Organic compounds

Patent metadata

Field	Value
Publication number	US-2020247806-A1
Application number	US-202016786240-A
Country	US
Kind code	A1
Filing date	Feb 10, 2020
Priority date	Apr 4, 2014
Publication date	Aug 6, 2020
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 sustained or delayed release pharmaceutical composition comprising the compound of formula I:

wherein:
R 1 is CH 3 ;
R 2 and R 3 are each D;
R 4 and R 5 are each H;
and wherein D is deuterium;

in free or salt form; in admixture with a pharmaceutically acceptable diluent or carrier.

2 . The composition according to claim 1 , wherein the compound of Formula I is dispersed or dissolved in a polymeric matrix.

3 . The composition according to claim 1 , wherein the polymeric matrix comprises polymers selected from polyesters of hydroxy fatty acids, alkyl alpha-cyanoacrylate polymers, polyalkylene oxalates, poly(ortho esters), polycarbonates, poly(ortho carbonates), poly(amino acids), hyaluronic acid esters, polylactides, polyglycolides, poly-lactide-co-glycolides, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxonones, poly(acetals), poly(lactic acid-caprolactones), poly(glycolic acid-caprolactones), polyanhydrides, albumin, casein, glycerol monostearate, glycerol distearate, and combinations thereof.

4 . The composition according to claim 2 , wherein the polymeric matrix comprises poly(d,l-lactide-co-glycolide).

5 . The composition according to claim 4 , wherein the polymeric matrix comprises PLGA 50:50, PLGA 75:35, PLGA 85:15, PLGA 90:10, or a combination thereof.

6 . The compound according to claim 2 , wherein the composition is formulated for administration by injection.

7 . The composition according to claim 1 , wherein the composition is formulated as an oral sustained or delayed release formulation.

8 . The composition according to claim 7 , wherein the composition comprises (a) a gelatin capsule containing the compound of Formula I in free or pharmaceutically acceptable salt form, (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule, (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer, and (c) an orifice formed or formable through the wall.

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

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

11 . The composition according to claim 7 , wherein the composition comprises a gelatin capsule containing a liquid comprising the compound of Formula I, wherein the gelatin capsule is surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semi-permeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall.

12 . The composition according to claim 7 , wherein the composition comprises a gelatin capsule containing a liquid comprising the compound of Formula I, wherein the gelatin capsule is surrounded by a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semi-permeable layer encompassing at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use.

13 . 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 the pharmaceutical composition according to claim 1 , wherein said disorder is selected from a group consisting of anxiety, depression, psychosis, schizophrenia, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.

14 . The method according to claim 13 , wherein said disorder is selected from anxiety, depression, psychosis and schizophrenia.

15 . The method according to claim 14 , wherein said disorder is schizophrenia.

16 . The method according to claim 15 , wherein the patient is suffering from residual symptoms of schizophrenia.

17 . The method according to claim 16 , wherein said residual phase symptoms are selected from negative symptoms such as 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; general psychopathology symptoms such as 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 14 , wherein said disorder is anxiety.

25 . The method according to claim 14 , wherein said disorder is depression.

26 . The method according to claim 25 , wherein said depression is bipolar disorder.

27 . The composition according to claim 7 , wherein the composition comprises (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprising the compound of Formula I in free or pharmaceutically acceptable salt form, and said second layer comprising a polymer, (b) an outer wall surrounding said two or more layers, and (c) an orifice in said outer wall.

Assignees

• Intra Cellular Therapies Inc

Inventors

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

Classifications

• A61P25/22

  Anxiolytics · CPC title

• A61P25/18

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/24

  Antidepressants · CPC title