MORPHAN AND MORPHINAN ANALOGUES, AND METHODS OF USE

• US 20150376197A1
• Filed: 08/24/2015
• Published: 12/31/2015
• 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.
• Granted Patent: US 9,416,137 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 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.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein R₁ is cyclobutyl.

3. The compound of claim 1, wherein R₂ is H.

4. The compound of claim 1, wherein one of R₃ or R₄, but not both, is hydroxyl, or alternatively, R₃ and R₄, together with the carbon atom to which they are attached, form C═

O.

21. 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.

22. The compound of claim 21, wherein the Emax is 15% to 35% in a GTPγ

S binding assay.

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

25. The compound of claim 24, having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.

26. 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.

27. The compound of claim 26, 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.

28. The compound of claim 26, wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.

38. 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.

41. The method of claim 38, 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.

44. A method of treating a disease or condition associated with the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing, hyperalgesia, and drug addiction in a subject comprising administering to the subject a pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

46. A method of treating a disease or condition in a subject by altering a response mediated by an opioid receptor comprising bringing into contact with the opioid receptor an effective amount of the compound of claim 1.

48. The compound of claim 1, wherein substituted acyl is

5-20. -20. (canceled)

23. (canceled)

29. (canceled)

30. 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;

31. (canceled)

32. (canceled)

33. 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:

34. (canceled)

35. 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:

36. (canceled)

37. (canceled)

39. (canceled)

40. (canceled)

42. (canceled)

43. (canceled)

45. (canceled)

47. (canceled)