Phosphonate compounds

• US 7,034,014 B2
• Filed: 01/15/2004
• Issued: 04/25/2006
• Est. Priority Date: 12/03/1999
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Beadle, James R., Hostetler, Karl Y., Kini, Ganesh D.
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/759,345
• Publication Number:
  US 20040127735A1
• Time in Patent Office: 831 Days
• Field of Search: 514/52, 514/75, 514/110, 514/261, 514/274, 568/8, 435/11, 544/264, 544/317, 558/85
• US Class Current: 514/110
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C07F 9/3873 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/404 containing hydroxy substituents in the hydrocarbon radicals
• CPC Class Codes: C07F 9/405 : containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/48 : Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
• CPC Class Codes: C07F 9/5728 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6512 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 : containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07H 19/04 : Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/10 : with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention relates to phosphonate compounds, compositions containing them, processes for obtaining them, and their use for treating a variety of medical disorders, e.g., osteoporosis and other disorders of bone metabolism, cancer, viral infections, and the like.

Claims

1. A compound, having a phosphonate ester formed by a covalent linking of an antiviral compound selected from the group consisting of cidofovir, adefovir, cyclic cidofovir and tenofovir, to an alcohol selected from the group consisting of an alkylglycerol, alkylpropanediol, 1-S-alkylthioglycerol, alkoxyalkanol or alkylethanediol, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the antiviral compound is cidofovir.

3. The compound of claim 2, wherein the alcohol is an alkylpropanediol.

4. The compound of claim 2, wherein the alcohol is an alkylethanediol.

5. The compound of claim 2, wherein the alcohol is an alkoxyalkanol.

6. The compound of claim 2 wherein the alcohol is an alkylglycerol.

7. The compound of claim 2, wherein the alcohol is an 1-S-alkylthioglycerol.

8. The compound of claim 1, wherein the antiviral compound is adefovir.

9. The compound of claim 8, wherein the alcohol is an alkylpropanediol.

10. The compound of claim 8, wherein the alcohol is an alkylethanediol.

11. The compound of claim 8, wherein the alcohol is an alkoxyalkanol.

12. The compound of claim 8, wherein the alcohol is an alkylglycerol.

13. The compound of claim 8, wherein the alcohol is an 1-S-alkylthioglycerol.

14. The compound of claim 1, wherein the antiviral compound is cyclic cidofovir.

15. The compound of claim 14 wherein the alcohol is an alkylpropanediol.

16. The compound of claim 14, wherein the alcohol is an alkylethanediol.

17. The compound of claim 14, wherein the alcohol is an alkoxyalkanol.

18. The compound of claim 14, wherein the alcohol is an alkylglycerol.

19. The compound of claim 14, wherein the alcohol is an 1-S-alkylthioglycerol.

20. The compound of claim 1, wherein the antiviral compound is tenofovir.

21. The compound of claim 20, wherein the alcohol is an alkylpropanediol.

22. The compound of claim 20, wherein the alcohol is an alkylethanediol.

23. The compound of claim 20, wherein the alcohol is an alkoxyalkanol.

24. The compound of claim 20, wherein the alcohol is an alkylglycerol.

25. The compound of claim 20 wherein the alcohol is an 1-S-alkylthioglycerol.

26. The compound of claim 1, wherein the phosphonate ester is formed by linking the antiviral compound to the alcohol through the 3-position of the alkylglycerol, alkylpropanediol, or 1-S-alkylthioglycerol.

27. The compound of claim 1, wherein the phosphonate moiety in the ester is a phosphonate or a methylene phosphonate.

28. The compound of claim 1, wherein the alcohol is an alkylpropanediol.

29. The compound of claim 26, wherein the antiviral compound is cidofovir.

30. The compound of claim 28, wherein the alkylpropanediol is 1-O-hexadecylpropanediol or 1-octadecylpropanediol.

31. The compound of claim 28, wherein the alkylpropanediol is 1-O-hexadecylpropanediol or 1-O-octadecylpropanediol and the antiviral compound is cyclic cidofovir.

32. The compound of claim 28, wherein the alkylpropanediol is 1-O-octadecylpropanediol.

33. The compound of claim 1, wherein the alcohol is an alkylethanediol.

34. The compound of claim 30, wherein the antiviral compound is cidofovir.

35. The compound of claim 33, wherein the alkylethanediol is 1-O-octadecylethanediol.

36. The compound of claim 1, wherein the alcohol is an alkylglycerol.

37. The compound of claim 36, wherein the antiviral compound is cidofovir.

38. The compound of claim 36, wherein the alkylglycerol is a 1-O-alkylglycerol.

39. The compound of claim 36, wherein the alkylglycerol is a 3-O-alkylglycerol.

40. The compound of claim 38, wherein the antiviral compound is cyclic cidofovir.

41. The compound of claim 39, wherein the antiviral compound is cyclic cidofovir.

42. The compound of claim 39, wherein the antiviral compound is cidofovir.

43. The compound of claim 38, wherein the antiviral compound is adefovir.

44. The compound of claim 39, wherein the antiviral compound is adefovir.

45. The compound of claim 38, wherein the antiviral compound is tenofovir.

46. The compound of claim 39, wherein the antiviral compound is tenofovir.

47. The compound of claim 1, wherein the alcohol is a 1-S-alkylthioglycerol.

48. The compound of claim 1, wherein the alcohol is an alkyoxyalkanol.

49. The compound of claim 48, wherein the alkoxyalkanol is a 1-O-alkylpropane-3-ol.

50. The compound of claim 49, wherein the antiviral compound is cidofovir.

51. The compound of claim 49, wherein the antiviral compound is cyclic cidofovir.

52. The compound of claim 49, wherein the antiviral compound is tenofovir.

53. The compound of claim 49, wherein the antiviral compound is adefovir.

54. A method for the treatment of a viral disease selected from human immunodeficiency virus, influenza, herpes simplex virus, human herpes virus, cytomegalovirus, hepatitis B and C virus, Epstein-Barr virus, varicella zoster virus, orthopox virus, ebola virus and papilloma virus comprising administering an effective amount of a compound of claim 16 optionally in a pharmaceutically acceptable carrier.

55. The method of claim 54 wherein the virus is an orthopox virus selected from variola major and minor, vaccinia, smallpox, cowpox, camelpox and monkeypox.

56. The method of claim 54, wherein the virus is human immunodeficiency virus.

57. The method of claim 54, wherein the virus is influenza.

58. The method of claim 54, wherein the virus is herpes.

59. The method of claim 54, wherein the virus is cytomegalovirus.

60. The method of claim 54, wherein the virus is hepatitis B.

61. The method of claim 54, wherein the virus is hepatitis C.

62. The method of claim 54, wherein the virus is Epstein-Barr virus.

63. The method of claim 54, wherein the virus is varicella zoster virus.

64. The method of claim 54, wherein the virus is papilloma.

65. The compound of claim 1, having the following structure or a pharmaceutically acceptable salt thereof:

66. The compound of claim 1, having the following structure or a pharmaceutically acceptable salt thereof:

75. A pharmaceutical composition comprising an effective amount of compound of any one of claims 1 and 65–

74 in combination with a pharmaceutically acceptable carrier.

67. 1-O-octadecylpropanediol-3-cidofovir.

68. 1-O-octadecylethanediol-2-cidofovir.

69. 1-O-hexadecylpropanediol-3-cidofovir.

70. 1-O-hexadecylpropanediol-3-cyclic cidofovir.

71. 1-O-octadecylpropanediol-3-cyclic cidofovir.

72. 1-O-octadecylethanediol-2-cyclic cidofovir.

73. 1-O-hexadecylpropanediol-3-adefovir.

74. 1-O-octadecyl-sn-glycero-3-adefovir.