Kappa opioid receptor antagonists and products and methods related thereto
Compounds are provided that antagonize the kappa-opioid receptor (KOR) and products containing such compounds, as well as to methods of their use and synthesis. Such compounds have the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof: wherein X, Y, R 1 , R 2 , R 4 , R 5 R 6 , R 7 , R 8 and R 11 are as defined herein.
1. A method for treating a malcondition for which antagonizing the kappa opioid receptor (KOR) is medically indicated comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (XI), or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof:
wherein
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl;
R 4 is lower alkyl;
R 8 is halo or cyano;
R 5 and R 7 are both H; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
2. The method of claim 1 , wherein the compound having the structure of Formula (XI) is a compound having one of the following structures, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof:
3. The method of claim 1 , wherein the compound has the following structure, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope or salt thereof:
wherein
X is O when Y is N or X is N when Y is O;
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
4. A method for antagonizing the KOR, comprising contacting the KOR with an effective amount of a compound having the structure of Formula (XI), or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope or salt thereof, or a composition comprising the same:
wherein
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl;
R 4 is lower alkyl;
R 8 is halo or cyano;
R 5 and R 7 are both H; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
5. A method for reducing serum prolactin levels, comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (XI), or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition comprising the same:
wherein
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl;
R 4 is lower alkyl;
R 8 is halo or cyano;
R 5 and R 7 are both H; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
6. The method of claim 5 , wherein the subject has a neuropsychiatric or behavioral condition characterized by an elevation in serum prolactin.
7. The method of claim 1 , wherein the malcondition is a substance abuse or addiction disorder.
8. The method of claim 1 , wherein the malcondition is a CNS-related disorder.
9. The method of claim 1 , wherein the malcondition is an anxiety disorder.
10. The method of claim 9 , wherein the anxiety disorder is a social anxiety disorder.
11. The method of claim 9 , wherein the anxiety disorder is phobia.
12. The method of claim 9 , wherein the anxiety disorder is a stress-related disorder.
13. The method of claim 9 , wherein the anxiety disorder is PTS.
14. The method of claim 9 , wherein the anxiety disorder is GAD.
15. The method of claim 1 , wherein the malcondition is a depressive disorder.
16. The method of claim 15 , wherein the depressive disorder is major depression.
17. The method of claim 15 , wherein the depressive disorder is MDD.
18. The method of claim 1 , wherein the malcondition is a mood disorder.
19. The method of claim 18 , wherein the mood disorder is anhedonia.
20. The method of claim 18 , wherein the mood disorder is major depression.
21. The method of claim 18 , wherein the mood disorder is MDD.
22. The method of claim 1 , wherein the malcondition is schizophrenia or a schizoaffective disorder.
23. The method of claim 1 , wherein the malcondition is obesity or an eating disorder.
24. The method of claim 1 , wherein the malcondition is migraine.
25. The method of claim 24 , wherein the method for treating migraine is for migraine prophylaxis.
26. The method of claim 1 , wherein the malcondition is postnatal depression.
27. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 1, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
28. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 12, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
29. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 30, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
30. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 36, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
31. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 54, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
32. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 55, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
33. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 56, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
34. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 57, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
35. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 80, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
36. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 88, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
37. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 94, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
38. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 97, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
39. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 98, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
40. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 99, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
41. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 109, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
42. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 111, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
43. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 116, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
44. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 118, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
45. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 121, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
46. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 122, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
47. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 127, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
48. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 128, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
49. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 134, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
50. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 135, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
51. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 136, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
52. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 137, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
53. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 142, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
54. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 172, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
55. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 173, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
56. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 174, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
57. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 177, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
58. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 181, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
59. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 186, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
60. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 189, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
61. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 190, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
62. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 193, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
63. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 197, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
64. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 200, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
65. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 208, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
66. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 211, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
67. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 215, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
68. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 218, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
69. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 221, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
70. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 226, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
71. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 229, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
72. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 232, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
73. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 235, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
74. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 240, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
75. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 243, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
76. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 244, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
77. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 248, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
78. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 256, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
79. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 259, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
80. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 260, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
81. The method of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 265, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.