Morphan and morphinan analogues, and methods of use

• US 10,287,250 B2
• Filed: 05/15/2017
• Issued: 05/14/2019
• 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, Deaver, Daniel R., Eyerman, David J., Wynn, Thomas Andrew
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US15/595,013
• Publication Number:
  US 20180016237A1
• Time in Patent Office: 729 Days
• Field of Search: 546 74, 514289
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 221/26 Benzomorphans
• CPC Class Codes: C07D 221/28 Morphinans
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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:

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.

Claims

1. A compound of Formula IV:

2. The compound of claim 1, wherein R₁ 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 R₂ is —

C(O)NH₂.

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

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 GTPγ

S 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 GTPγ

S binding assay.

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

S 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.