Morphan and morphinan analogues, and methods of use

• US 9,416,137 B2
• Filed: 08/24/2015
• Issued: 08/16/2016
• 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, Daniel R., Eyerman, David J., Wynn, Thomas Andrew
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US14/833,334
• Publication Number:
  US 20150376197A1
• Time in Patent Office: 358 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 analogues 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 of Formula I:

2. The compound of claim 1, wherein R₁ is cyclobutyl.

3. The compound of claim 1, wherein R₂ is H.

4. The compound of claim 1, wherein one of R₃ or R₄, but not both, is hydroxyl, or alternatively, R₃ and R₄, together with the carbon atom to which they are attached, form C═

O.

5. 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.

6. The compound of claim 5, wherein the Emax is 15% to 35% in a GTPγ

S binding assay.

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

8. The compound of claim 7, having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.

9. 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.

10. The compound of claim 9, 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.

11. The compound of claim 9, wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.

15. 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.

16. The method of claim 15, wherein the depressive symptom is acute stress disorder, adjustment disorders with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar II disorder, borderline and personality disorder, cyclothymia and dysthymia, depression such as major depressive disorder (MDD) and treatment-resistant disorder (TRD), Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoid, post-traumatic stress disorder, seasonal affective disorder, self-injury separation, sleep disorder, substance-induced mood disorder, Tourette syndrome and tic disorder, and/or Trichotillomania.

17. The compound of claim 1, wherein substituted acyl is

12. 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 μ

opioid receptor agonist of Formula I;

13. 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 Formula I:

14. 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 Formula I: