Morphan and morphinan analogues, and methods of use

• US 9,133,125 B2
• Filed: 05/23/2014
• Issued: 09/15/2015
• Est. Priority Date: 05/24/2013
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Blumberg, Laura Cook, Deaver, Dan, Eyerman, David
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US14/286,456
• Publication Number:
  US 20150045384A1
• Time in Patent Office: 480 Days
• Field of Search: 514/289, 546/74
• US Class Current: 1/1
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 221/26 Benzomorphans
• CPC Class Codes: C07D 221/28 Morphinans
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 489/00 : Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:

Abstract

The present application relates to analogs of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof.

Claims

1. A compound selected from

2. The compound of claim 1, wherein the compound is a μ

opioid receptor agonist having an Emax of 5% to 45% in a GTPγ

S binding assay.

3. The compound of claim 2, wherein the Emax is 15% to 35% in a GTPγ

S binding assay.

4. The compound of claim 1, having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over baseline in a rat.

5. The compound of claim 4, having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.

6. The compound of claim 1, wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.

7. The compound of claim 6, wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 3 mg/kg.

8. The compound of claim 6, wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.

9. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 2.

10. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 4.

11. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 6.

12. A method of treating a depressive symptom in a subject in need thereof, comprising administering to the subject the compound of claim 1, or a pharmaceutically acceptable salt thereof.

13. A compound having the following structural formula: