Pharmacologically active agents containing esterified phosphonates and methods for use thereof

• US 20050192246A1
• Filed: 02/07/2005
• Published: 09/01/2005
• Est. Priority Date: 02/05/2004
• Status: Active Grant

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture, Regents of the University of California (University of California)
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture, Regents of the University of California (University of California)
• Inventors: Hostetler, Karl Y., Wan, W. Brad
• Granted Patent: US 7,652,001 B2
• Time in Patent Office: Days
• US Class Current: 514/47
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain 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: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/65719 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonous acid derivative

Abstract

Compounds and compositions are provided for treatment, prevention, or amelioration of a variety of medical disorders associated with viral infections, cell proliferation and bone metabolism. The compounds provided herein are alkyl esters of phosphonates.

Claims

1. A compound of formula I:

P^x—

O—

R,

or a pharmaceutically acceptable derivative thereof,

wherein P^x is a pharmacologically active phosphonate, O is an oxygen atom, and R is a substituted or unsubstituted C₈-C₂₄ alkyl, substituted or unsubstituted C₈-C₂₄ alkenyl having from 1 to 6 double bonds or substituted or unsubstituted C₈-C₂₄ alkynyl having from 1 to 6 triple bonds wherein substituents when present are selected from one or more halogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, —

OR^w, —

SR^w, cyclo C_3-6 alkyl or epoxide, where each R^w is independently hydrogen or C_1-6 alkyl and where the alkyl, alkenyl, alkynyl groups may be substituted or unsubstituted.

2. The compound of claim 1, wherein P^x has formula II or III

3. The compound of claim 1, wherein P^x is a bisphosphonate, a phosphonate derivative of an antiviral nucleoside or a phosphonate derivative of an antiproliferative nucleoside.

4. The compound of claim 1 having formula:

5. The compound of claim 1 having formula:

6. The compound of claim 1 having formula:

7. The compound of claim 1 having formula:

8. The compound of claim 1, wherein P^x is adefovir, cidofovir, cyclic cidofovir, tenofovir, 9-(2-phosphonylmethoxyethyl)guanine or 9-(3hydroxy-2-phosphonylmethoxypropyl)adenine.

9. The compound of claim 1, wherein P^x is cidofovir, cyclic cidofovir or 9-(3hydroxy-2-phosphonylmethoxypropyl)adenine.

10. The compound of claim 1, wherein P^x is cidofovir or cyclic cidofovir.

11. The compound of claim 1, wherein P^x is 9-(3hydroxy-2-phosphonylmethoxypropyl)adenine.

12. The compound of claim 1, wherein P^x is selected from:

13. The compound of claim 1, wherein P^x selected from:

14. The compound of claim 2, wherein R₁ is an anti-neoplastic nucleoside.

15. The compound of claim 2, wherein R₁ is a cytosine arabinoside, gemcitabine, 5-fluorodeoxyuridine riboside, 5-fluorodeoxyuridine deoxyriboside, 2-chlorodeoxyadenosine, fludarabine, 1-β

-D-arabinofuranosyl-guanine, 2-chloro-deoxyadenosine, 1-β

-D-arabinofuranosyl-cytidine, fluorouridine, fluorodeoxyuridine, cladribine, fludarabine, pentostatin, 6-mercaptopurine, 6-thioguanine, 1-β

-D-arabinofuranosyl-guanine, 1-β

-D-arabinofuranosyl-adenosine, 1-β

-D-arabinofuranosyl-uridine, or a pharmaceutically acceptable derivative thereof.

16. The compound of claim 1, wherein P^x is 9-(2-phosphonylmethoxyethyl)guanine, 9-(2-(phosponomethoxy)ethyl)-2,6-diaminopurine or 9-(2-(phosphonomethoxy)ethyl)adenine.

17. The compound of claim 1, wherein the bisphosphonate is alendronate, etidronate, tiludronate, ibandronate, disodium 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonate, pamidronate, olpadronate, amino-olpadronate, clodronate, or risedronate.

18. The compound of claim 1, wherein R is a substituted or unsubstituted C₁₆-C₂₃ alkyl, substituted or unsubstituted C₁₆-C₂₃ alkenyl or substituted or unsubstituted C₁₆-C₂₃ alkynyl.

19. The compound of claim 1, wherein R is a substituted or unsubstituted C₁₆-C₂₃ alkyl or substituted or unsubstituted C₁₆-C₂₃ alkenyl.

20. The compound of claim 1, wherein R is substituted or unsubstituted C₁₇-C₁₉ alkyl or substituted or unsubstituted C₁₇-C₁₉ alkenyl.

21. The compound of claim 1, wherein R is substituted or unsubstituted C₁₇-C₂₂ alkyl.

22. The compound of claim 1, wherein R is C₁₇ alkyl.

23. The compound of claim 1, wherein R is C₁₈ alkyl.

24. The compound of claim 1, wherein R is C₁₉ alkyl.

25. The compound of claim 1, wherein R is C₂₀ alkyl.

26. The compound of claim 1, wherein R is C₂₁ alkyl.

27. The compound of claim 1, wherein R is C₂₂ alkyl.

28. The compound of claim 1, wherein R is substituted with one or more groups selected from C_1-6 alkyl and halo.

29. The compound of claim 28, wherein R is substituted with one or more groups selected from methyl and fluoro.

30. The compound of claim 29, wherein R is substituted with one or more methyl.

31. The compound of claim 29, wherein R is substituted with one or more fluoro.

32. The compound of claim 28, wherein the C_1-6 alkyl and halo substituent is present on the penultimate carbon of the R group.

33. The compound of claim 1, wherein the R is 7-methyl-octyl, 8-methyl-nonyl, 9-methyl-decyl, 10-methyl-undecyl, 11-methyl-dodecyl, 12-methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl-hexadecyl, 16-methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8-fluoro-nonyl, 9-fluoro-decyl, 10-fluoro-undecyl, 11-fluoro-dodecyl, 12-fluoro-tridecyl, 13-fluoro-tetradecyl, 14-fluoro-pentadecyl, 15-fluoro-hexadecyl, 16-fluoro-heptadecyl, 17-fluoro-octadecyl, 18-fluoro-nonadecyl, 19-fluoro-eicosyl, 20-fluoro-heneicosyl, 21-fluoro-docosyl or 22-fluoro-tricosyl.

34. The compound of claim 1, wherein the compound is an alkyl ester of cidofovir, cyclic cidofovir or HPMPA.

35. The compound of claim 1, wherein the compound is octyl cidofovir, dodecyl cidofovir, hexadecyl cidofovir, eicosyl cidofovir, docosyl cidofovir or tetracosyl cidofovir.

36. The compound of claim 1, wherein the compound is selected from eicosyl cidofovir, docosyl cidofovir and tetracosyl cidofovir.

37. The compound of claim 1, wherein the compound is selected from octyl cyclic cidofovir, dodecyl cyclic cidofovir, hexadecyl cyclic cidofovir, eicosyl cyclic cidofovir, docosyl cyclic cidofovir and cyclic cyclic tetracosyl cidofovir.

38. The compound of claim 1, wherein the compound is selected from cyclic eicosyl cidofovir, docosyl cyclic cidofovir and tetracosyl cyclic cidofovir.

39. The compound of claim 1, wherein the compound is Eicosyl-(S)-HPMPA.

40. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

41. A method for treating a viral infection in a mammal, wherein the method comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

42. The method of claim 41, wherein the viral infection is a caused by influenza, hepatitis B virus, hepatitis C virus, cytomegalovirus, Varicella zoster virus, Herpes simplex virus types and 2, Epstein-Barr virus, Herpes type 6 and type 8, Varicella zoster virus, Epstein Barr virus infections, retroviral infections, orthopox viruses, vaccinia, ebola virus, adenovirus and papilloma virus.

43. The method of claim 41, wherein the viral infection is orthopox viral infection selected from, smallpox, cowpox, camelpox, monkeypox.

44. The method of claim 41, wherein the viral infection is a herpes viral infection.

45. A method for treating a growing neoplasm in a mammal, wherein the method comprises administering effective amount of a compound of claim 1 to a subject in need thereof.

46. A method for modulating cell proliferation in a mammal, wherein the method comprises administering effective amount of a compound of claim 1 to a subject in need thereof.

47. A method for treating cancer in a mammal, wherein the method comprises administering effective amount of a compound of claim 1 to a subject in need thereof.

48. The method of claim 47, wherein the cancer is selected from lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non Hodgkin'"'"'s lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, and skin cancer.

49. A method for treating a disease associated with bone metabolism in a mammal, wherein the method comprises administering effective amount of a compound of claim 1 to a subject in need thereof.

50. The method of claim 49, wherein the disease is osteoporosis, metastatic bone cancers, Paget'"'"'s disease, osteogenesis imperfecta, fibrous dysplasia, rheumatoid arthritis, hyperparathyroidism, algodystrophy, stemo-costoclavicular hyperostosis, Gaucher'"'"'s disease, Engleman'"'"'s disease, certain non-skeletal disorders or periodontal disease.

51. The method of claim 50, wherein the disease is osteoporosis.

52. An article of manufacture, comprising packaging material and a compound of any of claims 1, contained within the packaging material, wherein the compound is effective for treatment of a disease associated with a viral infection, cell proliferation or bone metabolism and the packaging material includes a label that indicates that the compound is used for treatment of a disease associated with a viral infection, cell proliferation or bone metabolism.

53. The compound of claim 5, wherein B is selected from a natural or non natural purine and pyrimidine base.

54. The compound of claim 5, wherein B is selected from pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl and purin-9-yl residue.

55. The compound of claim 5, wherein B is selected from thymin-1-yl, cytosine-1-yl, adenine-9-yl and guanine-9-yl.

56. The compound of claim 1 selected from 7-methyl-octyl, 8-methyl-nonyl, 9-methyl-decyl, 10-methyl-undecyl, 11-methyl-dodecyl, 12-methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl-hexadecyl, 16-methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8-fluoro-nonyl, 9-fluoro-decyl, 10-fluoro-undecyl, 11-fluoro-dodecyl, 12-fluoro-tridecyl, 13-fluoro-tetradecyl, 14-fluoro-pentadecyl, 15-fluoro-hexadecyl, 16-fluoro-heptadecyl, 17-fluoro-octadecyl, 18-fluoro-nonadecyl, 19-fluoro-eicosyl, 20-fluoro-heneicosyl, 21-fluoro-docosyl and 22-fluoro-tricosyl ester of cidofovir.

57. The compound of claim 1 selected from 7-methyl-octyl, 8-methyl-nonyl, 9-methyl-decyl, 10-methyl-undecyl, 1-methyl-dodecyl, 12-methyl-tridecyl, 13-methyl-tetradecyl, 14-methyl-pentadecyl, 15-methyl-hexadecyl, 16-methyl-heptadecyl, 17-methyl-octadecyl, 18-methyl-nonadecyl, 19-methyl-eicosyl, 20-methyl-heneicosyl, 21-methyl-docosyl, 22-methyl-tricosyl, 7-fluoro-octyl, 8-fluoro-nonyl, 9-fluoro-decyl, 10-fluoro-undecyl, 11-fluoro-dodecyl, 12-fluoro-tridecyl, 13-fluoro-tetradecyl, 14-fluoro-pentadecyl, 15-fluoro-hexadecyl, 16-fluoro-heptadecyl, 17-fluoro-octadecyl, 18-fluoro-nonadecyl, 19-fluoro-eicosyl, 20-fluoro-heneicosyl, 21-fluoro-docosyl and 22-fluoro-tricosyl ester of cyclic cidofovir.

58. The compound of claim 6 having formula:

59. The compound of claim 46 wherein B is cytosinyl.

60. The method of claim 41, wherein the viral infection is a hepatitis viral infection.

61. A method of treating a disease associated with an orthopox viral infection, wherein the method comprises administering an effective amount of a compound of claim 6.

62. The pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier.