Morphan and morphinan analogues, and methods of use

Patent metadata

Field	Value
Publication number	US-9416137-B2
Application number	US-201514833334-A
Country	US
Kind code	B2
Filing date	Aug 24, 2015
Priority date	May 24, 2013
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

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 I:

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

R 2 is H 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 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 .

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

3. The compound of claim 1 , wherein R 2 is H.

4. The compound of claim 1 , wherein one of R 3 or R 4 , but not both, is hydroxyl, or alternatively, R 3 and R 4 , 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 GTPγS binding assay.

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

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:

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

R 2 is H 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 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 μ opioid receptor agonist exhibits an Emax of 5% to 45% in a GTPγS binding assay.

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:

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

R 2 is H 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 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 compound has a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.

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:

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

R 2 is H 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 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 compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 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

wherein R 11 is linear or branched C 1 -C 6 alkyl; R 12 is halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and R 13 is aryl or heteroaryl.

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

• A61P3/02

  Nutrients, e.g. vitamins, minerals · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title