Organic compounds

Patent metadata

Field	Value
Publication number	US-12440489-B2
Application number	US-202318502460-A
Country	US
Kind code	B2
Filing date	Nov 6, 2023
Priority date	Jan 26, 2016
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The 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 the 5-HT2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D1 and D2 receptor signaling system, and/or the μ-opioid receptor.

First claim

What is claimed:

1. A method for the treatment of a central nervous system disorder, comprising administering to a patient in need of such treatment, a compound of a Formula I:

wherein:
X is —NH—;
L is O; and
Z is —O—;
in toluenesulfonic acid addition salt form;
wherein the central nervous system disorder is selected from the group consisting of obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), general anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit-hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, pain disorder, chronic fatigue, opiate dependency, cocaine dependency, amphetamine dependency, alcohol dependency, substance addiction, substance-use disorder, substance-abuse disorder, and combinations thereof;
wherein said patient is not responsive to or cannot tolerate the side effects from treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or antipsychotic agents.

2. The method according to claim 1 , wherein the compound is administered to the patient in the form of a pharmaceutically acceptable composition comprising the compound, in admixture with a pharmaceutically acceptable diluent or carrier.

3. The method of claim 2 , wherein the pharmaceutically acceptable diluent or carrier comprises a polymeric matrix.

4. The method according to claim 3 , wherein the polymeric matrix is a biodegradable poly(d,l-lactide-co-glycolide) microsphere.

5. The method according to claim 1 , wherein the central nervous system disorder is selected from the group consisting of obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), general anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit-hyperactivity disorder (ADHD), attention deficit disorder (ADD), and impulse control disorder.

6. The method according to claim 5 , wherein the central nervous system disorder is obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD).

7. The method according to claim 1 , wherein said patient is not responsive to or cannot tolerate the side effects from treatment with selective serotonin reuptake inhibitors (SSRIs).

8. The method according to claim 7 , wherein the selective serotonin reuptake inhibitor (SSRI) is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

9. The method according to claim 1 , wherein said patient is not responsive to or cannot tolerate the side effects from treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs).

10. The method according to claim 9 , wherein the serotonin-norepinephrine reuptake inhibitor (SNRI) is selected from the group consisting of venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.

11. The method according to claim 1 , wherein said patient is not responsive to or cannot tolerate the side effects from treatment with antipsychotic agents.

12. The method according to claim 11 , wherein the antipsychotic agent is selected from the group consisting of clomipramine, risperidone, quetiapine and olanzapine.

13. The method according to claim 1 , wherein the pain disorder is selected from the group consisting of neuropathic pain, idiopathic pain, chronic pain, and fibromyalgia.

14. The method according to claim 1 , wherein the central nervous system disorder is a substance addiction, a substance-use disorder, or a substance-induced disorder.

15. The method according to claim 14 , wherein the central nervous system disorder is selected from the group consisting of intoxication, withdrawal, substance-induced psychosis, substance-induced bipolar disorder, substance-induced depressive disorder, substance-induced anxiety disorder, substance-induced obsessive-compulsive disorder, substance-induced sleep disorder, substance-induced sexual dysfunction, substance-induced delirium, and substance-induced neurocognitive disorder.

16. The method according to claim 1 , wherein the patient is not responsive to or cannot tolerate the side effects of non-narcotic analgesics and/or opiate and opioid drugs, or wherein the use of opiate drugs are contraindicated in said patient, due to prior substance abuse or a high potential for substance abuse.

17. The method according to claim 16 , wherein said drugs are selected from the group consisting of morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanyl, trefantinil, brifentanil, remifentanil, ocfentanil, sufentanil, carfentanyl, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or any combinations thereof.

Assignees

• Intra Cellular Therapies Inc

Inventors

• Yao Wei
• Li Peng
• Davis Robert
• Mates Sharon
• Vanover Kimberly
• Snyder Gretchen

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D241/40

  Benzopyrazines · CPC title

• A61K45/00

  Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00 · CPC title

• A61K9/16

  Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)} · CPC title