Methods for treating depressive symptoms

• US 9,656,961 B2
• Filed: 05/23/2014
• Issued: 05/23/2017
• 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, Eyerman, David J., Wynn, Thomas Andrew, Deaver, Daniel R.
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US14/286,499
• Publication Number:
  US 20150072971A1
• Time in Patent Office: 1,096 Days
• Field of Search: 514289
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 221/22 Bridged ring systems
• CPC Class Codes: C07D 221/28 Morphinans
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• 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:
• CPC Class Codes: C07D 489/09 containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems

Abstract

The present application relates methods for treating a depressive symptom comprising administering an effective amount of a μ opioid receptor agonist or a pharmaceutically acceptable salt thereof to a subject in need thereof. Non-limiting examples of such agonist include the compounds of Formulas I, II, III, and IV, as well as the compounds of Table A.

Claims

1. A method of treating a depressive symptom in a subject comprising administering to the subject a compound of Formula I:

2. The method according to claim 1, wherein the compound of Formula I is:

3. The method of claim 1, wherein the compound of Formula I exhibits an Emax of 5% to 45% in a GTPγ

S binding assay.

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

S binding assay.

5. The method of claim 3, wherein the compound of Formula I has a low risk of opioid dependence, opioid addiction, or symptoms of opioid withdrawal.

6. The method of claim 1, wherein the compound of Formula I exhibits a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.

7. The method 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.

8. The method of claim 1, wherein the depressive symptom is depressed mood, loss of pleasure, or post-partum depression.

9. The method of claim 1, wherein the depressive symptom is depression.

10. The method of claim 9, wherein the depression is major depressive disorder (MDD) or treatment-resistant disorder (TRD).

11. A method of treating a depressive symptom in a subject comprising administering to the subject a compound of Formula I:

12. The method of claim 11, wherein the depressive symptom is acute stress disorder, Asperger syndrome, attention deficit, borderline personality disorder, hyperactivity disorder, impulse control disorder, obsessive-compulsive personality disorder (OCD), paranoid disorder, self-injury disorder, separation disorder, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, or Trichotillomania.

13. The method of claim 11, wherein the depressive symptom is an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, agoraphobia, acute stress, or post-traumatic stress disorder.

14. The method according to claim 11, wherein the compound of Formula I is:

15. The method of claim 11, wherein the compound of Formula I exhibits an Emax of 5% to 45% in a GTPγ

S binding assay.

16. The method of claim 15, wherein the Emax is 15% to 35% in a GTPγ

S binding assay.

17. The method of claim 15, wherein the compound of Formula I has a low risk of opioid dependence, opioid addiction, or symptoms of opioid withdrawal.

18. The method of claim 11, wherein the compound of Formula I exhibits a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.

19. The method of claim 11, 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.