

CH(CH₂)_nR₉.

7. The compound of claim 2, wherein R₁ is —

(CH₂)_mC≡

C(CH₂)_nR₉.

8. The compound of any one of claims 1-7, wherein R₂ is C_1-6 alkyl.

9. The compound of claim 3, wherein R₆ and R₇ within R₁ are independently H, C_1-6 alkyl or —

(CH₂)_mCH═

CH(CH₂)_nR₉.

10. The compound of claim 4, wherein R₁ is —

SR₁₀, and the R₁₀ of the —

SR₁₀ is C_1-6 alkyl.

11. The compound of claim 8, wherein R₂ is isobutyl.

12. The compound of claim 9, wherein the C_1-6 alkyl within R₁₀ is selected from methyl, ethyl, n-butyl, or n-pentyl.

13. The compound of claim 9, wherein m is 1, n is 0, and R₉ is H.

14. The compound of claim 2, wherein R₁ is —

N(CH₃)CH₂CH₂CH₃.

15. The compound of claim 2, wherein p is 0.

16. The compound as in any of any one of claims 1-7, wherein R₂ is substituted C_1-6 alkyl.

17. The compound of claim 16, wherein R₂ is —

CH₂C(CH₃)₂(OH).

18. The compound of claim 2, wherein R₁ is —

S-cyclopropyl, —

S—

CH₂CH(CH₃)₂ or —

S—

CH₂CH₂CH₃.

19. The compound of claim 1, wherein R₁ is —

S—

C_3-6 cylcoalkyl.

20. The compound of claim 1, wherein R₆ and R₇ are taken together to form a substituted or unsubstituted heterocyclyl group.

21. The compound of claim 20, wherein said heterocyclyl group is selected from piperidinyl, pyrrolidinyl, azetidinyl, or aziridinyl.

28. The compound of claim 1, wherein the compound is selected from:

1-(4-Amino-2-propylsulfanyl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol;

1-(4-Amino-2-azetidin-1-yl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol;

1-(4-Amino-2-pyrrolidin-1-yl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol;

1-(4-Amino-2-cyclopropylsulfanyl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol;

or

1-(4-Amino-2-isobutylsulfanyl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol.

29. The compound of claim 1, wherein the compound is selected from:

N2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2,N2-dimethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-ethyl-N2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-methyl-1-(2-methylpropyl)-N2-propyl-1H-imidazo[4,5-c]quinoline-2,4-diamine;

1-(2-methylpropyl)-N2-propyl-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-butyl-N2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-methyl-1-(2-methylpropyl)-N2-pentyl-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-methyl-1-(2-methylpropyl)-N2-prop-2-enyl-1H-imidazo[4,5-c]quinoline-2,4-diamine;

1-(2-methylpropyl)-2-[phenylmethyl)thio]-1H-imidazo[4,5-c]quinolin-4-amine;

1-(2-methylpropyl)-2-(propylthio)-1H-imidazo[4,5-c]quinolin-4-amine;

2-[[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl](methyl)amino]ethanol;

2-[[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl](methyl)amino]ethyl acetate;

4-amino-1-(2-methylpropyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one;

N2-butyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-butyl-N2-methyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2-methyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

N2,N2-dimethyl-1-(2-methylpropyl)-N4,N4-bis(phenylmethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine;

1-{4-amino-2-[methyl(propyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol;

1-[4-amino-2-(propylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol;

or

N4,N4-dibenzyl-1-(2-methoxy-2-methylpropyl)-N2-propyl-1H-imidazo[4,5-c]quinoline-2,4-diamine.

36. A method of inducing interferon biosynthesis in a subject, comprising:

administering to the subject a compound according to any one of claims 2-29 in an amount sufficient to induce interferon biosynthesis.

37. A method of modulating an immune response in a subject, comprising:

administering a compound according to any one of claims 2-29.

38. A method for inducing the production of TNF-α

in a subject, comprising;

administering a compound according to any one of claims 2-29 to the subject in an amount sufficient to induce the production of TNF-α

in the subject.

39. The method of claim 38, wherein the compound has an average steady-state drug concentration in the blood of less than 20 μ

M.

40. A method of inducing an immune response in a subject, comprising:

administering a compound according to any one of claims 2-29 to the subject in an amount sufficient to induce an immune response in the subject.

41. The method of claim 40, wherein the immune response involves the production of cytokines.

42. The method of claim 40, wherein the immune response involves the increased production of TNF-α

.

43. The method of claim 40, wherein the subject is suffering from a microbial infection.

44. The method of claim 40, wherein the subject is suffering from a viral infection.

45. The method of claim 44, wherein the viral infection is a viral infection caused by the hepatitis C virus (HCV).

46. The method of claim 44, wherein the viral infection is caused by the human immunodeficiency virus (HIV).

47. The method of claim 40, wherein the subject is suffering from abnormal cellular proliferation or cancer.

48. The method of claim 40, wherein the subject is suffering from allergic diseases.

49. The method of claim 40, wherein the subject is suffering from asthma.

50. The method of claim 40, wherein the subject is suffering from precancerous lesions.

51. The method according to claim 50, wherein the precancerous lesions are actinic keratosis.

52. A method of inhibiting a kinase, comprising:

administering the compound according to any one of claims 2-29 to a subject, wherein the kinase is inhibited in the subject.

53. The method according to any one of claims 36, 37, 38, 40-47, 50, or 51 wherein the compound is administered topically.

54. A pharmaceutical composition, comprising:

the compound of any one of claims 2-29 and a pharmaceutically acceptable excipient.

55. A method of inducing an immune response in a subject, comprising:

administering to the subject a compound according to any one of claims 2-29 and an antigen, wherein the compound induces an immune response to the antigen in the subject.

56. A method of enhancing the immune response to an antigen in a subject, comprising:

administering to the subject a composition comprising a compound according to any one of claims 2-29 and an antigen, wherein the immune response to the antigen in the subject is enhanced.

57. A composition comprising the compound according to any one of claims 2-29 and an additional immunogenic composition or an antigen.

58. The composition of claim 57, wherein the additional immunogenic composition comprises an antigen.

59. The composition according to one of any one of claims 54, 57 or 58 further comprising an additional adjuvant.

60. The composition of claim 59 wherein the adjuvant is MF59.

61. The composition according to any one of claims 57-59, further comprising poly(lactide-co-glycolide) (PLG).

62. The composition according to claim 58, wherein the antigen is a bacterial antigen or a viral antigen.

63. The composition according to claim 62, wherein the antigen is a viral antigen from a virus selected from the group consisting of Hepatitis C virus, Human Immunodeficiency virus, Hepatitis B virus, Human Papilloma virus and Influenza virus.

64. The composition according to claim 63, wherein the antigen is an influenza antigen.

65. The composition of claim 64 wherein the influenza antigen comprises haemagglutinin and/or neuraminidase surface proteins.

66. The composition according to one of any one of claims 62-65 further comprising an additional adjuvant.

67. The composition of claim 66 wherein the adjuvant is MF59.

68. The composition according to any one of claims 62-67, further comprising poly(lactide-co-glycolide) (PLG).

69. A composition comprising the compound according to any one of claims 2-29 and an antigen.

70. The composition of claim 69 further comprising an additional adjuvant.

71. The composition of claim 70 wherein the adjuvant is MF59.

72. The composition according to any one of claims 69-71, further comprising poly(lactide-co-glycolide) (PLG).

73. The composition according to claim 69, wherein the antigen is a bacterial antigen or a viral antigen.

74. The composition according to claim 73, wherein the antigen is a viral antigen from a virus selected from the group consisting of Hepatitis C virus, Human Immunodeficiency virus, Hepatitis B virus, Human Papilloma virus and Influenza virus

75. The composition according to claim 69, wherein the antigen is an influenza antigen.

76. The composition of claim 75 wherein the influenza antigen comprises haemagglutinin and/or neuraminidase surface proteins.

77. The composition according to one of any one of claims 73-76 further comprising an additional adjuvant.

78. The composition of claim 77 wherein the adjuvant is MF59.

79. The composition according to any one of claims 73-78, further comprising poly(lactide-co-glycolide) (PLG).

22. A compound according to the structure:

23. A compound according to the structure:

24. A compound according to the structure:

25. A compound according to the structure:

26. A compound according to the structure:

27. A compound according to the structure:

30. A method of synthesizing a compound of formula (II)

31. The method of claim 30, wherein the coupling agent is 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride.

35. The method of any one of claims 30, 32, 33, or 34, wherein the protecting group is a benzyl group.

32. A method of synthesizing a compound of formula (V)

33. A method of synthesizing a compound of formula (VII)

34. A method of synthesizing a compound of formula (XI)