Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications

• US 8,232,402 B2
• Filed: 03/12/2009
• Issued: 07/31/2012
• Est. Priority Date: 03/12/2008
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Link Medicine Corp. (Astrazeneca PLC)
• Inventors: Lansbury, Peter T. Jr., Justman, Craig J., Fredenburg, Ross A., Meray, Robin Kate, Duggan, Mark E., Lin, Peter
• Primary Examiner(s): Seaman, D M
• Application Number:
  US12/402,910
• Publication Number:
  US 20090253655A1
• Time in Patent Office: 1,237 Days
• Field of Search: 546/159, 546/153, 546/312
• US Class Current: 546/159
• CPC Class Codes: C07D 215/36 Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

Novel quinolinone farnesyl transferase inhibitors are provided. These new compounds are useful in the treatment or prevention of synucleinopathies, such as Parkinson'"'"'s Disease, Diffuse Lewy Body Disease, multiple system atrophy, and disorders of brain iron concentration including pantothenate kinase-associated neurodegeneration (e.g., PANK1), or other neurodegenerative/neurological diseases. Provided compounds are also useful in the treatment of proliferative diseases such as cancer, and in the treatment of neurological diseases, such as cognitive impairment, depression, and anxiety. The treatment including administering to a subject a therapeutically effective amount of an inventive farnesyl transferase inhibitor compound.

Claims

1. A compound of the formula:

2. The compound of claim 1, wherein R₀ is substituted or unsubstituted pyridinyl.

3. The compound of claim 1, wherein R₀ is one of the formulae:

4. The compound of claim 1, wherein R₁ is substituted or unsubstituted aryl.

5. The compound of claim 1, wherein R₁ is substituted or unsubstituted phenyl.

6. The compound of claim 1, wherein R₁ is unsubstituted phenyl.

7. The compound of claim 1, wherein R₁ is of the formula:

8. The compound of claim 1, wherein R₁ is of the formula:

9. The compound of claim 1, wherein R₁ is thienyl.

10. The compound of claim 1, wherein R₁ is of the formula:

11. The compound of claim 1, wherein R₁ is substituted or unsubstituted heteroaryl.

12. The compound of claim 1, wherein R₁ is substituted or unsubstituted 5-membered heteroaryl.

13. The compound of claim 1, wherein R₁ is substituted or unsubstituted 6-membered heteroaryl.

14. The compound of claim 1, wherein R₁ is substituted or unsubstituted pyridinyl.

15. The compound of claim 1, wherein R₁ is pyridinyl, substituted with C₁-C₆ alkyl.

16. The compound of claim 1, wherein R₁ is one of the formulae:

17. The compound of claim 1, wherein R₁ is one of the formulae:

18. The compound of claim 1, wherein R₂ is hydrogen.

19. The compound of claim 1, wherein R₂ is fluorine.

20. The compound of claim 1, wherein R₂ is chlorine.

21. The compound of claim 1, wherein R₂ is —

NH₂.

22. The compound of claim 1, wherein R₂ is —

NH(CH₃).

23. The compound of claim 1, wherein R₂ is —

OH.

24. The compound of claim 1, wherein R₂ is alkoxy.

25. The compound of claim 1, wherein R₂ is —

OMe.

26. The compound of claim 1, wherein k is 0 or 1.

27. The compound of claim 1, wherein n is 0, 1, or 2.

28. The compound of claim 1, wherein at least one R₃ is halogen.

29. The compound of claim 1, wherein at least one R₃ is —

Cl.

30. The compound of claim 1, wherein at least one R₃ is —

Me.

31. The compound of claim 1, wherein at least one R₃ is —

CN.

32. The compound of claim 1, wherein at least one R₃ is —

OCH₃.

33. The compound of claim 1, wherein at least one R₃ is —

CH₂CO₂CH₃.

34. The compound of claim 1, wherein at least one R₃ is ethynyl.

35. The compound of claim 1, wherein n is 1, and R₃ is ethynyl.

36. The compound of claim 1, wherein R₅ is methyl.

37. The compound of claim 1, wherein R₅ is —

(CH₂)₂N(CH₃)₂.

38. The compound of claim 1 of the formula:

39. The compound of claim 38 having the stereochemistry of formula:

40. The compound of claim 38, wherein n is 1, 2, or 3.

41. The compound of claim 38, wherein m is 1, 2, or 3.

42. The compound of claim 38, wherein R₀ is substituted or unsubstituted 5-membered heteroaryl.

43. The compound of claim 38, wherein R₀ is substituted or unsubstituted 6-membered heteroaryl.

44. The compound of claim 38, wherein R₀ is substituted or unsubstituted pyridinyl.

45. The compound of claim 38, wherein R₀ is one of the formulae:

46. The compound of claim 38, wherein R₂ is hydrogen.

47. The compound of claim 38, wherein R₂ is fluorine.

48. The compound of claim 38, wherein R₂ is chlorine.

49. The compound of claim 38, wherein R₂ is —

NH₂.

50. The compound of claim 38, wherein R₂ is —

NH(CH₃).

51. The compound of claim 38, wherein R₂ is —

OH.

52. The compound of claim 38, wherein R₂ is —

OMe.

53. The compound of claim 38, wherein at least one R₃ is ethynyl, —

CF₃;

—

CHF₂;

—

CN, C_1-6alkyl, C_1-6alkoxy, or halogen.

54. The compound of claim 38, wherein n is 1, and R₃ is ethynyl.

55. The compound of claim 38 of formula:

56. The compound of claim 38, wherein R₄ is halogen.

57. The compound of claim 38, wherein m is 1, and R₄ is halogen.

58. The compound of claim 38, wherein m is 1 and R₄ is chlorine.

59. The compound of claim 38 of formula:

60. The compound of claim 59, wherein R₄ is halogen.

61. The compound of claim 59, wherein R₄ is chlorine.

62. The compound of claim 38, wherein R₅ is methyl.

63. The compound of claim 38 of one of the formulae:

78. A method of treating a synucleinopathic subject, the method comprising administering to a synucleinopathic subject a compound of claim 1 in a therapeutically effective amount.

79. The method of claim 78, wherein the synucleinopathic subject has a synucleinopathy selected from the group consisting of Parkinson'"'"'s disease, diffuse Lewy body disease, and multiple system atrophy disorder.

80. The method of claim 78, wherein the subject is a human.

81. The method of claim 78, wherein the effective amount of the farnesyl transferase inhibitor or a pharmaceutically acceptable salt form thereof comprises about 10 ng/kg of body weight to about 1000 mg/kg of body weight at a frequency of administration from once a day to once a month.

82. The method of claim 78 further comprising administering to the subject an amount of one or more non-farnesyl transferase inhibitor compounds effective to treat a neurological disorder.

83. The method of claim 82, wherein each non-farnesyl transferase inhibitor compound is selected from the group consisting of dopamine agonist, DOPA decarboxylase inhibitor, dopamine precursor, monoamine oxidase blocker, cathechol O-methyl transferase inhibitor, anticholinergic, and NMDA antagonist.

84. An article of manufacture comprising packaging material and a compound of claim 1, wherein the article of manufacture further comprises a label or package insert indicating that the compound can be administered to a subject for treating a synucleinopathy.

85. The article of manufacture of claim 84, wherein the synucleinopathy is selected from the group consisting of:

Parkinson'"'"'s disease, diffuse Lewy body disease, and multiple system atrophy disorder.

86. The article of manufacture of claim 84, further comprising one or more non-farnesyl transferase inhibitor compounds effective to treat a neurological disorder.

87. The article of manufacture of claim 84, wherein each non-farnesyl transferase inhibitor compound is selected from the group consisting of dopamine agonist, DOPA decarboxylase inhibitor, dopamine precursor, monoamine oxidase blocker, cathechol O-methyl transferase inhibitor, anticholinergic, and NMDA antagonist.

88. A pharmaceutical composition for treating a synucleinopathy comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

89. A method of reducing α

-synuclein toxicity in a cell, the method comprising;

administering to a cell a therapeutically effective amount of a compound of claim 1.

90. A method of treating a cognitive impairment in a subject suffering therefrom, the method comprising administering to a subject a compound of claim 1 in a therapeutically effective amount.

64. A compound of the formula:

65. The compound of claim 64, wherein R is substituted or unsubstituted aryl.

66. The compound of claim 64, wherein R is substituted or unsubstituted heteroaryl.

67. The compound of claim 64, wherein R is not pyridinyl.

68. The compound of claim 64, wherein R is not thienyl.

69. The compound of claim 64, wherein R is selected from the group consisting of thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

70. The compound of claim 64, wherein R is substituted or unsubstituted 6-membered heteroaryl.

71. The compound of claim 64, wherein R is substituted or unsubstituted pyridyl.

72. The compound of claim 64, wherein R is substituted or unsubstituted 5-membered heteroaryl.

73. The compound of claim 64, wherein R is substituted or unsubstituted thienyl.

74. The compound of claim 64 of the formula:

75. The compound of claim 64 of the formula:

76. The compound of claim 75 of formula:

77. The compound of claim 75 of one of the formulae: