Substituted-quinoxaline-type piperidine compounds and the uses thereof

• US 8,846,929 B2
• Filed: 02/24/2010
• Issued: 09/30/2014
• Est. Priority Date: 08/31/2007
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P., Shionogi & Co., Ltd.
• Inventors: Fuchino, Kouki, Goehring, R. Richard, Shao, Bin, Taoda, Yoshiyuki, Tsuno, Naoki, Yao, Jiangchao, Whitehead, John William Frank
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): YANG, KAIPEEN E
• Application Number:
  US12/712,042
• Publication Number:
  US 20100216726A1
• Time in Patent Office: 1,679 Days
• Field of Search: None
• US Class Current: 546/184
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/04 : with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/14 : containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to Substituted-Quinoxaline-Type Piperidine Compounds, compositions comprising an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted-Quinoxaline-Type Piperidine Compound.

Claims

1. A compound of Formula (I) or (II):

2. The compound of claim 1, wherein the compound is a compound of Formula (II):

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y₁ is O.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the dashed line is present as a bond in a double bond and only one R₄ is present.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo, fused pyridino, fused pyrimidino, fused pyrazino, or fused pyridazino.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo or fused pyridino.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein a is 0.

9. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A and B are each —

H.

10. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A and B together form a bridge such that the bridged-piperidine is:

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein A and B together form a bridge such that the bridged-piperidine is:

12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the 6- membered, nitrogen-containing ring that is fused to the Q group is in the endo configuration with respect to the A-B bridge of the bridged-piperidine.

13. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein each R_z is independently —

H or —

CH₃.

15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein each R_z is independently —

H or —

CH₃.

17. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

18. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the R₁ group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is radiolabeled.

20. The compound of claim 1, wherein the pharmaceutically acceptable salt is a HCl-salt, a sodium-salt, or a potassium-salt.

21. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

22. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.

72. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -(5- or 6-membered)heterocycle optionally substituted with 1, 2 or 3 independently selected R₈ groups.

73. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein there is one R₈ group which is —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉.

74. The compound of claim 73 or a pharmaceutically acceptable salt thereof, wherein the R₉ attached to the R₈ nitrogen atom is (C₁-C₆)alkyl and the R₉ attached to the R₈ oxygen atom is H.

75. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -(5- or 6-membered)heterocycle optionally substituted with 1, 2 or 3 independently selected R₈ groups.

76. The compound of claim 75 or a pharmaceutically acceptable salt thereof, wherein there is one R₈ group which is —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉.

77. The compound of claim 76 or a pharmaceutically acceptable salt thereof, wherein the R₉ attached to the R₈ nitrogen atom is (C₁-C₆)alkyl and the R₉ attached to the R₈ oxygen atom is H.

78. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is optionally substituted cyclooctyl.

79. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is optionally substituted —

(C₆-C₁₄)bicycloalkyl.

96. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each Y is S.

99. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A-B together form a —

CH₂—

O—

CH₂—

bridge.

101. The compound of claim 2, wherein the pharmaceutically acceptable salt is a HC1-salt, a sodium-salt, or a potassium-salt.

104. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 2 and a pharmaceutically acceptable carrier or excipient.

108. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 2.

23. A compound of Formula (I) or (II):

24. The compound of claim 23, wherein the compound is a compound of Formula (II):

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein Y₁ is O.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the dashed line is present as a bond in a double bond and only one R₄ is present.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo, fused pyridino, fused pyrimidino, fused pyrazino, or fused pyridazino.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo or fused pyridino.

29. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein Q is fused benzo.

30. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein a is 0.

31. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is:

(a) —

C(═

Y)YX;

or

(b) —

N(R₉)X.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein X of —

N(R₉)X is —

(C₁-C₆)alkyl substituted with one R₈ group, -(5- or 6-membered)heterocycle substituted with one R₈ group, -phenyl substituted with one R₇ group, or -(5- or 6-membered)heteroaryl substituted with one R₇ group.

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein each R₇ or R₈ is —

C(═

O)OR₉.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein each R₉ of the R₇ or R₈—

C(═

O)OR₉ is —

H.

35. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is —

N(H)X and X is a -(5- or 6-membered)heterocycle substituted with one R₈ group.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein the R₈ group is —

C(═

O)OR₉.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the R₈ group is —

COOH.

38. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is —

N(H)X, X is —

(C₁-C₆)alkyl substituted with one R₈ group, and the R₈ group is —

C(═

O)OR₉.

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein the R₈ group is —

COOH.

40. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is -(5- or 6-membered)heterocycle-X and X is phenyl or -(5- or 6-membered)heteroaryl, each of which is substituted with one R₇ group.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein the R₇ group is —

C(═

O)OR₉.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R₉ of the R₇—

C(═

O)OR₉ group is —

H.

43. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X and X is phenyl or -(5- or 6-membered)heteroaryl, each of which is substituted with one R₇ group.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein the R₇ group is —

C(═

O)OR₉.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R₉ of the R₇—

C(═

O)OR₉ group is —

H.

46. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -(5- or 6-membered)heterocycle or -(5- or 6-membered)heteroaryl, each of which is optionally substituted with —

C(═

O)OR₉.

47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein the R₉ of the —

C(═

O)OR₉ group is —

H.

48. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -tetrazolyl.

49. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A and B are independently —

H or —

(C₁-C₆)alkyl.

50. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein A and B are each —

H.

51. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A and B together form a bridge such that the bridged-piperidine is:

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein A and B together form a bridge such that the bridged-piperidine is:

53. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein the 6-membered, nitrogen-containing ring that is fused to the Q group is in the endo configuration with respect to the A-B bridge of the bridged-piperidine.

54. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is —

(C₁-C₁₀)alkyl, —

(C₂-C₁₀)alkenyl, —

(C₂-C₁₀)alkynyl, —

(C₃-C₁₄)cycloalkyl, —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R₈ groups.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R₁ is —

(C₃-C₁₄)cycloalkyl, —

(C₃-C₁₄)cycloalkenyl, —

(C₆-C₁₄)bicycloalkyl, —

(C₇-C₁₄)bicycloalkenyl, or —

(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R₈ groups.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein R₁ is:

57. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein each R_z is independently —

H or —

CH₃.

59. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein each R_z is independently —

H or —

CH₃.

61. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is:

62. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein a is 1 and R₂ is -halo.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein the R₂ -halo is —

F.

64. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein the R₁ group is in the exo-configuration with respect to the A-B bridge of the bridged piperidine.

65. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein —

Z—

R₁ is;

(a) (C₆-C₁₂)cycloalkyl;

or

(b) (C₆-C₁₂)cycloalkenyl;

or

(c)

66. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein the —

Z—

R₁ (C₆-C₁₂)cycloalkyl is cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, or cyclododecyl.

67. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein the —

Z—

R₁ (C₆-C₁₂)cycloalkenyl is cyclohexenyl, cycloheptenyl, or cyclooctenyl.

68. The compound of claim 23 or a pharmaceutically acceptable salt thereof, which is radiolabeled.

69. The compound of claim 23, wherein the pharmaceutically acceptable salt is a HCl-salt, a sodium-salt, or a potassium-salt.

70. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 23 and a pharmaceutically acceptable carrier or excipient.

71. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 23.

80. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -(5- or 6-membered)heterocycle optionally substituted with 1, 2 or 3 independently selected R₈ groups.

81. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein there is one R₈ group which is —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉.

82. The compound of claim 81 or a pharmaceutically acceptable salt thereof, wherein the R₉ attached to the R₈ nitrogen atom is (C₁-C₆)alkyl and the R₉ attached to the R₈ oxygen atom is H.

83. The compound of claim 52 or a pharmaceutically acceptable salt thereof, wherein R₄ is X and X is -(5- or 6-membered)heterocycle optionally substituted with 1, 2 or 3 independently selected R₈ groups.

84. The compound of claim 83 or a pharmaceutically acceptable salt thereof, wherein there is one R₈ group which is —

N(R₉)(C₁-C₆)alkyl-C(═

O)OR₉.

85. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein the R₉ attached to the R₈ nitrogen atom is (C₁-C₆)alkyl and the R₉ attached to the R₈ oxygen atom is H.

86. The compound of claim 85 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is optionally substituted cyclooctyl.

87. The compound of claim 85 or a pharmaceutically acceptable salt thereof, wherein h is 0 and R₁ is optionally substituted —

(C₆-C₁₄)bicycloalkyl.

97. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein each Y is S.

100. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein A-B together form a —

CH₂—

O—

CH₂—

bridge.

102. The compound of claim 28, wherein the pharmaceutically acceptable salt is a HC1-salt, a sodium-salt, or a potassium-salt.

105. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 28 and a pharmaceutically acceptable carrier or excipient.

109. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 28.

88. A compound of Formula (IIa):

89. The compound of claim 88, wherein the compound is a compound of Formula (IIb) or (IIc):

90. The compound of claim 88 or a pharmaceutically acceptable salt thereof, wherein a is 0.

91. The compound of claim 88, wherein the pharmaceutically acceptable salt is a HCl-salt, a sodium-salt, or a potassium-salt.

92. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 88 and a pharmaceutically acceptable carrier or excipient.

93. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 88.

98. The compound of claim 88 or a pharmaceutically acceptable salt thereof, wherein each Y is S.

103. The compound of claim 89, wherein the pharmaceutically acceptable salt is a HC1-salt, a sodium-salt, or a potassium-salt.

106. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 89 and a pharmaceutically acceptable carrier or excipient.

110. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 89.

94. A compound which is:

95. The compound of claim 94, wherein the pharmaceutically acceptable salt is a HCl-salt, a sodium-salt, or a potassium-salt.

107. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 94 and a pharmaceutically acceptable carrier or excipient.

111. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 95.