Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines

• US 5,977,144 A
• Filed: 08/29/1997
• Issued: 11/02/1999
• Est. Priority Date: 08/31/1992
• Status: Expired due to Term

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Papke, Roger, Day, Arthur, Meyer, Edwin, Kem, William, De Fiebre, Christopher M., van haaren, Franz, Zoltewicz, John A.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/924,008
• Time in Patent Office: 795 Days
• Field of Search: 514/334, 514/318, 546/193, 546/259
• US Class Current: 514/334
• 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 25/34 Tobacco-abuse
• 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 211/82 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon 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 405/14 containing three or more hetero rings

Abstract

This invention relates to compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the alpha7 receptor subtype with little or no activation of the alpha4beta2 or other receptor subtypes.

Claims

1. A composition of matter comprising a compound of the formula:

##STR20## or a salt thereof, wherein R¹, R⁶, and R⁷ are hydrogen or C₁ -C₄ alkyl; and

R² is ═

CHCH═

CHX, wherein X is ##STR21## wherein R³, R⁴, and R⁵ are selected from the group consisting of hydrogen, C₁ -C₄ alkyl optionally substituted with NN-dialkylamino having 1 to 4 carbons in each of the alkyls, C₁ -C₆ alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amino having 1 to 4 carbons in the acyl, cyano, N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, and nitro.

2. The composition according to claim 1, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

3. The composition according to claim 2, wherein R³, which is attached to the 4- or the 2-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

4. The composition according to claim 3, wherein R³ is hydroxyl.

5. The composition according to claim 3, wherein R³ is acetylamino.

6. The composition according to claim 3, wherein R³ is acetoxy.

7. The composition according to claim 3, wherein R³ is methoxy.

8. The composition according to claim 7, wherein R¹ and R⁴ are hydrogen, R³ is attached to the 2-position of the phenyl ring, and R⁵, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

9. The composition according to claim 4, claim 5, claim 6, or claim 7, wherein R¹, R⁴, and R⁵ are hydrogen.

10. A composition of matter comprising a cinnamylidene-anabaseine.

11. The composition according to claim 10, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene)anabaseine, 3-(2,4-dimethoxycinnamylidene) anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.

12. A composition of matter comprising 3-(4-isopropoxybenzylidene) anabaseine.

13. A method of moderating or preventing tobacco-withdrawal effects in a mammal in need thereof, comprising administering to an animal in need thereof a therapeutically effective amount of a compound of the formula:

##STR22## or a pharmaceutically acceptable salt thereof, wherein R¹, R⁶, and R⁷ are hydrogen or C₁ -C₄ alkyl; and

R² is ═

CHX, ═

CCH₃ X, or ═

CHCH═

CHX, wherein X is ##STR23## wherein R³, R⁴, and R⁵ are selected from the group consisting of hydrogen, C₁ -C₄ alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C₁ -C₆ alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amino having 1 to 4 carbons in the acyl, cyano, N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, and nitro.

14. The method according to claim 13, wherein R² is ═

CH--X or ═

CCH₃ X.

15. The method according to claim 14, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

16. The method according to claim 15, wherein R³, which is attached to the 4-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, isopropoxy, and nitro.

17. The method according to claim 16, wherein R³ is hydroxyl.

18. The method according to claim 16, wherein R³ is methoxy or isopropoxy.

19. The method according to claim 16, wherein R³ is amino.

20. The method according to claim 15, wherein R¹ is hydrogen, R³ is methoxy, R⁴ is hydroxyl or methoxy, and R⁵ is hydrogen.

21. The method according to claim 20, wherein R³ is attached to the 4-position of the phenyl ring and R⁴ is attached to the 2-position of the phenyl ring.

22. The method according to claim 20, wherein R³ is attached to the 2-position of the phenyl ring and R⁴ is attached to the 4-position of the phenyl ring.

23. The method according to claim 15, wherein R¹ is hydrogen, R³, R⁴ and R⁵ are all methoxy.

24. The method according to claim 15, wherein R³ is 4-dimethylamino, and R⁴ and R⁵ are both hydrogen.

25. The method according to claim 13, wherein R² is ═

CHCH═

CHX.

26. The method according to claim 25, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

27. The method according to claim 26, wherein R³, which is attached to the 4- or the 2-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

28. The method according to claim 27, wherein R³ is hydroxyl.

29. The method according to claim 27, wherein R³ is acetylamino.

30. The method according to claim 27, wherein R³ is acetoxy.

31. The method according to claim 27, wherein R³ is methoxy.

32. The method according to claim 31, wherein R¹ and R⁴ are hydrogen, R³ is attached to the 2-position of the phenyl ring, and R⁵, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

33. The method according to claim 28, claim 29, claim 30, or claim 31, wherein R¹, R⁴, and R⁵ are hydrogen.

34. The method according to claim 13, wherein the animal is human.

35. A method of treating tobacco-withdrawal symptoms comprising administering to an animal in need thereof a therapeutically effective amount of a benzylidene-anabaseine or a cinnamylidene-anabaseine capable of selectively activating alpha7 receptors, or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein the benzylidene-anabaseine is selected from the group consisting of 3-(2,4-dimethoxybenzylidene) anabaseine, 3-(4-hydroxybenzylidene) anabaseine, 3-(4-methoxybenzylidene) anabaseine, 3-(4-aminobenzylidene) anabaseine, 3-(4-hydroxy-2-methoxybenzylidene) anabaseine, 3-(2-hydroxy-4-methoxybenzylidene) anabaseine, 3-(4-isopropoxybenzylidene) anabaseine, and (7'"'"'-methyl-3-(2,4dimethoxybenzylidene)) anabaseine.

37. The method of claim 35, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene) anabaseine, 3-(2,4-dimethoxycinnamylidene) anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.

38. A method of stimulating brain alpha7 receptors antagonized by ethanol in a mammal, comprising administering to an animal in need thereof a therapeutically effective amount of a compound of the formula:

##STR24## or a pharmaceutically acceptable salt thereof, wherein R¹, R⁶, and R⁷ are hydrogen or C₁ -C₄ alkyl; and

R² is ═

CHX, ═

CCH₃ X, or ═

CHCH═

CHX, wherein X is ##STR25## wherein R³, R⁴, and R⁵ are selected from the group consisting of hydrogen, C₁ -C₄ alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C₁ -C₆ alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amino having 1 to 4 carbons in the acyl, cyano, N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, and nitro.

39. The method according to claim 38, wherein R² is ═

CH--X or ═

CCH₃ X.

40. The method according to claim 39, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

41. The method according to claim 40, wherein R³, which is attached to the 4-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, isopropoxy, and nitro.

42. The method according to claim 41, wherein R³ is hydroxyl.

43. The method according to claim 41, wherein R³ is methoxy or isopropoxy.

44. The method according to claim 41, wherein R³ is amino.

45. The method according to claim 40, wherein R¹ is hydrogen, R³ is methoxy, R⁴ is hydroxyl or methoxy, and R⁵ is hydrogen.

46. The method according to claim 45, wherein R³ is attached to the 4-position of the phenyl ring and R⁴ is attached to the 2-position of the phenyl ring.

47. The method according to claim 45, wherein R³ is attached to the 2-position of the phenyl ring and R⁴ is attached to the 4-position of the phenyl ring.

48. The method according to claim 40, wherein R¹ is hydrogen, R³, R⁴ and R⁵ are all methoxy.

49. The method according to claim 40, wherein R³ is 4-dimethylamino, and R⁴ and R⁵ are both hydrogen.

50. The method according to claim 38, wherein R² is ═

CHCH═

CHX.

51. The method according to claim 50, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

52. The method according to claim 51, wherein R³, which is attached to the 4- or the 2-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

53. The method according to claim 52, wherein R³ is hydroxyl.

54. The method according to claim 52, wherein R³ is acetylamino.

55. The method according to claim 52, wherein R³ is acetoxy.

56. The method according to claim 52, wherein R³ is methoxy.

57. The method according to claim 56, wherein R¹ and R⁴ are hydrogen, R³ is attached to the 2-position of the phenyl ring, and R⁵, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

58. The method according to claim 53, claim 54, claim 55, or claim 56, wherein R¹, R⁴, and R⁵ are hydrogen.

59. The method according to claim 38, wherein the animal is human.

60. A method of stimulating brain alpha7 receptors antagonized by ethanol comprising administering to an animal in need thereof a therapeutically effective amount of a benzylidene-anabaseine or a cinnamylidene-anabaseine capable of selectively activating alpha7 receptors, or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the benzylidene anabaseine is selected from the group consisting of 3-(2,4-dimethoxybenzylidene) anabaseine, 3-(4-hydroxybenzylidene) anabaseine, 3-(4-methoxybenzylidene) anabaseine, 3-(4-aminobenzylidene) anabaseine, 3-(4-hydroxy-2-methoxybenzylidene) anabaseine, 3-(2-hydroxy-4-methoxybenzylidene) anabaseine, 3-(4-isopropoxybenzylidene) anabaseine, and (7'"'"'-methyl-3-(2,4-dimethoxybenzylidene)) anabaseine.

62. The method of claim 60, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene)anabaseine, 3-(2,4-dimethoxycinnamylidene)anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.

63. A method of protecting against cell loss induced by ischemia in a mammal, comprising administering to an animal in need thereof a therapeutically effective amount of a compound of the formula:

##STR26## or a pharmaceutically acceptable salt thereof, wherein R¹, R⁶, and R⁷ are hydrogen or C₁ -C₄ alkyl; and

R² is ═

CHX, ═

CCH₃ X, or ═

CHCH═

CHX, wherein X is ##STR27## wherein R³, R⁴, and R⁵ are selected from the group consisting of hydrogen, C₁ -C₄ alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C₁ -C₆ alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amino having I to 4 carbons in the acyl, cyano, N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, and nitro.

64. The method according to claim 63, wherein R² is ═

CH--X or ═

CCH₃ X.

65. The method according to claim 64, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

66. The method according to claim 65, wherein R³, which is attached to the 4-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, isopropoxy, and nitro.

67. The method according to claim 66, wherein R³ is hydroxyl.

68. The method according to claim 66, wherein R³ is methoxy or isoproxy.

69. The method according to claim 66, wherein R³ is amino.

70. The method according to claim 65, wherein R¹ is hydrogen, R³ is methoxy, R⁴ is hydroxyl or methoxy, and R⁵ is hydrogen.

71. The method according to claim 70, wherein R³ is attached to the 4-position of the phenyl ring and R⁴ is attached to the 2-position of the phenyl ring.

72. The method according to claim 70, wherein R³ is attached to the 2-position of the phenyl ring and R⁴ is attached to the 4-position of the phenyl ring.

73. The method according to claim 65, wherein R¹ is hydrogen, R³, R⁴ and R⁵ are all methoxy.

74. The method according to claim 65, wherein R³ is 4-dimethylamino, and R⁴ and R⁵ are both hydrogen.

75. The method according to claim 63, wherein R² is ═

CHCH═

CHX.

76. The method according to claim 75, wherein R² is attached to the 3-position of the tetrahydropyridine ring.

77. The method according to claim 76, wherein R³, which is attached to the 4- or the 2-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

78. The method according to claim 77, wherein R³ is hydroxyl.

79. The method according to claim 77, wherein R³ is acetylamino.

80. The method according to claim 77, wherein R³ is acetoxy.

81. The method according to claim 77, wherein R³ is methoxy.

82. The method according to claim 81, wherein R¹ and R⁴ are hydrogen, R³ is attached to the 2-position of the phenyl ring, and R⁵, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

83. The method according to claim 78, claim 79, claim 80, or claim 81, wherein R¹, R⁴, and R⁵ are hydrogen.

84. The method according to claim 63, wherein the animal is human.

85. The method of claim 63, wherein the cell loss is from stroke.

86. The method of claim 63, wherein the cell loss is from glutamate-induced excitotoxicity.

87. A method of protecting against cell loss induced by ischemia comprising administering to an animal in need thereof a therapeutically effective amount of a benzylidene-anabaseine or a cinnamylidene-anabaseine capable of selectively activating alpha7 receptors, or a pharmaceutically acceptable salt thereof.

88. The method of claim 87, wherein the benzylidene-anabaseine is selected from the group consisting of 3-(2,4-dimethoxybenzylidene) anabaseine, 3-(4-hydroxybenzylidene) anabaseine, 3-(4-methoxybenzylidene) anabaseine, 3-(4-aminobenzylidene) anabaseine, 3-(4-hydroxy-2-methoxybenzylidene) anabaseine, 3-(2-hydroxy-4-methoxybenzylidene) anabaseine, 3-(4-isopropoxybenzylidene) anabaseine, and (7'"'"'-methyl-3-(2,4-dimethoxybenzylidene)) anabaseine.

89. The method of claim 87, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene)anabaseine, 3-(2,4-dimethoxycinnamylidene)anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.

90. A method of prophylaxis against cell loss from focal ischemic insult, comprising administering to a mammal in need thereof an amount of an alpha7 nicotinic agonist selected from the group consisting of a benzylidene-anabaseine and a cinnamylidene-anabaseine before occurrence of ischemia in an amount effective to protect against the cell loss.

91. The method according to claim 90, wherein the benzylidene-anabaseine is selected from the group consisting of 3-(2,4-dimethoxybenzylidene) anabaseine, 3-(4-hydroxybenzylidene) anabaseine, 3-(4-methoxybenzylidene) anabaseine, 3-(4-aminobenzylidene) anabaseine, 3-(4-hydroxy-2-methoxybenzylidene) anabaseine, 3-(2-hydroxy-4-methoxybenzylidene) anabaseine, 3-(4-isopropoxybenzylidene) anabaseine, and (7'"'"'-methyl-3-(2,4-dimethoxybenzylidene)) anabaseine.

92. The method according to claim 90, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene)anabaseine, 3-(2,4-dimethoxycinnamylidene) anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.

93. A method of treating age related learning or memory impairment comprising administering to an animal in need thereof a therapeutically effective amount of a cinnamylidene-anabaseine.

94. The method according to claim 93, wherein the cinnamylidene-anabaseine is selected from the group consisting of 3-(4-acetylaminocinnamylidene) anabaseine, 3-(4-hydroxycinnamylidene) anabaseine, 3-(4-methoxycinnamylidene) anabaseine, 3-(4-hydroxy-2-methoxycinnamylidene)anabaseine, 3-(2,4-dimethoxycinnamylidene) anabaseine, and 3-(4-acetoxycinnamylidene) anabaseine.