Nitric oxide releasing prodrugs of MDA and MDMA
Provided herein are compounds of Formula (I), Formula (II), and Formula (III) or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), Formula (II), or Formula (III) and methods of using a compound of Formula (I), Formula (II), or Formula (III), e.g., in the treatment of a mental health disease or disorder.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof; wherein,
R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 or —(C═O)(CR 9 R 9′ ) m —CH(NH 2 )CH 2 ONO 2 ;
R 2 is H, C 1 -C 4 alkyl, or CF 3 ;
R 3 and R 4 are independently H or F;
R 5 and R 6 are independently H, C 1 -C 6 alkyl, or CF 3 ;
R 7 is H or CH 3 ;
R 8 is H, C 1 -C 6 alkyl, or CF 3 ;
R 9 and R 9′ are independently H, halogen, or C 1 -C 6 alkyl;
X and Y are independently H, F, Cl, Br, or OR 8 ;
n is an integer from 1 to 9; and
m is an integer from 1 to 9.
2. The compound of claim 1 , wherein R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 .
3. The compound of claim 1 , wherein R 1 is —(C═O)(CR 9 R 9′ ) m — CH(NH 2 )CH 2 ONO 2 .
4. The compound of claim 1 , wherein R 1 is —(C═O)(CH 2 ) m —CH(NH 2 )CH 2 ONO 2 .
5. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl.
6. The compound of claim 1 , wherein R 2 is methyl.
7. The compound of claim 1 , wherein R 2 is CF 3 .
8. The compound of claim 1 , wherein R 3 and R 4 are H.
9. The compound of claim 1 , wherein R 3 and R 4 are F.
10. The compound of claim 1 , wherein R 5 and R 6 are H.
11. The compound of claim 1 , wherein R 5 and R 6 are C 1 -C 6 alkyl.
12. The compound of claim 1 , wherein R 5 and R 6 are CF 3 .
13. The compound of claim 1 , wherein R 7 is H.
14. The compound of claim 1 , wherein R 7 is CH 3 .
15. The compound of claim 1 , wherein X and Y are H.
16. The compound of claim 1 , wherein X and Y are F.
17. The compound of claim 1 , wherein m is 2.
18. The compound of claim 1 , wherein n is 3.
19. The compound of claim 1 , wherein n is 4.
20. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
21. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof; wherein,
R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 or —(C═O)(CR 9 R 9′ ) m —CH(NH 2 )CH 2 ONO 2 ;
R 2 is H, C 1 -C 4 alkyl, or CF 3 ;
R 3 and R 4 are independently H or F;
R 5 and R 6 are independently unsubstituted C 1 -C 6 alkyl, or CF 3 ;
R 7 is H or CH 3 ;
R 8 is H, C 1 -C 6 alkyl, or CF 3 ;
R 9 and R 9′ are independently H, halogen, or C 1 -C 6 alkyl;
X and Y are independently H, F, Cl, Br, or OR 8 ;
n is an integer from 1 to 9; and
m is an integer from 1 to 9.
22. The compound of claim 21 , wherein R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 .
23. The compound of claim 21 , wherein R 1 is —(C═O)(CR 9 R 9′ ) m — CH(NH 2 )CH 2 ONO 2 .
24. The compound of claim 21 , wherein R 1 is —(C═O)(CH 2 ) n —ONO 2 .
25. The compound of claim 21 , wherein R 1 is —(C═O)(CH 2 ) m — CH(NH 2 )CH 2 ONO 2 .
26. The compound of claim 21 , wherein R 2 is C 1 -C 4 alkyl.
27. The compound of claim 21 , wherein R 2 is methyl.
28. The compound of claim 21 , wherein R 2 is CF 3 .
29. The compound of claim 21 , wherein R 3 and R 4 are H.
30. The compound of claim 21 , wherein R 3 and R 4 are F.
31. The compound of claim 21 , wherein R 5 and R 6 are unsubstituted C 1 -C 6 alkyl.
32. The compound of claim 21 , wherein R 5 and R 6 are CF 3 .
33. The compound of claim 21 , wherein R 7 is H.
34. The compound of claim 21 , wherein R 7 is CH 3 .
35. The compound of claim 21 , wherein X and Y are H.
36. The compound of claim 21 , wherein X and Y are F.
37. The compound of claim 21 , wherein m is 2.
38. The compound of claim 21 , wherein n is 3.
39. The compound of claim 21 , wherein n is 4.
40. A compound of Formula (III):
or a pharmaceutically acceptable salt thereof; wherein,
A is
R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 or —(C═O)(CR 9 R 9′ ) m —CH(NH 2 )CH 2 ONO 2 ;
R 2 is H, C 1 -C 4 alkyl, or CF 3 ;
R 3 and R 4 are independently H or F;
R 7 is H or CH 3 ;
R 8 is H, C 1 -C 6 alkyl, or CF 3 ;
R 9 and R 9′ are independently H, halogen, or C 1 -C 6 alkyl;
X and Y are independently H, F, Cl, Br, or OR 8 ;
n is an integer from 1 to 9; and
m is an integer from 1 to 9.
41. The compound of claim 40 , wherein R 1 is —(C═O)(CR 9 R 9′ ) n —ONO 2 .
42. The compound of claim 40 , wherein R 1 is —(C═O)(CR 9 R 9′ ) m — CH(NH 2 )CH 2 ONO 2 .
43. The compound of claim 40 , wherein R 1 is —(C═O)(CH 2 ) n —ONO 2 .
44. The compound of claim 40 , wherein R 1 is —(C═O)(CH 2 ) m — CH(NH 2 )CH 2 ONO 2 .
45. The compound of claim 40 , wherein R 2 is C 1 -C 4 alkyl.
46. The compound of claim 40 , wherein R 2 is methyl.
47. The compound of claim 40 , wherein R 2 is CF 3 .
48. The compound of claim 40 , wherein R 3 and R 4 are H.
49. The compound of claim 40 , wherein R 3 and R 4 are F.
50. The compound of claim 40 , wherein R 7 is H.
51. The compound of claim 40 , wherein R 7 is CH 3 .
52. The compound of claim 40 , wherein X and Y are H.
53. The compound of claim 40 , wherein X and Y are F.
54. The compound of claim 40 , wherein m is 2.
55. The compound of claim 40 , wherein n is 3.
56. The compound of claim 40 , wherein n is 4.
57. The compound of claim 40 , wherein A is
58. The compound of claim 40 , wherein A is
59. The compound of claim 40 , wherein A is
60. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
61. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
62. A method of treating a mental health disease or disorder, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.