Organic compounds

Patent metadata

Field	Value
Publication number	US-11376249-B2
Application number	US-201816634055-A
Country	US
Kind code	B2
Filing date	Jul 20, 2018
Priority date	Jul 26, 2017
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

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 thereof a compound of a Formula I:

wherein:
X is —NH—;
L is O;
Z is —O— or —C(O)—;
in free or salt form;
optionally in an isolated or purified free or salt form;
wherein the central nervous system disorder is (a) a pain disorder, and the patient also suffers from a gastrointestinal disorder and/or a pulmonary disorder, or (b) a pain disorder, wherein the pain disorder is traumatic pain and the patient also suffers from opioid use disorder.

2. The method according to claim 1 , wherein Z is —C(═O)—.

3. The method according to claim 1 , wherein Z is —O—.

4. The method according to claim 1 wherein the compound is in the form of a salt.

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

6. The method of claim 5 , wherein the pharmaceutically acceptable diluent or carrier comprises a polymeric matrix.

7. The method according to claim 6 , wherein the polymeric matrix is a biodegradable poly(d,l-lactide-co-glycolide) microsphere.

8. The method according to claim 1 , wherein said patient is not responsive to or cannot tolerate the side effects from non-narcotic analgesics and/or opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient.

9. The method according to claim 8 , wherein said patient is not responsive to or cannot tolerate the side effects from-opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient, and said opioid 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-methylfentantyl, alfentanyl, trefantinil, brifentanil, remifentanil, octfentanil, sufentanil, carfentanyl, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or any combinations thereof.

10. The method according to claim 1 , wherein the disorder is a pain disorder and the patient also suffers from a gastrointestinal disorder and/or a pulmonary disorder.

11. The method according to claim 10 wherein the pain disorder is selected from the group consisting of cephalic pain, idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, dental pain, and traumatic pain.

12. The method according to claim 11 , wherein the pain disorder is neuropathic pain or traumatic pain.

13. The method according to claim 10 , wherein the method further comprises the administration of an additional therapeutic agent selected from the group consisting of an agonist partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.

14. The method according to claim 13 , wherein said additional therapeutic agent is selected from the group consisting of naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, and norbinaltorphimine.

15. The method according to claim 1 , wherein the central nervous system disorder is a pain disorder, wherein the pain disorder is traumatic pain and said patient also suffers from opioid use disorder.

16. The method according to claim 15 , wherein the method further comprises administration of one or more additional therapeutic agents selected from the group consisting of an agonist, partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.

17. The method according to claim 16 , wherein said additional therapeutic agents are selected from the group consisting of buprenorphine, methadone, naloxone, and naltrexone.

18. The method according to claim 15 , wherein the method further comprises the administration of an additional therapeutic agent selected from the group consisting of an agonist, partial agonist, inverse agonist, and antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors.

19. The method according to claim 18 , wherein said additional therapeutic agent is selected from the group consisting of naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, and norbinaltorphimine.

Assignees

• Intra Cellular Therapies Inc

Inventors

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

Classifications

• A61P25/36

  Opioid-abuse · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/4985 Primary

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