Phosphonate compounds

• US 7,790,703 B2
• Filed: 03/07/2007
• Issued: 09/07/2010
• Est. Priority Date: 12/03/1999
• Status: Expired due to Fees

• 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:
  US11/715,604
• Publication Number:
  US 20070161602A1
• Time in Patent Office: 1,280 Days
• Field of Search: 514/110, 544/264, 544/317, 261/274
• 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 the structure of Formula I:

R₃—

O(CH₂)_a—

R₁ 

 

(I)

wherein;

R₁ is —

O—

(CH₂)_t—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

R₃ is either Formula II or Formula III;

2. The compound of claim 1, wherein said compound is in the form of an enantiomer, diastereomer, racemate, or a mixture thereof.

19. The compound of claim 1, wherein a is 3 and t is 15 or 17.

23. The compound of claim 1, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is —

CH₂OH; and

Z is

24. The compound of claim 1, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is CH₃; and

Z is

25. The compound of claim 1, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is H; and

Z is

26. The compound of claim 1, wherein a is 3;

t is 15 or 17;

R₃ has Formula III; and

Z is

27. The compound of claim 1, the compound having the structure:

28. The compound of claim 1, the compound having the structure:

3. A pharmaceutical composition comprising an effective amount of a compound having the structure of Formula I:

R₃—

O(CH₂)_a—

R₁ 

 

(I)

wherein;

R₁ is —

O—

(CH₂)_t—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

R₃ is either Formula II or Formula III;

4. The pharmaceutical composition of claim 3 in a solid dosage form.

5. The pharmaceutical composition of claim 3 in a capsule, tablet, aerosol, solution, suspension, or in a topical formulation.

6. A method for the treatment of a viral disease selected from the group consisting of human immunodeficiency virus (HIV), influenza, herpes simplex virus, human herpes virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, varicella zoster virus, orthopox virus, ebola virus and papilloma virus comprising administering an effective amount of a compound having the structure of Formula I:

R₃—

O(CH₂)_a—

R₁ 

 

(I)

wherein;

R₁ is —

O—

(CH₂)_t—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

R₃ is either Formula II or Formula III;

7. The method of claim 6, wherein the orthopox is selected from the group consisting of variola major, variola minor, vaccinia, smallpox, cowpox, camelpox and monkeypox.

8. The method of claim 6, wherein the virus is HIV.

9. The method of claim 6, wherein the virus is influenza.

10. The method of claim 6, wherein the virus is herpes.

11. The method of claim 6, wherein the virus is cytomegalovirus.

12. The method of claim 6, wherein the virus is hepatitis B.

13. The method of claim 6, wherein the virus is hepatitis C.

14. The method of claim 6, wherein the virus is Epstein-Barr virus.

15. The method of claim 6, wherein the virus is varicella zoster virus.

16. The method of claim 6, wherein the virus is papilloma.

20. The method of claim 6, wherein Z is

21. The method of claim 6, wherein a is 3 and t is 15 or 17.

22. The method of claim 6, wherein Z is

29. The method of claim 6, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is —

CH₂OH; and

Z is

30. The method of claim 6, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is CH₃; and

Z is

31. The method of claim 6, wherein a is 3;

t is 15 or 17;

R₃ has Formula II;

B is H; and

Z is

32. The method of claim 6, wherein a is 3;

t is 15 or 17;

R₃ has Formula III; and

Z is

33. The method of claim 6, wherein the compound has the structure:

34. The method of claim 6, wherein the compound has the structure:

35. The method of claim 6, wherein the compound is topically administered.

36. The method of claim 35, wherein the compound is administered as a spray.

37. The method of claim 35, wherein the compound is administered through the skin by an appliance.

38. The method of claim 37, wherein the compound is administered through the skin by a transdermal patch.

39. The method of claim 6, wherein the compound is rectally administered.

40. The method of claim 6, wherein the compound is applied though nasal administration.

41. The method of claim 6, wherein the compound is parenterally administered.

42. The method of claim 6, wherein the compound is administered through subcutaneous, intravenous, intra-arterial, intramuscular, intravitaeal injection or infusion.

43. The method of claim 6, wherein the compound is administered orally.

44. The method of claim 43, wherein the compound is administered orally in the form of tablets, capsules, solutions, emulsions or suspensions, inhalded liquid, solid particles, microencapsulated particles.

45. The method of claim 6, wherein the compound is

46. The method of claim 6, wherein the viral disease is human herpes virus.

47. The method of claim 6, wherein the viral disease is ebola virus.

17. A pharmaceutical composition comprising a compound having the structure (A) or a pharmaceutically acceptable salt thereof

18. A pharmaceutical composition comprising a compound having the structure (A) or a pharmaceutically acceptable salt thereof