(S)-N-Stereoisomers of 7,8-Saturated-4,5-Epoxy-Morphinanium Analogs

• US 20080207669A1
• Filed: 11/21/2007
• Published: 08/28/2008
• Est. Priority Date: 11/22/2006
• Status: Abandoned Application

• Current Assignee: Progenics Pharmaceuticals Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Progenics Pharmaceuticals Inc. (Lantheus Holdings, Inc.)
• Inventors: Han, Amy Qi, Perez, Julio, Rotshteyn, Yakov
• Application Number:
  US11/944,242
• Publication Number:
  US 20080207669A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 489/08 Oxygen atom

Abstract

Novel (S)-N-stereoisomers of 7,8-saturated-4,5-epoxy-morphinanium analogs are disclosed. Pharmaceutical compositions containing the (S)-N-stereoisomers of 7,8-saturated-4,5-epoxy-morphinanium analogs and methods for their pharmaceutical uses are also disclosed. Such analogs are disclosed as being useful in treating, among varying conditions, hypermotility of the gastrointestinal tract.

Claims

1. An isolated compound of the (S) configuration with respect to the nitrogen of Formula I(c):

2. An isolated compound of the (S) configuration with respect to the nitrogen of formula I:

3. The compound of Formula I according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the anion is a halide, sulfate, phosphate, nitrate, or anionic-charged organic species.

4. The compound of Formula (I) according to claim 3, or a pharmaceutically acceptable salt form or prodrug form thereof wherein the halide is bromide.

5. The compound of Formula (I) according to claim 3, or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the halide is iodide.

6. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, having at least 90% purity.

7. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, having at least 95% purity.

8. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, comprising a crystalline form.

9. The compound of Formula (I) according to claim 4, or a pharmaceutically acceptable salt form or prodrug form thereof, comprising a crystalline form.

10. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the S-configuration is 95% pure with respect to the quaternary nitrogen

11. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof;

wherein the S-configuration is 98% pure with respect to the quaternary nitrogen.

12. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the S-configuration is 99.5% pure with respect to the quaternary nitrogen.

13. The compound of Formula (I) according to claim 2, or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the S-configuration is 99.8% pure with respect to the quaternary nitrogen.

14. A composition comprising the compound according claim 2 or a pharmaceutically acceptable salt form or prodrug form thereof, wherein the S-configuration is 99.8% pure with respect to the quaternary nitrogen.

15. The composition of claim 14, wherein the composition is a solution.

16. The composition of claim 14, wherein the composition is a solid.

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 2, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 wherein the composition is an oral formulation.

19. The pharmaceutical composition of claim 17 wherein the composition is in a controlled release or sustained release formulation.

20. The pharmaceutical composition of claim 17, wherein the composition is a topical formulation.

21. The pharmaceutical composition of claim 17, wherein the composition is lyophilized.

22. The pharmaceutical composition of claim 17, wherein the composition is a suppository.

23. An inhaler containing the pharmaceutical composition of claim 17.

24. A nasal spray device containing the pharmaceutical composition of claim 17.

25. A pharmaceutical composition of claim 17, further comprising a therapeutic agent other than the compound of compound of claim 2.

26. The pharmaceutical composition of claim 25, wherein the therapeutic agent is an opioid agonist.

27. The pharmaceutical composition of claim 26, wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), saturatedcodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucuronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, tramadol, and combinations thereof.

28. The pharmaceutical composition of claim 26, wherein the opioid or opioid agonist has substantially no central nervous system (CNS) activity.

29. The pharmaceutical composition of claim 25, wherein the therapeutic agent is not an opioid, opioid agonist or an opioid antagonist.

30. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an non-opioid analgesic/anti-oyretic, antiviral agent, an antibiotic agent, an antifungal agent, antibacterial agent, antiseptic agent, anti-protozoal agent, anti-parasitic agent, an anti-inflammatory agent, a vasoconstrictor agent, a local anesthetic agent, an anti-diarrheal agent, an anti-hyperalgesia agent, or combinations thereof.

31. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an anti-diarrhea agent that is loperamide, loperamide analogs, N-oxides of loperamide and analogs, metabolites and prodrugs thereof, diphenoxylate, cisapride, antacids, aluminum hydroxide, magnesium aluminum silicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, polycarbophil, simethicone, hyoscyamine, atropine, furazolidone, difenoxin, octreotide, lansoprazole, kaolin, pectin, activated charcoal, sulphaguanidine, succinylsulphathiazole, phthalylsulphathiazole, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, bismuth subnitrate and bismuth subgallate, opium tincture (paregoric), herbal medicines, plant-derived anti-diarrheal agents or combinations thereof.

32. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an anti-inflammatory agent that is a non-steroidal anti-inflammatory drug (NSAID), a tumor necrosis factor inhibitor, basiliximab, daclizumab, infliximab, mycophenolate, mofetil, azothioprine, tacrolimus, steroids, sulfasalazine, olsalazine, mesalamine, or combinations thereof.

33. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an anti-viral agent.

34. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an anti-bacterial agent.

35. The pharmaceutical composition of claim 29, wherein the therapeutic agent is an anti-hyperalgesia agent.

36. A method for inhibiting diarrhea in a subject comprising administering to a subject in need of such treatment the pharmaceutical composition of claim 17 in an amount effective to treat or prevent the diarrhea.

37. The method of claim 36, further comprising administering to the subject an anti-diarrhea agent that is not (S)-N-stereoisomer of the compound of claim F.

38. The method of claim 37, wherein the anti-diarrhea agent that is not the (S)-N-stereoisomer of the compound of claim 2 is an opioid or an opioid agonist.

39. A method of reducing a volume of discharge from a ileostomy or colostomy in a subject comprising administering to the subject in need of such reduction the pharmaceutical composition of claim 17 in an amount effective to reduce the volume of discharge from the ileostomy or colostomy.

40. A method of reducing a rate of discharge from a ileostomy or colostomy in a subject comprising administering to the subject in need of such reduction the pharmaceutical composition of claim 17 in an amount effective to reduce the rate of discharge from the ileostomy or colostomy.

41. A method for inhibiting gastrointestinal motility in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition of claim 17 in an amount effective to inhibit gastrointestinal motility in the subject.

42. The method of claim 41 further comprising administering to the subject an opioid or an opioid agonist.

43. A method for treating irritable bowel syndrome comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 17, in an amount effective to ameliorate at least one symptom of the irritable bowel syndrome.

44. A method for inhibiting pain in a subject comprising administering the pharmaceutical composition of claim 17 in an amount sufficient to prevent or treat the pain.

45. The method of claim 44 further comprising administering to the subject a therapeutic agent other than the (S)-N-stereoisomer of the compound of claim 2 in the composition.

46. The method of claim 45, wherein the therapeutic agent other than (S)-N-stereoisomer of the compound of claim 2 in the composition is an opioid.

47. The method of claim 45, wherein the therapeutic agent other than (S)-N-stereoisomer of the compound of claim 2 in the composition is an antiviral agent, an antibiotic agent, an antifungal agent, antibacterial agent, antiseptic agent, anti-protozoal agent, anti-parasitic agent, an anti-inflammatory agent, a vasoconstrictor agent, a local anesthetic agent, an anti-diarrheal agent, or an anti-hyperalgesia agent.

48. The method of claim 44, wherein the pain is peripheral hyperalgesia.

49. The method of claim 44, wherein the pharmaceutical composition is administered locally to a site of the pain.

50. The method of claim 44, wherein the administration is intra-articular.

51. The method of claim 44, wherein the administration is systemic.

52. The method of claim 44, wherein the administration is topical.

53. The method of claim 44, wherein the composition is administered to the eye.

54. A method for inhibiting inflammation in a subject comprising administering to a subject in need thereof the pharmaceutical composition of claim 17 in an amount effective to inhibit the inflammation.

55. The method of claim 54 further comprising administering to the subject a therapeutic agent other than (S)-N-stereoisomer of the compound of claim 2 in the composition.

56. The method of claim 55 wherein the therapeutic agent other than (S)-N-stereoisomer of the compound of claim 2 is an anti-inflammatory agent.

57. A method of inhibiting production of tumor necrosis factor (TNF) in a subject, comprising administering to the subject a composition comprising TNF production-inhibitory amount of a pharmaceutical composition of claim 17.

58. A kit comprising a package containing a sealed container comprising the pharmaceutical composition of claim 17 and instructions for use.

59. The kit according to claim 58, further comprising a combination of compatible therapeutic agents wherein one of the therapeutic agents is a peripheral opioid antagonist.

60. The method of claim 17, wherein the peripheral opioid antagonist is the counterpart (R)-N-stereoisomer of the compound.

61. A composition comprising an (S) compound of claim 2, wherein the composition is free of HPLC detectable counterpart (R)-stereoisomer at a detection limit of 0.02% and at a quantitation limit of 0.05%.

62. An isolated compound of the (S) configuration with respect to the nitrogen of formula Ia:

63. An isolated compound of the (S) configuration with respect to the nitrogen of Formula Ib: