Methods for treating depressive symptoms

Patent metadata

Field	Value
Publication number	US-9656961-B2
Application number	US-201414286499-A
Country	US
Kind code	B2
Filing date	May 23, 2014
Priority date	May 24, 2013
Publication date	May 23, 2017
Grant date	May 23, 2017

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.

First claim

The invention claimed is:

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

or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl,

R 2 is H, hydroxyl, or methoxy; and
R 3 and R 4 are each, independently, H, hydroxyl, or NR 5 R 6 , wherein R 5 and R 6 are each independently H, alkyl or optionally substituted acyl, or alternatively, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 ;
wherein the depressive symptom is selected from the group consisting of depressed mood, loss of pleasure, post-partum depression, adjustment disorders with depressed mood, bereavement, bipolar I disorder, bipolar II disorder, cyclothymia, dysthymia, depression, dysthymic disorder, mixed mania, post-traumatic stress disorder, and seasonal affective disorder.

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

or a pharmaceutically acceptable salt thereof.

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

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

or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl,

R 2 is H, hydroxyl, or methoxy; and
R 3 and R 4 are each, independently, H, hydroxyl, or NR 5 R 6 , wherein R 5 and R 6 are each independently H, alkyl or optionally substituted acyl, or alternatively, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 ;
wherein the depressive symptom is selected from the group consisting of acute stress disorder, anxiety disorder, Asperger syndrome, attention deficit, borderline personality disorder, fatigue, hyperactivity disorder, impulse control disorder, loss of appetite, obsessive-compulsive personality disorder (OCD), paranoid disorder, psychomotor changes, self-injury disorder, separation disorder, sleep disturbance, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, and Trichotillomania.

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:

or a pharmaceutically acceptable salt thereof.

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

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

Assignees

• Alkermes Pharma Ireland Ltd

Inventors

• Blumberg Laura Cook
• Deaver Daniel R
• Eyerman David J
• Wynn Thomas Andrew

Classifications

• A61P25/24

  Antidepressants · CPC title

• A61K31/485 Primary

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

• C07D223/04

  with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D489/09

  containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems · CPC title

• C07D217/04

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title