Substituted pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalines for the treatment of nervous system disorders

Patent metadata

Field	Value
Publication number	US-9428506-B2
Application number	US-201314394467-A
Country	US
Kind code	B2
Filing date	Apr 14, 2013
Priority date	Apr 14, 2012
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

The invention relates to particular substituted heterocycle fused gamma-carbolines, of Formula I, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT 2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D 2 receptor signaling systems, such as disease of the central nervous system.

First claim

The invention claimed is:

1. A compound of formula I:

wherein:
X is N(H) or N(C 1-4 alkyl);
R 1 is H or C 1-6 alkyl;
R 2 is H or OR 3 , wherein R 3 is H or C 1-6 alkyl;
provided that R 1 and R 2 are not both H, and R 1 and R 3 are not both H;

in free base or pharmaceutically acceptable salt form.

2. The compound according to claim 1 , wherein R 2 is OR 3 .

3. The compound according to claim 2 , wherein R 1 is C 1-6 alkyl.

4. The compound according to claim 3 , wherein R 1 is CH 3 .

5. The compound according to claim 1 , wherein R 2 is OR 3 and R 3 is C 1-6 alkyl.

6. The compound according to claim 5 , wherein R 3 is CH 3 .

7. The compound according to claim 1 , wherein X is N(C 1-4 alkyl).

8. The compound according to claim 7 , wherein X is N(CH 3 ).

9. The compound according to claim 1 , wherein X is N(H).

10. The compound according to claim 1 , wherein said compound is in pharmaceutically acceptable salt form.

11. The compound according to claim 10 , wherein the pharmaceutically acceptable salt is selected from a group consisting of toluenesulfonic, fumaric and phosphoric acid addition salts.

12. The compound according to claim 1 , which is:

13. The compound according to claim 1 , which is:

14. A pharmaceutical composition comprising the compound according to claim 1 , in free base or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier.

15. The pharmaceutical composition according to claim 14 , further comprising a second therapeutic agent selected from a group consisting of an anti-depressant, an anti-psychotic, a hypnotic agent, and an agent for the treatment of Parkinson's disease, mood disorders or dementia.

16. A pharmaceutical composition comprising the compound according to claim 1 , in free base or pharmaceutically acceptable salt form, in a polymeric matrix.

17. The pharmaceutical composition according to claim 16 , wherein the compound is in the form of microparticles or nanoparticles.

18. The pharmaceutical composition according to claim 16 , wherein the polymeric matrix comprises poly(D,L-lactide-co-glycolide).

19. The pharmaceutical composition according to claim 18 , wherein the molar ratio of lactide to glycolide is 75:25.

20. A method for modulating 5-hydroxytryptamine receptor 2A activity in a patient and/or modulating serotonin transporter activity in a patient, comprising administering to a patient in need thereof an active amount of the compound according to claim 1 , in free base or pharmaceutically acceptable salt form.

21. The method according to claim 20 , wherein said patient suffers from a disorder selected from a group consisting of obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, agitation, gastrointestinal disorders, dysfunction of the gastrointestinal tract motility, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.

22. The method according to claim 20 , wherein said patient suffers from one or more disorders associated with dementia selected from a group consisting of one or more disorders associated with mild cognition impairment and dementing illnesses, one or more disorders associated with senile dementia, one or more disorders associated with Alzheimer's disease, one or more disorders associated with Pick's disease, one or more disorders associated with frontotemporal dementia, one or more disorders associated with parasupranculear palsy, one or more disorders associated with dementia with Lewy bodies, one or more disorders associated with vascular dementia, one or more disorders associated with Huntington's disease, one or more disorders associated with Parkinson's disease, one or more disorders associated with multiple sclerosis, one or more disorders associated with amyotrophic lateral sclerosis, one or more disorders associated with Down syndrome, one or more disorders associated with elderly depression, Wernicke-Korsakoff s syndrome, one or more disorders associated with corticobasal degenerations and one or more disorders associated with prion disease.

23. The method according to claim 20 , wherein said patient suffers from one or more disorders associated with dementia.

24. The method according to claim 20 , wherein said patient suffers from a disorder involving the serotonin 5-HT 2A receptor pathway, dopamine D2 receptor pathway and/or serotonin reuptake transporter pathway.

25. The method according to claim 20 , wherein said patient suffers from a disorder selected from a group consisting of agitation and aggressive behaviors.

26. The method according to claim 20 , wherein said patient suffers from one or more disorders selected from a group consisting of schizophrenia, depression, anxiety, sleep disorder, agitation, aggressive behaviors, post-traumatic stress disorder and impulse control disorder.

27. The method according to claim 26 , wherein said disorder is schizophrenia.

28. The method according to claim 26 , wherein said disorder is post-traumatic stress disorder.

29. The method according to claim 26 , wherein said disorder is impulse control disorder.

30. The method according to claim 29 , wherein said disorder is intermittent explosive disorder.

Assignees

• Intra Cellular Therapies Inc

Inventors

• Mates Sharon
• Davis Robert
• Li Peng
• Wennogle Lawrence
• Vanover Kimberly

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title