Morphan and morphinan analogues, and methods of use

Patent metadata

Field	Value
Publication number	US-9682936-B2
Application number	US-201615216061-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	May 24, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

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.

First claim

The invention claimed is:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, or alkoxyalkyl;
R 2 and R 3 are each C 1 -C 4 alkyl, or alternatively, R 2 and R 3 , together with the carbon atoms to which they are attached, form a 6-membered carbocyclic ring which is optionally substituted with a ketone, a hydroxyl, or a NR 5 R 6 group wherein R 5 and R 6 are each independently H, alkyl, or substituted acyl group;
when is a single bond, R 4 is H; and
when is a double bond, R 4 is O.

2. The compound of claim 1 , wherein R 1 is C 2 -C 6 alkenyl or cycloalkyl.

3. The compound of claim 1 , wherein R 2 and R 3 are each methyl.

4. The compound of claim 1 , wherein is a single bond, and R 4 is H.

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

or a pharmaceutically acceptable salt thereof.

6. 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.

7. The compound of claim 6 , wherein the Emax is 15% to 35% in a GTPγS binding assay.

8. The compound of claim 6 , wherein the agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.

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

10. The compound of claim 9 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.

11. 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.

12. The compound 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 3 mg/kg.

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

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

15. 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 μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.

16. 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 has a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.

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

18. 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.

19. The method of claim 18 , 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.

20. The method of claim 18 , wherein the depressive symptom is 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, psychomotor changes, self-injury separation, sleep disturbance, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, or Trichotillomania.

21. The method of claim 20 , 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.

22. The method of claim 18 , wherein the depressive symptom is depression.

23. The method of claim 18 , wherein the subject is a human.

24. The method of claim 22 , wherein the depression is major depressive disorder (MDD) or treatment-resistant disorder (TRD).

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

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/22

  Anxiolytics · CPC title