Organic compounds

Patent metadata

Field	Value
Publication number	US-2025243201-A1
Application number	US-202519066829-A
Country	US
Kind code	A1
Filing date	Feb 28, 2025
Priority date	Apr 4, 2014
Publication date	Jul 31, 2025
Grant date	—

Abstract

This invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, 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-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms.

First claim

1 . A pharmaceutical composition comprising a compound of formula I:

wherein:
R 1 is CH 3 ;
R 2 and R 3 are each independently H or D;
R 4 and R 5 are each H;
provided that R 2 and R 3 are not both H,

and wherein D is deuterium;

in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier, wherein the compound has a diastereomeric excess of greater than 90%.

2 . (canceled)

3 . (canceled)

4 . (canceled)

5 . The composition according to claim 1 , wherein R 2 and R 3 are both D.

6 . (canceled)

7 . (canceled)

8 . The composition according to claim 1 , wherein R 2 is D and R 3 is H.

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

10 . The composition according to claim 9 , wherein the salt is selected from a group consisting of toluenesulfonic, fumaric and phosphoric acid addition salt.

11 . The compound composition according to claim 10 , wherein the salt is a toluenesulfonic acid addition salt.

12 . A method for the treatment or prophylaxis of a central nervous system disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 1 .

13 . The method according to claim 12 , wherein said disorder is selected from a group consisting of obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders (particularly sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual disorders, migraine, social phobias, agitation, agitation in dementia, agitation in autism and related autistic disorders, gastrointestinal disorders, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.

14 . The method according to claim 12 , wherein said disorder is one or more disorders associated with dementia, wherein said disorders associated with mild cognition impairment and dementing illnesses are selected from the group consisting of senile dementia, Alzheimer's disease, Pick's disease, fronto-temporal dementia, parasupranuclear palsy, dementia with Lewy bodies, vascular dementia, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoff's syndrome, cortico-basal degenerations and prion disease, autism, and attention deficit hyperactivity disorder.

15 . The method according to claim 12 , wherein said disorder is a disorder involving one of the serotonin 5-HT 2A , dopamine D2 and/or serotonin reuptake transporter (SERT) pathways.

16 . The method according to claim 12 , wherein the central nervous system disorder is residual symptoms of schizophrenia, delusional disorder, major depression with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophreniform disorder, or schizoaffective disorder.

17 . The method according to claim 12 , wherein said residual phase symptoms are selected from blunted affect, emotional withdrawal, poor rapport, passive or apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking; somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation and active social avoidance; cognitive impairment and sleep disorders.

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . (canceled)

24 . The method according to claim 13 , wherein the depression is refractory depression or major depressive disorder.

25 . The method according to claim 13 , wherein the agitation in dementia is agitation in Alzheimer's disease.

26 . A method for the treatment or prophylaxis of a central nervous system disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 11 .

27 . The method according to claim 24 , wherein said disorder is selected from a group consisting of obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, social phobias, agitation, agitation in dementia, agitation in autism and related autistic disorders, gastrointestinal disorders, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.

28 . The method according to claim 24 , wherein said disorder is one or more disorders associated with dementia, wherein said disorders associated with mild cognition impairment and dementing illnesses are selected from the group consisting of senile dementia, Alzheimer's disease, Pick's disease, fronto-temporal dementia, parasupranuclear palsy, dementia with Lewy bodies, vascular dementia, Huntington's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Down syndrome, elderly depression, Wernicke-Korsakoff's syndrome, cortico-basal degenerations and prion disease, autism, and attention deficit hyperactivity disorder.

29 . The method according to claim 24 , wherein said disorder is a disorder involving one of the serotonin 5-HT 2A , dopamine D2 and/or serotonin reuptake transporter (SERT) pathways.

30 . The method according to claim 24 , wherein the central nervous system disorder is residual symptoms of schizophrenia, delusional disorder, major depression with psychosis, bipolar disorder with psychotic symptoms, brief psychotic disorder, schizophreniform disorder, or schizoaffective disorder.

31 . The method according to claim 28 , wherein said residual phase symptoms are selected from blunted affect, emotional withdrawal, poor rapport, passive or apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation and stereotyped thinking; somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation and active social avoidance; cognitive impairment and sleep disorders.

32 . The method according to claim 27 , wherein the depression is refractory depression or major depressive disorder.

33 . The method according to claim 27 , wherein the agitation in dementia is agitation in Alzheimer's disease.

Assignees

• Intra Cellular Therapies Inc

Inventors

• Mates Sharon
• Li Peng
• Wennogle Lawrence P
• Davis Robert

Classifications

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/24

  Antidepressants · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title