Morphan and morphinan analogues, and methods of use

Patent metadata

Field	Value
Publication number	US-10287250-B2
Application number	US-201715595013-A
Country	US
Kind code	B2
Filing date	May 15, 2017
Priority date	May 24, 2013
Publication date	May 14, 2019
Grant date	May 14, 2019

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.

First claim

The invention claimed is:

1. A compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclopropyl or cyclobutyl;
X is H, hydroxyl, or methoxy;
Y and Z are each, independently, H, hydroxyl, or NR 5 R 6 wherein R 5 and R 6 are each independently H, alkyl or substituted acyl, or alternatively, Y and Z, together with the carbon atom to which they are attached, form C═O or C═CH 2 ;
R 3 is H or hydroxyl; and
R 2 is —C(O)NH 2 , or —NH—CH 2 -phenyl, wherein the phenyl can be substituted.

2. The compound of claim 1 , wherein R 1 is cyclopropyl.

3. The compound of claim 1 , wherein X is H or hydroxyl.

4. The compound of claim 1 , wherein Y and Z are each, independently, H or hydroxyl, or alternatively, Y and Z, together with the carbon atom to which they are attached, form C═O.

5. The compound of claim 1 , wherein R 2 is —C(O)NH 2 .

6. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .

8. 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 1 , wherein the compound is a p opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.

9. The method of claim 8 , wherein said agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.

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 the compound of claim 1 having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.

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

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. The method of claim 12 , wherein the depressive symptom is depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, and/or post-partum depression.

14. The method of claim 12 , wherein the depressive symptom is acute stress disorder, anxiety disorder, Asperger syndrome, attention deficit, borderline personality disorder, major depressive disorder (MDD), treatment-resistant disorder (TRD), fatigue, hyperactivity disorder, impulse control disorder, loss of apetitie, obsessive-compulsive personality disorder (OCD), paranoid, psychomotor changes, self-injury separation, sleep disturbance, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, or Trichotillomania.

15. The method of claim 14 , wherein the depressive symptom is an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, agoraphobia, acute stress, and/or post-traumatic stress disorder.

16. The method of claim 12 , wherein the depressive symptom is associated with chronic or recurrent depression.

17. The compound of claim 1 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.

18. The compound of claim 17 , wherein the Emax is 15% to 35% in a GTPγS binding assay.

19. The compound of claim 17 , wherein the agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.

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

21. The compound of claim 20 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.

22. 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.

23. 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 3 mg/kg.

24. 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 10 mg/kg.

Assignees

• Alkermes Pharma Ireland Ltd

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/24

  Antidepressants · CPC title