Derivatives of venlafaxine and methods of preparing and using the same

• US 20040106576A1
• Filed: 11/25/2003
• Published: 06/03/2004
• Est. Priority Date: 04/06/1999
• Status: Active Grant

• Current Assignee: Sepracor Incorporated
• Original Assignee: Sepracor Incorporated
• Inventors: Jerussi, Thomas P., Bhongle, Nandkumar N., Senanayake, Chrisantha H.
• Granted Patent: US 8,269,040 B2
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 23/00 Anaesthetics
• 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 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• 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: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 215/64 : with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 217/74 : with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 233/18 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 255/36 : the carbon skeleton being further substituted by hydroxy groups
• CPC Class Codes: C07C 255/37 : the carbon skeleton being further substituted by etherified hydroxy groups
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids

Abstract

Methods of preparing, and compositions comprising, derivatives of venlafaxine are disclosed. Also disclosed are methods of treating and preventing diseases and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, Parkinson'"'"'s disease, epilepsy, cerebral function disorders, obesity and weight gain, incontinence, dementia and related disorders.

Claims

1. A pharmaceutical composition which comprises venlafaxine derivative, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, and a pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition of claim 1 wherein the venlafaxine derivative is selected from the group consisting of (±

)-O-desmethylvenlafaxine, (±

)-N-desmethylvenlafaxine, (±

)-N,O-didesmethylvenlafaxine, and (±

)-N,N-didesmethylvenlafaxine.

3. The pharmaceutical composition of claim 2 wherein the venlafaxine derivative is (±

)-O-desmethylvenlafaxine or (±

)-N,O-didesmethylvenlafaxine.

4. The pharmaceutical composition of claim 1 adapted for intravenous infusion, transdermal delivery, or oral delivery.

5. The pharmaceutical composition of claim 1 wherein the venlafaxine derivative comprises a hydrochloride salt thereof.

6. The pharmaceutical composition of claim 1 wherein said pharmaceutically acceptable excipient comprises lactose, croscarmellose sodium, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

7. The pharmaceutical composition of claim 1 wherein said pharmaceutical composition is substantially free of all mono- or di-saccharides.

8. The pharmaceutical composition of claim 7 wherein said pharmaceutical composition is lactose-free.

9. The pharmaceutical composition of claim 1 wherein the venlafaxine derivative is (±

)-O-desmethylvenlafaxine and the excipient comprises lactose.

10. The pharmaceutical composition of claim 9 wherein the excipient further comprises microcrystalline cellulose, pre-gelatinized starch, magnesium stearate, and croscarmellose sodium.

11. A pharmaceutical dosage form which comprises a therapeutically effective amount of venlafaxine derivative or a pharmaceutically acceptable salt, solvate, or clathrate thereof and a pharmaceutically acceptable carrier or excipient.

12. The dosage form of claim 11 wherein said dosage form is a tablet or a capsule.

13. The dosage form of claim 11 adapted for intravenous infusion, transdermal delivery, or oral delivery.

14. The dosage form of claim 13 wherein the therapeutically effective amount is from about 10 mg to about 1000 mg.

15. The dosage form of claim 14 wherein the therapeutically effective amount is from about 50 mg to about 500 mg.

16. The dosage form of claim 15 wherein the therapeutically effective amount is from about 75 mg to about 350 mg.

17. A method of preparing (±

)-N-desmethylvenlafaxine which comprises contacting a compound of Formula 5;

18. The method of claim 17 wherein the reductant is BH₃.Me₂S.

19. A method of preparing (±

)-N,N-didesmethylvenlafaxine which comprises contacting a compound of Formula 2;

20. The method of claim 19 wherein the reductant is CoCl₂/NaBH₄.

21. A method of preparing (±

)-O-desmethylvenlafaxine which comprises contacting (±

)-venlafaxine with lithium diphenylphosphide for a time and at a temperature sufficient to form (±

)-O-desmethylvenlafaxine.

22. Substantially pure (±

)-O-desmethylvenlafaxine and pharmaceutically acceptable salts, solvates, and clathrates thereof.

23. Substantially pure (±

)-N,O-didesmethylvenlafaxine and pharmaceutically acceptable salts, solvates, and clathrates thereof.

24. Substantially pure (±

)-O-desmethyl-N,N-didesmethylvenlafaxine and pharmaceutically acceptable salts, solvates, and clathrates thereof.

25. (±

)-N-desmethylvenlafaxine and pharmaceutically acceptable salts, solvates, and clathrates thereof.

26. (±

)-N,N-didesmethylvenlafaxine and pharmaceutically acceptable salts, solvates, and clathrates thereof.

27. A method of treating an affective disorder in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

28. The method of treating an affective disorder in a human according to claim 27 in which said amount of venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof, is sufficient to alleviate the affective disorder but insufficient to cause adverse effects associated with the administration of racemic venlafaxine.

29. The method of claim 27 wherein the affective disorder is selected from the group consisting of depression, attention deficit disorder, and attention deficit disorder with hyperactivity.

52. The method of claim 27 wherein the venlafaxine derivative is selected from the group consisting of (±

)-O-desmethylvenlafaxine, (±

)-N-desmethylvenlafaxine, (±

)-N,O-didesmethylvenlafaxine, and (±

)-N,N-didesmethylvenlafaxine.

53. The method of claim 52 wherein the venlafaxine derivative is (±

)-O-desmethylvenlafaxine or (±

)-N,O-didesmethylvenlafaxine.

54. The method of claim 27 wherein venlafaxine derivative is administered by intravenous infusion, transdermal delivery, or orally as a tablet or a capsule.

55. The method of claim 27 wherein the amount administered is from about 10 mg to about 1000 mg per day.

56. The method of claim 55 wherein the amount administered is from about 50 mg to about 500 mg per day.

57. The method of claim 56 wherein the amount administered is from about 75 mg to about 350 mg per day.

58. The method of claim 27 wherein the venlafaxine derivative, or a pharmaceutically acceptable salt thereof, is administered together with a pharmaceutically acceptable carrier.

59. The method of claim 27 wherein the venlafaxine derivative is administered as a hydrochloride salt.

30. A method for treating obesity or weight gain in a human which comprises administering to a human in need of a reduction or maintenance in weight, a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

31. The method for treating obesity or weight gain in a human according to claim 30 wherein said amount is sufficient to alleviate obesity or weight gain but insufficient to cause the adverse effects associated with administration of racemic venlafaxine.

33. The method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human according to claim 31 in which said amount is sufficient to alleviate said disorders but insufficient to cause adverse effects associated with administration of racemic venlafaxine.

32. A method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

34. The method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human according to claim 32 wherein said monoamine is dopamine.

35. The method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human according to claim 32 wherein said disorder is Parkinson'"'"'s disease or epilepsy.

37. The method for treating cerebral function disorders in a human according to claim 35 wherein said amount is sufficient to alleviate cerebral function disorders but insufficient to cause adverse effects associated with administration of racemic venlafaxine.

38. The method for treating cerebral function disorders in a human according to claim 35 wherein said disorder is caused by a cerebrovascular disease.

39. The method for treating cerebral function disorders in a human according to claim 38 wherein said cerebrovascular disease is selected from the group consisting of cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis and head injuries.

40. The method for treating cerebral function disorders in a human according to claim 35 wherein said cerebral function disorder is selected from the group consisting of senile dementia, Alzheimer'"'"'s type dementia, memory loss and amnesia/amnestic syndrome.

36. A method for treating cerebral function disorders in humans which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

41. A method for treating pain in humans which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt thereof, solvate or clathrate thereof.

42. The method for treating pain in a human according to claim 41 wherein said amount is sufficient to alleviate pain but insufficient to cause adverse effects associated with administration of racemic venlafaxine.

43. The method for treating pain in a human according to claim 41 wherein the pain is chronic pain.

44. A method of treating an obsessive-compulsive disorder in a human, which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

45. A method of treating substance abuse in a human, which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

46. A method of treating or preventing pre-menstrual syndrome in a human, which comprises administering to a human in need of such treatment or prevention a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

47. A method of treating anxiety in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

48. A method of treating an eating disorder in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

49. A method of treating or preventing migraine, or migraine headaches, in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

50. A method for treating or preventing incontinence in a human which comprises administering to a human in need of such treatment a therapeutically effective amount of a venlafaxine derivative, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

51. The method of claim 50 wherein said incontinence is selected from the group consisting fecal incontinence, overflow incontinence, passive incontinence, reflex incontinence, stress urinary incontinence, urge incontinence, urinary exertional incontinence, and incontinence of urine.