Phosphonate compounds

• US 6,716,825 B2
• Filed: 11/06/2002
• Issued: 04/06/2004
• 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: Kini, Ganesh D., Beadle, James R., Hostetler, Karl Y.
• Primary Examiner(s): Solola, Taofiq
• Application Number:
  US10/148,374
• Publication Number:
  US 20040019232A1
• Time in Patent Office: 517 Days
• Field of Search: 514/52, 514/75, 568/8, 435/1.1
• US Class Current: 514/52
• 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 disorder, e.g., osteoporosis and other disorders of bone metabolisum, cancer, viral infections, and the like.

Claims

1. A phosphonate compound having the structure:

wherein;

R₁ and R₁′

are independently —

H, optionally substituted —

O(C₁-C₂₄)alkyl, —

O(C₁-C₂₄)alkenyl, —

O(C₁-C₂₄)acyl, —

S(C₁-C₂₄)alkyl, —

S(C₁-C₂₄)alkenyl, or —

S(C₁-C₂₄)acyl, wherein at least one of R₁ and R₁′

are not —

H, and wherein said alkenyl or acyl optionally have 1 to about 6 double bonds,

R₂ and R₂′

are independently —

H, optionally substituted —

O(C₁-C₇)alkyl, —

O(C₁-C₇)alkenyl, —

S(C₁-C₇)alkyl, —

S(C₁-C₇)alkenyl, —

O(C₁-C₇)acyl, —

S(C₁-C₇)acyl, —

N(C₁-C₇)acyl, —

NH(C₁-C₇)alkyl, —

N((C₁-C₇)alkyl)₂, oxo, halogen, —

NH₂, —

OH, or —

SH;

R₃ is a phosphonate derivative of a pharmacologically active compound linked to a functional group on optional linker L or to an available oxygen atom on C^α

;

X, when present, is;

L is a valence bond or a bifunctional linking molecule of the formula —

J—

(CR₂)_t—

G—

, wherein t is an integer from 1 to 24, J and G are independently —

O—

, —

S—

, —

C(O)O—

, or —

NH—

, and R is —

H, substituted or unsubstituted alkyl, or alkenyl;

m is an integer from 0 to 6; and

n is 0 or 1.

2. The phosphonate compound according to claim 1, wherein R₃ is a bisphosphonate.

3. The phosphonate compound according to claim 2, wherein the bisphosphonate is alendronate, etidronate, tiludronate, ibandronate, EB-1053, pamidronate, olpadronate, amino-olpadronate, clodronate, or risedronate.

4. The phosphonate compound according to claim 1, wherein R₃ is a phosphonate derivative of an antiviral nucleoside.

5. The phosphonate compound according to claim 4, wherein said phosphonate derivative is adefovir, cidofovir, cyclic cidofovir, or tenofovir.

6. The phosphonate compound according to claim 4, wherein said phosphonate derivative is a derivative of azidothymidine (AZT).

7. The phosphonate compound according to claim 1, wherein R₃ is a phosphonate derivative of an anti-neoplastic nucleoside.

8. The phosphonate compound according to claim 7, wherein said phosphonate is a derivative of cytosine arabinoside, gemcitibine, 5-fluorodeoxyuridine riboside, 5-fluorodeoxyuridine deoxyriboside, 2-chlorodeoxyadenosine, fludarabine, or 1-β

-D-arabinoftiranosyl-guanine.

9. A pharmaceutical composition comprising a phosphonate compound according to claim 1 and a pharmaceutically acceptable carrier therefor.

10. A method for treating osteoporosis in a mammal, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.

11. A method for augmenting bone mineral density, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.

12. A method for preventing osteoblast and osteocyte apoptosis in a mammal, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.

13. A method for treating a viral infection in a mammal, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.

14. A method for treating a growing neoplasm in a mammal, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.

15. A method for modulating cell proliferation, said method comprising administering to a subject in need thereof an effective amount of a phosphonate compound according to claim 1.