Neuroactive steroids, compositions, and uses thereof
Described herein are steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 , and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, carbocyclyl, or —OR A ;
represents a single or double bond, wherein when one is a double bond, the other is a single bond;
wherein when the between —CR 6 and —CR 5a R 5b is a double bond, then one of R 5a or R 5b is absent; and
when one of the is a double bond, R 6 is absent;
each of R 5a and R 5b is independently absent, hydrogen, C 1- C 6 alkyl, or halo;
R 6 is absent or hydrogen;
Z is —CR 7a R 7b —, wherein each of R 7a and R 7b is independently hydrogen or C 1- C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1- C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1- C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring.
2. The compound of claim 1 , wherein R 1 is C 2- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, carbocyclyl, or heterocyclyl.
3. The compound of claim 1 , wherein R 1 is C 1- C 6 alkyl.
4. The compound of claim 3 , wherein R 1 is methyl.
5. The compound of claim 1 , wherein R 2a or R 2b is hydrogen.
6. The compound of claim 1 , wherein both R 2a and R 2b are hydrogen.
7. The compound of claim 1 , wherein R 1 is C 1- C 6 alkyl and both R 2a and R 2b are hydrogen.
8. The compound of claim 1 , wherein R 1 is methyl and R 2a or R 2b is hydrogen.
9. The compound of claim 7 , wherein R 1 is methyl and both R 2a and R 2b are hydrogen.
10. The compound of claim 1 , wherein R 3 is C 1- C 6 alkyl, carbocyclyl, heterocyclyl, or —C(O)NR B R C .
11. The compound of claim 10 , wherein R 3 is C 1- C 6 alkyl.
12. The compound of claim 1 , wherein R 1 is methyl and R 3 is C - C 6 alkyl.
13. The compound of claim 10 , wherein R 3 is heterocyclyl.
14. The compound of claim 1 , wherein R 1 is methyl and R 3 is heterocyclyl.
15. The compound of claim 10 , wherein R 3 is C(O)NR B R C .
16. The compound of claim 1 , wherein R 1 is methyl and R 3 is C(O)NR B R C .
17. The compound of claim 1 , wherein R 4 is C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, or carbocyclyl.
18. The compound of claim 1 , wherein R 4 is —OR A and R A is hydrogen or C 1- C 6 alkyl.
19. The compound of claim 1 , wherein R 4 is hydrogen, C 1- C 6 alkyl, or —OH.
20. The compound of claim 19 , wherein R 4 is —OH.
21. The compound of claim 19 , wherein R 4 is hydrogen.
22. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.
23. The compound of claim 1 , wherein R 1 is methyl, the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.
24. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.
25. The compound of claim 1 , wherein R 1 is methyl, the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.
26. The compound of claim 1 , wherein both R 2a and R 2b are hydrogen, the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.
27. The compound of claim 1 , wherein both R 2a and R 2b are hydrogen, the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.
28. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl or —OR A , the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.
29. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl or —OR A , the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.
30. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a double bond, one of R 5a or R 5b is hydrogen, and the other of R 5a or R 5b is absent.
31. The compound of claim 1 , wherein Z is —CH 2 —.
32. The compound of claim 1 , wherein R 7a is hydrogen and R 7b is C 1 -C 6 alkyl.
33. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or OR A ;
each of R 5a and R 5b is independently absent, hydrogen, C 1 -C 6 alkyl, or halo;
Z is —CR 7a R 7b —, wherein each of R 7a and R 7b is independently hydrogen or C 1 -C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; or
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
34. The compound of claim 33 , wherein R 1 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl.
35. The compound of claim 33 , wherein R 1 is C 1 -C 6 alkyl.
36. The compound of claim 35 , wherein R 1 is methyl.
37. The compound of claim 33 , wherein R 2a or R 2b is hydrogen.
38. The compound of claim 33 , wherein both R 2a and R 2b are hydrogen.
39. The compound of claim 33 , wherein R 1 is C 1 -C 6 alkyl and both R 2a and R 2b are hydrogen.
40. The compound of claim 33 , wherein R 1 is methyl and R 2a or R 2b is hydrogen.
41. The compound of claim 33 , wherein R 1 is methyl and both R 2a and R 2b are hydrogen.
42. The compound of claim 33 , wherein R 3 is C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, or —C(O)NR B R C .
43. The compound of claim 33 , wherein R 3 is C 1 -C 6 alkyl.
44. The compound of claim 33 , wherein R 1 is methyl and R 3 is C 1 -C 6 alkyl.
45. The compound of claim 33 , wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or carbocyclyl.
46. The compound of claim 33 , wherein R 4 is hydrogen, C 1 -C 6 alkyl, or —OH.
47. The compound of claim 46 , wherein R 4 is hydrogen.
48. The compound of claim 33 , wherein R 5a or R 5b is hydrogen.
49. The compound of claim 33 , wherein R 1 is methyl and R 5a or R 5b is hydrogen.
50. The compound of claim 33 , wherein both R 5a and R 5b are hydrogen.
51. The compound of claim 33 , wherein R 1 is methyl and both R 5a and R 5b are hydrogen.
52. The compound of claim 33 , wherein both R 2a and R 2b are hydrogen and R 5a or R 5b is hydrogen.
53. The compound of claim 33 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.
54. The compound of claim 33 , wherein R 4 is C 1 -C 6 alkyl and R 5a or R 5b is hydrogen.
55. The compound of claim 33 , wherein R 4 is C 1 -C 6 alkyl and both R 5a and R 5b are hydrogen.
56. The compound of claim 33 , wherein the compound of Formula (Ia) is selected from a group consisting of:
57. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or OR A ;
each of R 5a and R 5b is independently absent, hydrogen, C 1 -C 6 alkyl, or halo;
Z is —CR 7a R 7b —, wherein each of R 7a and R 7b is independently hydrogen or C 1 -C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; or
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
58. The compound of claim 57 , wherein R 1 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl.
59. The compound of claim 57 , wherein R 1 is C 1 -C 6 alkyl.
60. The compound of claim 59 , wherein R 1 is methyl.
61. The compound of claim 57 , wherein R 2a or R 2b is hydrogen.
62. The compound of claim 57 , wherein both R 2a and R 2b are hydrogen.
63. The compound of claim 57 , wherein R 1 is C 1 -C 6 alkyl and both R 2a and R 2b are hydrogen.
64. The compound of claim 57 , wherein R 1 is methyl and R 2a or R 2b is hydrogen.
65. The compound of claim 57 , wherein R 1 is methyl and both R 2a and R 2b are hydrogen.
66. The compound of claim 57 , wherein R 3 is C 1 -C 6 alkyl.
67. The compound of claim 57 , wherein R 1 is methyl and R 3 is C 1 -C 6 alkyl.
68. The compound of claim 57 , wherein R 3 is heterocyclyl.
69. The compound of claim 57 , wherein R 1 is methyl and R 3 is heterocyclyl.
70. The compound of claim 57 , wherein R 3 is C(O)NR B R C .
71. The compound of claim 57 , wherein R 1 is methyl and R 3 is C(O)NR B R C .
72. The compound of claim 57 , wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or carbocyclyl.
73. The compound of claim 57 , wherein R 4 is hydrogen, C 1 -C 6 alkyl, or hydroxyl.
74. The compound of claim 71 , wherein R 4 is —OH.
75. The compound of claim 71 , wherein R 4 is hydrogen.
76. The compound of claim 57 , wherein R 5a or R 5b is hydrogen.
77. The compound of claim 57 , wherein R 1 is methyl and R 5a or R 5b is hydrogen.
78. The compound of claim 57 , wherein both R 2a and R 5b are hydrogen.
79. The compound of claim 57 , wherein R 1 is methyl and both R 5a and R 5b are hydrogen.
80. The compound of claim 57 , wherein both R 2a and R 2b are hydrogen and R 5a or R 5b is hydrogen.
81. The compound of claim 57 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.
82. The compound of claim 57 , wherein R 4 is C 1 -C 6 alkyl and R 5a or R 5b is hydrogen.
83. The compound of claim 57 , wherein R 4 is C 1 -C 6 alkyl and both R 5a and R 5b are hydrogen.
84. The compound of claim 57 , wherein the compound of Formula (Ib) is selected from a group consisting of:
85. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable excipient.