Phosphate management with small molecules

1. A method for inhibiting the transport of phosphate across the membrane of human epithelial cells, comprising administering to a human subject in need of phosphate transport inhibition in an amount effective to achieve a beneficial therapeutic outcome a compound selected from the group consisting of Formulae:

and a combination of any of the foregoing;

wherein

X is O, S, NH, or N-alkyl;

Y is O or S;

each Z independently is O, S, NH, or CH 2 ;

n is 0, 1 or 2;

m is 1 to 6;

R 1 is halogen, OH, O-alkyl, N-dialkyl, or NHCO-alkyl at single or multiple positions;

R 2 is H, alkyl, or substituted benzyl;

R 3 is halogen, alkyl, substituted benzyl, OH, O-alkyl, N-dialkyl, or NHCO-alkyl at single or multiple positions;

R 4 is H, halogen, O-alkyl, S-alkyl, N-dialkyl, or NHCO-alkyl;

R 5 is alkyl, aryl, or substituted aryl;

R 6 is alkyl, benzyl, or aromatic substituted benzyl;

R 7 is H, alkyl, benzyl, or aromatic substituted benzyl;

R 8 is H, alkyl, aryl, benzyl, or aromatic substituted benzyl;

R 9 is H or alkyl;

R 10 is hydrogen, alkyl, O-alkyl, S-alkyl, aryl, NR 11 2 , or NCOR 11 ;

R 11 is alkyl or aryl;

R 12 is halogen;

R 13 is halogen, OR 14 , NR 15 2 , PO 3 H 2 , SO 3 H, COOH, or NH 2 ;

R 14 is methyl, ethyl, isopropyl, tert-butyl, allyl, substituted benzyl, or unsubstituted benzyl;

R 15 is methyl, ethyl, isopropyl, allyl, substituted benzyl, or unsubstituted benzyl;

R 16 is SO 3 H, COOH, or NH 2 ;

R 17 is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, aryl, or heteroaryl;

R 18 is methyl, ethyl, isopropyl, tert-butyl, halogen, OH, O-alkyl, N-dialkyl or NHCO-alkyl at single or multiple positions;

R 19 is halogen, NR 11 2 , NHCOR 11 , SR 11 or heteroaryl;

R 20 is halogen, methyl, ethyl, isopropyl, tert-butyl, N(CH 3 ) 2 , N(Et) 2 , N(iPr) 2 , NHCOCH 3 , NHCOCF 3 , or NHCOPh; and, R 21 is alkyl, halogenated alkyl, O-alkyl, substituted aryl, or heteroaryl;

with the proviso that when n = 0 , R 5 =aryl, and R 21 is CF 3 , then the phenyl ring of Formula XXXII is optionally substituted with fluorine; or

a compound selected from the group consisting of

2. A method for preventing, stabilizing, or reversing the progress of a disease associated with a disorder in phosphate metabolism or impaired phosphate transport comprising administering to a human subject having a disease associated with a disorder in phosphate metabolism or impaired phosphate transport in an amount effective to prevent, stabilize, or reverse the progress of the disease associated with phosphate metabolism or impaired phosphate transport a compound selected from the group consisting of Formulae:

and a combination of any of the foregoing;

wherein

X is O, S, NH, or N-alkyl;

Y is O or S;

each Z independently is O, S, NH, or CH 2 ;

n is 0, 1 or 2;

m is 1 to 6;

R 1 is halogen, OH, O-alkyl, N-dialkyl, or NHCO-alkyl at single or multiple positions;

R 2 is H, alkyl, or substituted benzyl;

R 3 is halogen, alkyl, substituted benzyl, OH, O-alkyl, N-dialkyl, or NHCO-alkyl at single or multiple positions;

R 4 is H, halogen, O-alkyl, S-alkyl, N-dialkyl, or NHCO-alkyl;

R 5 is alkyl, aryl, or substituted aryl;

R 6 is alkyl, benzyl, or aromatic substituted benzyl;

R 7 is H, alkyl, benzyl, or aromatic substituted benzyl;

R 8 is H, alkyl, aryl, benzyl, or aromatic substituted benzyl;

R 9 is H or alkyl;

R 10 is hydrogen, alkyl, O-alkyl, S-alkyl, aryl, NR 11 2 , or NCOR 11 ;

R 11 is alkyl or aryl;

R 12 is halogen;

R 13 is halogen, OR 14 , NR 15 2 , PO 3 H 2 , SO 3 H, COOH, or NH 2 ;

R 14 is methyl, ethyl, isopropyl, tert-butyl, allyl, substituted benzyl, or unsubstituted benzyl;

R 15 is methyl, ethyl, isopropyl, allyl, substituted benzyl, or unsubstituted benzyl;

R 16 is SO 3 H, COOH, or NH 2 ;

R 17 is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, aryl, or heteroaryl;

R 18 is methyl, ethyl, isopropyl, tert-butyl, halogen, OH, O-alkyl, N-dialkyl or NHCO-alkyl at single or multiple positions;

R 19 is halogen, NR 11 2 , NHCOR 11 , SR 11 or heteroaryl;

R 20 is halogen, methyl, ethyl, isopropyl, tert-butyl, N(CH 3 ) 2 , N(Et) 2 , N(iPr) 2 , NHCOCH 3 , NHCOCF 3 , or NHCOPh; and,

R 21 is alkyl, halogenated alkyl, O-alkyl, substituted aryl, or heteroaryl;

with the proviso that when n =0, R 5 =aryl, and R 21 is CF 3 , then the phenyl ring of Formula XXXII is optionally substituted with fluorine; or a compound selected from the group consisting of

3. The method of claim 2 , wherein the disease is selected from the group consisting of hyperparathyroidism, metabolic bone disease, uremic bone disease, renal bone disease, soft tissue calcification, cardiovascular calcification, cardiovascular events, calciphylaxis, and osteoporosis.

4. The method of claim 1 , for the treatment or prevention of a disease wherein the accumulation of phosphate in serum can occur and comprising administering to a human subject in need of serum phosphate reduction or serum phosphate maintenance in an amount effective to reduce or maintain serum phosphate levels a compound according to claim 1 .

5. The method of claim 4 , wherein the disease is selected from the group consisting of hyperphosphatemia, chronic kidney disease, secondary hyperparathyroidism, hyperparathyroidism, and hypoparathyroidism.

6. The method of claim 5 , for treating, delaying, or preventing hyperphosphatemia wherein the hyperphosphatemia results or would result from pharmaceutical intervention for the treatment of a disease in a human subject in need of such intervention, comprising administering to said human subject in an amount effective to treat, delay, or prevent hyperphosphatemia a compound according to claim 1 .

7. The method of claim 6 , wherein the pharmaceutical intervention is vitamin D based therapy.

8. The method of claim 6 , wherein the disease is secondary hyperparathyroidism.

9. The method of claim 1 , further comprising administering in combination at least two of said compounds.

10. The method of claim 1 , wherein the compound is administered in a pharmaceutically acceptable formulation.

11. The method of claim 10 , wherein the pharmaceutically acceptable formulation comprises a pharmaceutically acceptable carrier, diluent, exipient, or a mixture of any of the foregoing.

12. The method of claim 10 , wherein the formulation is administered orally or by injection.

13. The method of claim 11 , wherein the formulation is administered orally as an elixir, liquid, gel, syrup, slurry, capsule, tablet, or pill.

14. The method of claim 11 , wherein the formulation is administered by injection subcutaneously, intravenously, or intraperitoneally.

15. The method of claim 1 , wherein the compound is administered in dose of about 0.001 to about 1 gram per kilogram of body weight per day.

16. The method of claim 1 , wherein the compound is selected from the group consisting of:

and a combination of any of the foregoing.

17. The method of claim 16 , wherein the compound is selected from the group consisting of:

and a combination of any of the foregoing.

18. The method of claim 17 , wherein the compound is selected from the group consisting of:

a combination of any of the foregoing.

19. A method for inhibiting the transport of phosphate across the membrane of human epithelial cells, comprising administering to a human subject in need of phosphate transport inhibition in an amount effective to achieve a beneficial therapeutic outcome a compound selected from the group consisting of:

and a combination of any of the foregoing.