Phosphonate Compounds

• US 20100173870A1
• Filed: 02/05/2010
• Published: 07/08/2010
• Est. Priority Date: 12/03/1999
• Status: Active Grant

• 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.
• Granted Patent: US 8,008,308 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• 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. An antiviral nucleoside compound having the structure of Formula I:

wherein;

R₁ is —

O—

(CH₂)_t—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, —

CH₃, or —

CH₂OH,

Z is

and the symbol * indicates that -*CH₂—

in Formula I is attached to Z via N* in Formula A or B;

or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 1, wherein a is 2 or 3.

4. The compound of claim 1, wherein t is 15 or 17.

5. The compound of claim 1, wherein B is —

CH₃.

6. The compound of claim 1 has the following structure

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising an effective amount of an antiviral nucleoside compound of Formula I

wherein:

R₁ is —

O—

(CH₂)—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, —

CH₃, or —

CH₂OH, Z is

and the symbol * indicates that -*CH₂—

in Formula I is attached to Z via N* in Formula A or B,

or a pharmaceutically acceptable salt thereof;

in combination with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 is in a solid dosage form.

9. The pharmaceutical composition of claim 7 is in a capsule, tablet, aerosol, solution, suspension, or in a topical formulation.

10. The pharmaceutical composition of claim 7, wherein the compound has the structure

or a pharmaceutically acceptable salt thereof.

11. A method for the treatment of a viral disease comprising administering an effective amount of an antiviral nucleoside compound of Formula I

wherein:

R₁ is —

O—

(CH₂)_t—

CH₃, wherein t is 11 to 19;

a is 2 to 4;

B is hydrogen, —

CH₃, or —

CH₂OH,

Z is

and the symbol * indicates that -*CH₂—

in Formula I is attached to Z via N* in Formula A or B,

or a pharmaceutically acceptable salt thereof;

optionally in a pharmaceutically acceptable carrier.

12. The method of claim 11, wherein the viral disease is selected from the group consisting of 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.

13. The method of claim 12, wherein the orthopox is selected from variola major and minor, vaccinia, smallpox, cowpox, camelpox and monkeypox.

14. The method of claim 11, wherein the virus is HIV.

15. The method of claim 11, wherein the virus is influenza.

16. The method of claim 11, wherein the virus is herpes.

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

18. The method of claim 11, wherein the virus is hepatitis B.

19. The method of claim 11, wherein the virus is hepatitis C.

20. The method of claim 11, wherein the virus is Epstein-Barr virus.

21. The method of claim 11, wherein the virus is varicella zoster virus.

22. The method of claim 11, wherein the virus is papilloma.

23. The method of claim 11, wherein the compound has the structure

or a pharmaceutically acceptable salt thereof.