Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide
Treatment of CNS disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful.
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula PQ:
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition according to claim 1 , of formula P or Q:
or a pharmacuetically acceptable salt thereof.
3. A pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine according or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 1 to 4 .
6. A tablet or capsule according to any claims 1 to 4 .
7. A method for treating CNS disorders in a human, the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of:
(a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(c) a mixture of P and Q; or
(d) a pharmaceutically acceptable salt thereof.
8. The method according to claim 7 , wherein the CNS disorder is a mood disorder.
9. The method according to claim 8 , wherein the mood disorder is depression.
10. The method according to claim 7 , wherein the CNS disorder is and anxiety-related disorder.
11. The method according to claim 10 , wherein the anxiety-related disorder is obsessive compulsive disorder.
12. The method according to claim 7 , wherein the CNS disorder is a disruptive behavior disorder.
13. The method according to claim 12 , wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit/hyperactivity disorder (ADHD).
14. The method according to claim 7 , wherein the CNS disorder is a sexual dysfunction.
15. The method according to claim 7 , wherein the CNS disorder is a substance abuse disorder.
16. The method according to claim 7 , wherein the CNS disorder is an eating disorder.
17. A method according to claim 7 , wherein the CNS disorder is premenstrual syndrome disorder.
18. A method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of a compound chosen from:
(a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(c) a mixture of P and Q; and
(d) a pharmaceutically acceptable salt thereof.
19. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
(a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(c) a mixture of P and Q; or
(d) a pharmaceutically acceptable salt thereof, together with
(e) a therapeutically effective amount of a D 2 antagonist, or a pharmaceutically acceptable salt thereof.
20. The method according to claim 19 , wherein the D 2 antagonist is olanzapine.
21. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
(a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(c) a mixture of P and Q; or
(d) a pharmaceutically acceptable salt thereof, together with
(e) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof.
22. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, the process comprising:
(a) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide; and
(b) hydrolyzing the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthalen-1-yl]formamide with aqueous acid, yielding 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine.
23. A compound of formula:
24. A compound according to claim 23 , of formula E:
25. A compound according to claim 23 , of formula F:
26. A compound according to claim 23 , of formula A, B, C, or D:
27. (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to claim 23 .
28. (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to claim 23 .
29. (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to claim 23 .
30. (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to claim 23 .
31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 23 to 30 .
32. A tablet or capsule according to claim 31 .
33. A method for treating CNS disorders in a human, the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
34. A method according to claim 33 , the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of:
(a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(e) a mixture of A and B;
(f) a mixture of C and D; or
(g) a pharmaceutically acceptable salt thereof.
35. The method according to claim 33 , wherein the CNS disorder is a mood disorder.
36. The method according to claim 35 , wherein the mood disorder is depression.
37. The method according to claim 33 , wherein the CNS disorder is anxiety-related disorder.
38. The method according to claim 37 , wherein the anxiety-related disorder is obsessive compulsive disorder.
39. The method according to claim 33 , wherein the CNS disorder is a disruptive behavior disorder.
40. The method according to claim 39 , wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit/hyperactivity disorder (ADHD).
41. The method according to claim 33 , wherein the CNS disorder is a sexual dysfunction.
42. The method according to claim 33 , wherein the CNS disorder is a substance abuse disorder.
43. The method according to claim 33 , wherein the CNS disorder is an eating disorder.
44. A method according to claim 33 , wherein the CNS disorder is premenstrual syndrome disorder.
45. A method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
46. A method according to claim 45 , the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of a compound chosen from:
(a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(e) a mixture of A and B;
(f) a mixture of C and D; or
(g) a pharmaceutically acceptable salt thereof.
47. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
48. A method according to claim 47 , the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
(a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(e) a mixture of A and B;
(f) a mixture of C and D; or
(g) a pharmaceutically acceptable salt thereof, together with
(h) a therapeutically effective amount of a D 2 antagonist, or a pharmaceutically acceptable salt thereof.
49. The method according to claim 48 , wherein the D 2 antagonist is olanzapine.
50. A method according to claim 47 , the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
(a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide
(e) a mixture of A and B;
(f) a mixture of C and D; or
(g) a pharmaceutically acceptable salt thereof, together with
(h) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof.
51. A process for preparing N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
52. The process according to claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is of the (S) configuration and the N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1yl]formamide is a 1:1 mixture of(1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
53. The process according to claim 52 , further comprising separating the (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
54. The process according to claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is of the (R) configuration and the N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide is a 1:1 mixture of (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
55. The process according to claim 54 , further comprising separating the (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.
56. The process according to claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is racemic and the process further comprises separating the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide into cis N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and trans N-[4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydronaphthalen-1-yl]formamide.