Prodrugs and methods of making and using the same

• US 20080318905A1
• Filed: 12/05/2007
• Published: 12/25/2008
• Est. Priority Date: 12/05/2006
• Status: Abandoned Application

• Current Assignee: Neurogesx, Inc.
• Original Assignee: Neurogesx, Inc.
• Inventors: Bley, Keith R., Muhammad, Naweed
• Application Number:
  US11/999,660
• Publication Number:
  US 20080318905A1
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Prodrugs of parent drugs and methods of making and using the same are described. The prodrugs comprise an amine-containing parent drug moiety and a prodrug moiety, such as methoxyphosphonic acid or ethoxyphosphonic acid. The prodrugs may be employed in therapy for the treatment of various indications, such as pain, and in methods of decreasing the abuse potential of abuse-prone drugs and/or delaying the onset of parent drug activity and/or prolonging parent drug activity as compared to administration of a parent drug.

Claims

1. A compound comprising:

(a) a parent drug moiety; and

,

(b) a prodrug moiety of the formula;

provided that when the prodrug moiety is of the formula (2), the parent drug moiety is not a moiety of an parent drug selected from the group consisting of levomethadyl, methadone, propoxyphene, buprenorphine, butorphanol, codeine, diphenoxylate, fentanyl, hydrocodone, hydromorphone, loperamide, meperidine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, sufentanil, alprazolam, clorazepate, clonazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam and triazolam.

2. The compound of claim 1, wherein the prodrug moiety is of the formula (1A) or (1B) and the parent drug moiety is a moiety of an opiod, benzodiazepine, CNS drug, stimulant or anorexiant.

3. The compound of claim 2, wherein the compound is of the formula (I):

wherein;

R¹ is selected from the group consisting of hydrogen, C₁-C₁₀ alkanoate, hydroxyl and a substituted or unsubstituted C₁-C₁₀ alkyl and substituted or unsubstituted C₁-C₁₀ alkoxy;

R² is selected from the group consisting of hydrogen, ═

O, hydroxyl, a substituted or unsubstituted C₁-C₁₀ alkyl, a substituted or unsubstituted C₂-C₁₀ alkenyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R³ is selected from the group consisting of hydrogen, hydroxyl, C₁-C₁₀ alkanoate, a substituted or unsubstituted C₁-C₁₀ alkyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R⁴ is selected from a group consisting of hydrogen, C₁-C₁₀ alkanoate, a substituted or unsubstituted C₁-C₁₀ alkyl, a substituted or unsubstituted C₂-C₁₀ alkenyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R⁵ is the prodrug moiety (1A), (1B) or (2);

Y is null or is selected from O and S;

ring C has zero, one or two double bonds;

X⁻

is pharmaceutical acceptable anion;

or any stereoisomer, salt, hydrate or solvate thereof.

4. The compound of claim 2 or 3, wherein the prodrug moiety is of the formula (2).

5. The compound of claim 3, wherein R¹ is hydroxyl, R² and R³ are hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is null.

6. The compound of claim 3, wherein R¹ is hydroxyl, R² and R³ are hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (2) and Y is null.

7. The compound of claim 3, wherein R¹ is methoxy, R² is hydroxy, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is oxygen and ring C has no double bond.

8. The compound of claim 3, wherein R¹ is methoxy, R² is hydroxy, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (2) and Y is oxygen and ring C has no double bond.

9. The compound of claim 3, wherein R¹ is ethoxy, R² is hydroxy, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is oxygen and ring C has one double bond between carbon 7 and 8.

10. The compound of claim 3, wherein R¹ is ethoxy, R² is hydroxy, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (2) and Y is oxygen and ring C has one double bond between carbon 7 and 8.

11. The compound of claim 3, wherein R¹ is methoxy, R² is ═

O, R³ is hydroxyl, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is oxygen.

12. The compound of claim 3, wherein R¹ is methoxy, R² is ═

O, R³ is hydroxyl, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is oxygen.

13. The compound of claim 3, wherein R¹ is hydroxyl, R² is ═

O, R³ is hydroxyl, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B) and Y is oxygen.

14. The compound of claim 3, wherein R¹ is hydroxyl, R² is ═

O, R³ is hydroxyl, R⁴ is methyl, R⁵ is the prodrug moiety (2) and Y is oxygen.

15. The compound of claim 3, wherein R¹ is methoxy, R² is hydroxyl, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B), Y is oxygen and C₇ and C₈ are connected by a double bond.

16. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydroxyl, R³ is hydrogen, R⁴ is methyl, R⁵ is the prodrug moiety (1A) or (1B), Y is oxygen and C₇ and C₈ are connected by a double bond.

17. The compound of claim 3, wherein R¹ is hydroxyl, R² is ═

O, R³ is hydroxyl, R⁴ is cyclopropylmethyl and Y is O.

18. The compound of claim 3, wherein R¹ is hydroxyl, R² is ═

O, R³ is hydroxyl, R⁴ is propen-3-yl and Y is O.

19. The compound of claim 3, wherein R¹ is hydroxyl, R² is ethenyl, R³ is hydroxyl, R⁴ is cyclopropylmethyl and Y is O.

20. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydroxyl, R³ is hydrogen, R⁴ is propen-3-yl and Y is O.

21. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydroxyl, R³ is hydroxyl, R⁴ is cyclobutylmethyl and Y is O.

22. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydrogen, R³ is hydrogen, R⁴ is cyclopropylmethyl and Y is null.

23. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydrogen, R³ is hydroxyl, R⁴ is cyclopropylmethyl and Y is null.

24. The compound of claim 3, wherein R¹ is hydroxyl, R² is hydrogen, R³ is hydrogen, R⁴ is propen-3-yl and Y is null.

25. The compound of claim 2, wherein the compound is of the formula (II):

wherein;

R¹ is selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted C₁-C₁₀ alkyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R² is selected from the group consisting of hydrogen, hydroxyl, a substituted or unsubstituted C₁-C₁₀ alkyl, a substituted or unsubstituted C₂-C₁₀ alkenyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R⁴ is selected from a group consisting of hydrogen, a substituted or unsubstituted C₁-C₁₀ alkyl and a substituted or unsubstituted C₁-C₁₀ alkoxy;

R⁵ is the prodrug moiety (1A) or (1B) or (2);

Y is selected from a group consisting of null, O and S;

ring C has zero or one double bond;

X⁻

is pharmaceutical acceptable anion;

or any stereoisomer, salt, hydrate or solvate thereof.

26. The compound of claim 25, wherein R¹ is hydroxyl, R² is methoxy, R⁴ is cyclopropylmethyl, R⁵ is methoxyphosphonic acid and Y is oxygen.

27. The compound of claim 25, wherein R¹ is hydroxyl, R² is methoxy, R⁴ is cyclopropylmethyl, R⁵ is ethoxyphosphonic acid and Y is oxygen.

28. The compound of claim 2, wherein the compound is of the formula (III):

wherein;

R¹ is selected from the group consisting of hydroxyl, propylbenzene, ethylbenzene, 2-propylthiophene, methyl butyrate, 1-ethyl-4-ethyl-1H-tetrazol-5(4H)-one and 1-ethyl-4-propyl-1H-tetrazol-5(4H)-one, a substituted or unsubstituted C₁-C₁₀ alkyl and a substituted or unsubstituted C₁-C₁₀ alkoxy, alkylcarbonylalkoxy;

R² is selected from the group consisting of hydrogen, ═

O, hydroxyl, a substituted or unsubstituted C₁-C₁₀ alkyl and C₁-C₁₀ alkoxy, C₁-C₁₀ alkanoate, C₂-C₁₀ alkoxyalkyl;

R³ is the prodrug moiety (1A), (1B) or (2);

X⁻

is a pharmaceutically acceptable anion;

or any stereoisomer, salt, hydrate or solvate thereof.

29. The compound of claim 28, wherein R¹ is propylbenzene, R² is hydrogen, and R³ is methoxyphosphonic acid.

30. The compound of claim 28, wherein R¹ is propylbenzene, R² is hydrogen, and R³ is ethoxyphosphonic acid.

31. The compound of claim 28, wherein R¹ is propylbenzene, R² is R² is methyl formoate, and R³ is methoxyphosphonic acid.

32. The compound of claim 28, wherein R¹ is propylbenzene, R² is R² is methyl formoate, and R³ is ethoxyphosphonic acid.

33. The compound of claim 28, wherein R¹ is 2-propylthiophene, R² is methoxy methyl, and R³ is methoxyphosphonic acid.

34. The compound of claim 28, wherein R¹ is 2-propylthiophene, R² is methoxy methyl, and R³ is ethoxyphosphonic acid.

35. The compound of claim 28, wherein R¹ is 1-ethyl-4-ethyl-1H-tetrazol-5(4H)-one, R² is methoxy methyl, and R³ is methoxyphosphonic acid.

36. The compound of claim 28, wherein R¹ is 1-ethyl-4-ethyl-1H-tetrazol-5(4H)-one, R² is methoxy methyl, and R³ is ethoxyphosphonic acid.

37. The compound of claim 28, wherein R¹ is methyl butyrate, R² is methyl formoate, and R³ is methoxyphosphonic acid.

38. The compound of claim 28, wherein R¹ is methyl butyrate, R² is methyl acetate, and R³ is ethoxyphosphonic acid.

43. The compound of claim 2 or 3, wherein the prodrug moiety is of the formula (1A) or (1B).

46. The compound of claim 1, wherein the compound is of the formula (IV):

wherein R⁴ and R⁵ are independently alkyl;

R² is the prodrug moiety (1A), (1B) or (2);

R¹ is alkaryl or alkenyl and X⁻

is a pharmaceutically acceptable anion, and any stereoisomer, salt, hydrate or solvate thereof.

48. The compound of claim 1, wherein the compound is of the formula (V):

wherein R¹ is an alkanoate or acarbonylalkyl;

R², R³ and R⁴ are independently a substituted or unsubstituted alkyl;

R⁵ is the prodrug moiety (1A), (1B) or (2);

n is an integer from 1 to 10 and X⁻

is a pharmaceutically acceptable anion, and any stereoisomer, salt, hydrate or solvate thereof.

49. The compound of claim 46 wherein R¹ is propanoate or propionyl;

R², R³ and R⁴ are independently a substituted or unsubstituted C₁-C₅ alkyl;

R⁵ is the prodrug moiety (1A), (1B) or (2);

n is an integer from 1 to 5 and X⁻

is a pharmaceutically acceptable anion, and any stereoisomer, salt, hydrate or solvate thereof.

50. The compound of claim 1, wherein the compound is of the formula (VI):

wherein;

R¹ is selected from the group consisting of bromine, chlorine, and nitro;

R² is selected from the group consisting of hydrogen and methyl;

R³ is selected from a group consisting of hydrogen and fluorine;

R⁴ is selected from a group consisting of hydrogen, and a carboxyl;

R⁵ is the prodrug moiety (1A), (1B) or (2);

or any stereoisomer, salt, hydrate or solvate thereof.

51. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1A).

52. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1B).

53. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (2).

54. The compound of claim 50, wherein R¹ is a nitro, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1A).

55. The compound of claim 50, wherein R¹ is a nitro, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1B).

56. The compound of claim 50, wherein R¹ is a nitro, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (2).

57. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1A).

58. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1B).

59. The compound of claim 50, wherein R¹ is chloride, R² is methyl, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (2).

60. The compound of claim 50, wherein R¹ is a nitro, R² is methyl, R³ is fluoride, R⁴ is hydrogen and R⁵ the prodrug moiety (1A).

61. The compound of claim 50, wherein R¹ is a nitro, R² is methyl, R³ is fluoride, R⁴ is hydrogen and R⁵ the prodrug moiety (1B).

62. The compound of claim 50, wherein R¹ is a nitro, R² is methyl, R³ is fluoride, R⁴ is hydrogen and R⁵ the prodrug moiety (2).

63. The compound of claim 50, wherein R¹ is chloride, R² is hydrogen, R³ is hydrogen, R⁴ is acetyl and R⁵ the prodrug moiety (1A).

64. The compound of claim 50, wherein R¹ is chloride, R² is hydrogen, R³ is hydrogen, R⁴ is acetyl and R⁵ the prodrug moiety (1B).

65. The compound of claim 50, wherein R¹ is chloride, R² is hydrogen, R³ is hydrogen, R⁴ is acetyl and R⁵ the prodrug moiety (2).

66. The compound of claim 50, wherein R¹ is bromide, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1A).

67. The compound of claim 50, wherein R¹ is bromide, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (1B).

68. The compound of claim 50, wherein R¹ is bromide, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen and R⁵ the prodrug moiety (2).

69. The compound of claim 1, wherein the compound is of the formula (VII):

wherein;

R¹ is hydrogen,

R² is methyl;

R³ is the prodrug moiety (1A), (1B) or (2);

or any stereoisomer, salt, hydrate or solvate thereof.

70. The compound of claim 69, wherein R¹ is hydrogen, R² is methyl, and R³ is the prodrug moiety (1A).

71. The compound of claim 50, wherein R¹ is hydrogen, R² is methyl, and R³ is the prodrug moiety (1B).

72. The compound of claim 50, wherein R¹ is hydrogen, R² is methyl, and R³ is the prodrug moiety (2).

73. The compound of claim 1, wherein the compound is of the formula (VIII):

wherein;

R¹ is selected from the group consisting of hydrogen and methyl;

R² is hydrogen;

R³ is the prodrug moiety (1A), (1B) or (2);

or any stereoisomer, salt, hydrate or solvate thereof.

74. The compound of claim 73, wherein R¹ is hydrogen, R² is hydrogen, and R³ is the prodrug moiety (1A).

75. The compound of claim 73, wherein R¹ is hydrogen, R² is hydrogen, and R³ is the prodrug moiety (1B).

76. The compound of claim 73, wherein R¹ is hydrogen, R² is hydrogen, and R³ is the prodrug moiety (2).

77. The compound of claim 73, wherein R¹ is methyl, R² is hydrogen, and R³ is the prodrug moiety (1A).

78. The compound of claim 73, wherein R¹ is methyl, R² is hydrogen, and R³ is the prodrug moiety (1B).

79. The compound of claim 73, wherein R¹ is methyl, R² is hydrogen, and R³ is the prodrug moiety (2).

80. The compound of claim 1, wherein the compound is of the formula (IX):

wherein;

R¹ is selected from the group consisting of hydrogen and methyl;

R² is the prodrug moiety (1A), (1B) or (2);

or any stereoisomer, salt, hydrate or solvate thereof.

81. The compound of claim 80, wherein R¹ is hydrogen and R² is the prodrug moiety (1A).

82. The compound of claim 73, wherein R¹ is hydrogen and R² is the prodrug moiety (1B).

83. The compound of claim 73, wherein R¹ is hydrogen and R² is the prodrug moiety (2).

84. The compound of claim 80, wherein R¹ is methyl and R² is the prodrug moiety (1A).

85. The compound of claim 73, wherein R¹ is methyl and R² is the prodrug moiety (1B).

86. The compound of claim 73, wherein R¹ is methyl and R² is the prodrug moiety (2).

39. A method of delaying the onset of parent drug activity in an individual in need of parent drug therapy, the method comprising administering to the individual an effective amount of a prodrug comprising a parent drug moiety and a prodrug moiety of the formula:

or any stereoisomer, salt, hydrate or solvate thereof, wherein the prodrug provides a slower onset of parent drug activity as compared to the parent drug.

42. The method of any one of claims 39-41, wherein the prodrug is selected from a prodrug of the formulae (I)-(IX) as detailed herein, or any stereoisomer, salt, hydrate or solvate thereof.

40. A method of prolonging parent drug action in an individual in need of parent drug therapy, the method comprising administering to an individual an effective amount of a prodrug comprising a parent drug moiety and a prodrug moiety of the formula:

or any stereoisomer, salt, hydrate or solvate thereof, wherein the prodrug provides prolonged parent drug action as compared to the parent drug.

41. A method of decreasing the abuse potential of an APD in an individual in need of APD therapy, the method comprising administering to an individual an effective amount of a compound comprising an APD moiety and a prodrug moiety of the formula:

or any stereoisomer, salt, hydrate or solvate thereof, wherein the prodrug is less susceptible to abuse as compared to the parent APD.

44. A kit comprising:

(a) an opioid prodrug comprising an opioid moiety and a prodrug moiety of the formula;

and (b) instructions for use of in the treatment, prevention, or delaying the onset and/or development of pain.

47. The compound of claim 44 wherein R⁴ and R⁵ are independently selected a substituted or unsubstituted C₁-C₅ alkyl;

R² is the prodrug moiety (1A), (1B) or (2);

R¹ is —

(CH₂)_n-phenyl where n is selected from 1 to 5 or a C₂-C₁₀ alkenyl and X⁻

is a pharmaceutically acceptable anion, and any stereoisomer, salt, hydrate or solvate thereof.

45. A pharmaceutical composition comprising (a) a prodrug comprising an parent drug moiety and a prodrug moiety of the formula:

and (b) a pharmaceutically acceptable carrier.