PRODRUGS OF NH-ACIDIC COMPOUNDS: ESTER, CARBONATE, CARBAMATE AND PHOSPHONATE DERIVATIVES

• US 20110319422A1
• Filed: 06/24/2011
• Published: 12/29/2011
• Est. Priority Date: 06/24/2010
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Blumberg, Laura Cook, Remenar, Julius F., Almarsson, Örn, Zeidan, Tarek A.
• Granted Patent: US 8,592,427 B2
• Time in Patent Office: Days
• US Class Current: 514/253.07
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2

Abstract

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

Claims

1. A prodrug compound of Formula I, II or III:

3. A compound of claim 1, wherein R₁ is selected from Table 1, 2, 3 or 4.

4. A compound of claim 1 having the formula:

5. A compound of claim 4 having the formula:

6. A compound of claim 5, wherein R₅ is selected from:

7. A compound of claim 5, wherein Cy1 is selected from:

8. A compound of claim 5 having the formula:

9. A compound of claim 8 having the formula:

10. A compound of claim 9 selected from Table IX-X, wherein R₁ is as defined above.

13. A compound of claim 5 having the formula:

14. A compound of claim 13 having the formula:

15. A compound of claim 14 having the formula:

16. A compound of claim 15 having the formula:

17. A compound of claim 15 having the formula:

18. A compound of claim 17 having the formula:

19. A compound of claim 18 having the formula:

24. A compound of claim 13 selected from Table XI-XII wherein R₁ is as defined above.

27. A compound of claim 24, selected from Tables A-F.

28. A compound of claim 5, selected from Table VI-VII, wherein R₁ is as defined above.

29. A compound of claim 1 having the formula:

30. A compound of claim 29 having the formula:

37. A compound of claim 1 having the Formula XXXIII, XXXIV, XXXV, XXXVI or XXXVII:

39. A compound of claim 1 having the Formula XXXVIII or XXXIX:

41. A compound of claim 1 having the formula:

44. A compound of claim 1 having the Formula XLII, XLIII or XLIV:

47. A compound of claim 1 having the Formula III, selected from Table III wherein R₁ is as defined above.

55. A compound of claim 1 selected from Tables A-F.

2. (canceled)

11. (canceled)

12. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

25. (canceled)

26. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. (canceled)

36. (canceled)

38. (canceled)

40. (canceled)

42. (canceled)

43. (canceled)

45. (canceled)

46. (canceled)

48. A method of sustained delivery of a lactam, amide, imide, sulfonamide, carbamate, urea, benzamide, and acylaniline containing parent drug to a subject in need thereof, said method comprising the step of administering to the subject an effective amount of a prodrug compound produced by substituting a labile, hydrophobic prodrug moiety on the lactam, amide, imide, sulfonamide, carbamate, urea, benzamide, or acylaniline nitrogen atom or the carbonyl group.

49. The method of claim 48, wherein the prodrug compound has decreased solubility compared to the parent drug when measured at room temperature in a pH 7.4 phosphate buffer.

50. The method of claim 48, wherein the parent drug is represented by Formula LV or LVI:

51. (canceled)

52. (canceled)

53. (canceled)

54. (canceled)

56. (canceled)

57. A compound of Formula I-XXXVII wherein R₁ is selected from —

C(O)OR₂₀, —

C(O)NR₂OR₂₁, —

PO₃MY, —

P(O)(OR₂₀)(OR₂₁), —

C(O)[C(R_A)(R_B)O]_z—

R₂₀, —

C(O)O[C(R_A)(R_B)O]_z—

R₂₀, —

C(O)N(H)-[C(R_A)(R_B)O]_z—

R₂₀;

wherein z is 1, 2, 3, 4, 5, 6, or 7;

wherein each R_A and R_B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

Y and M are the same or different and each is a monovalent cation;

or M and Y together is a divalent cation.

58. The compound of claim 57, wherein R₂₀ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic and substituted aliphatic.

59. The compound of claim 57, wherein R₁ is selected from —

C(O)O—

CH₂—

OC(O)R₂₁ or —

C(O)NH—

CH₂—

OC(O)R₂₁ or —

C(O)O—

CH₂—

OC(O)N(R₂₁)₂.

60. The compound of claim 57, wherein R₁ is selected from —

C(O)O—

CH(CH₃)—

OC(O)R₂₁ or —

C(O)NH—

CH(CH₃)—

OC(O)R₂₁ or —

C(O)O—

CH(CH₃)—

OC(O)N(R₂₁)₂.

61. The compound of claim 57, wherein R₁ is selected from —

C(O)O—

CH(C₆H₅)—

OC(O)R₂₁ or —

C(O)NH—

CH(C₆H₅)—

OC(O)R₂₁ or —

C(O)O—

CH(C₆H₅)—

O(O)N(R₂₁)₂.