NOVEL DICARBOXYLIC ACID LINKED AMINO ACID AND PEPTIDE PRODRUGS OF OPIOIDS AND USES THEREOF

• US 20100286186A1
• Filed: 04/01/2010
• Published: 11/11/2010
• Est. Priority Date: 04/02/2009
• Status: Abandoned Application

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Franklin, Richard, Golding, Bernard T., Tyson, Robert G.
• Application Number:
  US12/753,042
• Publication Number:
  US 20100286186A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Abstract

The present invention concerns dicarboxylic acid linked amino acid and peptide prodrugs of opioid analgesics and pharmaceutical compositions containing such prodrugs. Methods for providing pain relief, decreasing the adverse GI side effects of the opioid analgesic and increasing the bioavailability of the opioid analgesic with the aforementioned prodrugs are also provided. In one embodiment, prodrugs having the amino acid side chains of valine, leucine, isoleucine and glycine; and mono-, di- and tripeptides thereof are provided.

Claims

1. An oxycodone prodrug having the structure:

2. The oxycodone prodrug of claim 1 wherein n₁ is an integer selected from 0 to 4.

3. The oxycodone prodrug of claim 1 wherein R₂ is

4. The oxycodone prodrug of claim 1 wherein X is absent and n₁ is 1, 2 or 3.

5. The oxycodone prodrug of claim 1 wherein R₁ is

6. The oxycodone prodrug of claim 5 wherein n₁ is 2.

7. The oxycodone prodrug of claim 1 wherein R₂ is

8. The oxycodone prodrug of claim 7 wherein n₁ is 2.

9. The oxycodone prodrug of claim 1 wherein R₁ is

10. The oxycodone prodrug of claim 9 wherein n₁ is 2.

11. The oxycodone prodrug of claim 1 wherein R₂ is

12. The oxycodone prodrug of claim 11 wherein n₁ is 2.

13. The oxycodone prodrug of claim 1 wherein X is —

O—

, n₁ is 0, 1 or 2, n₂ is 1 or 2 and R₅ is H.

14. The oxycodone prodrug of claim 13 wherein n₁ is 2 and R₁ is

15. The oxycodone prodrug of claim 1 wherein X is —

NH—

, n₁ is 0, 1 or 2, n₂ is 1 or 2 and R₅ is H.

16. The oxycodone prodrug of claim 15 wherein n₁ is 2 and R₁ is

17. The oxycodone prodrug of claim 1 wherein n₁ is 1 or 2, n₂ is 1, 2 or 3, and R₅ is H.

18. The oxycodone prodrug of claim 1 wherein n₂ is 1, 2 or 3, and R₃, R₄ and R₅ are H.

19. The oxycodone prodrug of claim 18 wherein n₂ is 1.

20. The oxycodone prodrug of claim 18 wherein n₂ is 2.

21. The oxycodone prodrug of claim 18 wherein n₂ is 1 or 2 and each occurrence of R_AA is independently a proteinogenic amino acid side chain.

22. The oxycodone prodrug of claim 1 wherein X is —

O—

, n₁ is 1, 2, 3 or 4, n₂ is 1, or 3 and R₅ is H.

23. The oxycodone prodrug of claim 22 wherein at least one occurrence of R₃ is methyl.

24. The oxycodone prodrug of claim 1 wherein X is —

NH—

, n₁ is 0, 1 or 2, n₂ is 1 or 2 and R₅ is H.

25. The oxycodone prodrug of claim 1 wherein X is —

NH—

, n₁ is 1, 2, 3 or 4, n₂ is 1, 2 or 3 and R₅ is H.

26. The oxycodone prodrug of claim 25 wherein at least one occurrence of R₃ is methyl.

27. The oxycodone prodrug of claim 1 wherein X is absent, n₁ is 2, one occurrence of R₃ is —

CH₃, and one occurrence of R₄ is —

CH₃.

28. The oxycodone prodrug of claim 27 wherein R₅ is hydrogen.

29. The oxycodone prodrug of claim 27 wherein the one occurrence of R₃ and R₄ groups that are methyl occur on the same carbon atom.

30. The oxycodone prodrug of claim 1 wherein X is absent, n₁ is 2, and one occurrence of R₃ or R₄ is —

CH₃.

31. The oxycodone prodrug of claim 30 wherein R₅ is hydrogen.

32. The oxycodone prodrug of claim 1 wherein X is absent, n₁ is 3, one occurrence of R₃ is —

CH₃, and one occurrence of R₄ is —

CH₃.

33. The oxycodone prodrug of claim 32 wherein R₅ is hydrogen.

34. The oxycodone prodrug of claim 32 wherein the one occurrence of R₃ and R₄ groups that are methyl occur on the same carbon.

35. The oxycodone prodrug of claim 1 wherein X is absent, n₁ is 2, and one occurrence of R₃ or R₄ is

36. The oxycodone prodrug of claim 35 wherein R₅ is hydrogen.

37. The oxycodone prodrug of claim 1 wherein R_AA is the side chain of an amino acid selected from the group consisting of valine, leucine and isoleucine.

38. Oxycodone-[succinyl-valine] enol ester.

39. The composition of claim 38 comprising oxycodone-[succinyl-(S)-valine] enol ester.

40. The composition of claim 38 comprising oxycodone-[succinyl-(R)-valine] enol ester.

41. A pharmaceutical composition comprising oxycodone-[succinyl-valine] enol ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

42. Oxycodone succinyl-leucine enol ester.

43. The composition of claim 42 comprising oxycodone-[succinyl-(S)-leucine] enol ester.

44. The composition of claim 42 comprising oxycodone-[succinyl-(R)-leucine] enol ester.

45. A pharmaceutical composition comprising oxycodone-[succinyl-leucine] enol ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

46. Oxycodone-[glutaryl-valine] enol ester.

47. The composition of claim 46 comprising oxycodone-[glutaryl-(S)-valine] enol ester.

48. The composition of claim 46 comprising oxycodone-[glutaryl-(R)-valine] enol ester.

49. A pharmaceutical composition comprising oxycodone-[glutaryl-valine] enol ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

50. Oxycodone-[glutaryl-leucine] enol ester.

51. The composition of claim 50 comprising oxycodone-[glutaryl-(S)-leucine] enol ester.

52. The composition of claim 50 comprising oxycodone-glutaryl-(R)-leucine enol ester.

53. A pharmaceutical composition comprising oxycodone-[glutaryl-leucine] enol ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

54. A prodrug comprising oxycodone, a dicarboxylic acid linker, and a proteinogenic amino acid.

55. The prodrug of claim 54 wherein the dicarboxylic acid linker is succinic acid.

56. The prodrug of claim 54 wherein the dicarboxylic acid linker is glutaric acid.

57. The prodrug of claim 54 wherein the proteinogenic amino acid is valine.

58. The prodrug of claim 54 wherein the proteinogenic amino acid is leucine.

59. A method for reducing the incidence or severity of constipation associated with oral opiate administration which comprises orally administering to a patient in need thereof a prodrug comprising oxycodone, a dicarboxylic acid linker, and a proteinogenic amino acid.

60. The method of claim 59 wherein the prodrug is oxycodone-[succinyl-valine] enol ester.

61. The method of claim 59 wherein the prodrug is oxycodone-[succinyl-leucine] enol ester.

62. The method of claim 59 wherein the prodrug is oxycodone-[glutaryl-valine] enol ester.

63. The method of claim 59 wherein the prodrug is oxycodone-[glutaryl-leucine] enol ester.

64. A method for reducing the abuse of an opioid which comprises administering to a patient in need thereof a prodrug comprising oxycodone, a dicarboxylic acid linker, and a proteinogenic amino acid, wherein abuse of the prodrug by intranasal administration results in lower oxycodone absorption compared to intranasal administration of oxycodone itself.

65. The method of claim 64 wherein the prodrug is oxycodone-[succinyl-valine] enol ester.

66. The method of claim 64 wherein the prodrug is oxycodone-[succinyl-leucine] enol ester.

67. The method of claim 64 wherein the prodrug is oxycodone-[glutaryl-valine] enol ester.

68. The method of claim 64 wherein the prodrug is oxycodone-[glutaryl-leucine] enol ester.

69. A method of maintaining the plasma concentration of an opioid which comprises orally administering to a patient in need thereof a prodrug comprising oxycodone, a dicarboxylic acid linker, and a proteinogenic amino acid;

wherein the plasma concentration of the oxycodone is sustained longer than the oxycodone plasma concentration following oral administration of oxycodone itself.

70. The method of claim 69 wherein the prodrug is oxycodone-[succinyl-valine] enol ester.

71. The method of claim 69 wherein the prodrug is oxycodone-[succinyl-(S)-leucine] enol ester.

72. The method of claim 69 wherein the prodrug is oxycodone-[glutaryl-(S)-valine] enol ester.

73. The method of claim 69 wherein the prodrug is oxycodone-[glutaryl-(S)-leucine] enol ester.

74. A method of improving the bioavailability of an opioid which comprises orally administering to a patient in need thereof a prodrug comprising oxycodone, a dicarboxylic acid linker, and a proteinogenic amino acid;

wherein the bioavailability of the oxycodone is greater than the oxycodone bioavailability following oral administration of oxycodone itself.