Oligomer-calcimimetic conjugates and related compunds

1. A compound according to Formula II-Ce:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

is 3-methoxyphenyl, 3-chlorophenyl or 1-naphthyl;

each R 4 is independently —H, —F, —Cl, —Br, —I, phenyl, —CF 3 , —CF 2 H, —CFH 2 , lower alkyl, —O-lower alkyl, —OCH 2 CF 3 , —OH, —CN, —NO 2 , —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)NH-lower alkyl, —C(O)N-(lower alkyl) 2 , —OC(O)-lower alkyl, or —NH—C(O)-lower alkyl;

a is an integer from 1 to 5;

R 5 is lower alkyl;

R is a residue of polyol, polythiol or polyamine bearing from 3 to about 50 hydroxyl, thiol or amino groups;

POLY is a water-soluble, non-peptidic polymer;

each of X and Q is independently —(CR x R y ) a′ —K w —(CR x R y ) b —(CH 2 CH 2 O) c —(CR x R y ) d —K z —, an amino acid residue, or combination thereof;

each of R x and R y , in each occurrence, is independently H, alkyl substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or substituted aryl;

each of K w and K z is independently —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —O—, —S—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NH—, or —NHC(O)O—;

each a′ is independently an integer from 0 to 12;

each b is independently an integer from 0 to 12;

each c is independently an integer from 0 to 25;

each d is independently an integer from 0 to 12;

with the proviso that neither X nor Q is —O—O—, —NH—O—, nor —NH—NH—; and

q is an integer from 3 to about 50.

2. The compound of claim 1 , wherein POLY is a poly(alkylene oxide).

3. The compound of claim 2 , wherein the poly(alkylene oxide) is a poly(ethylene oxide).

4. The compound of claim 1 , wherein the water-soluble, non-peptidic polymer has a molecular weight of greater than 2,000 Daltons.

5. A composition comprising a compound of claim 1 , and optionally, a pharmaceutically acceptable excipient.

6. A composition of matter comprising a compound of claim 1 , wherein the compound is present in a dosage form.

7. A method comprising administering to a mammal a compound of claim 1 .

8. The compound of claim 1 , wherein R 4 is —H, —F, —Cl, —Br, —I, —CF 3 , —CF 2 H, —CFH 2 , —CH 3 , —OCH 3 , —OCH 2 CF 3 , —OH, —CN, —NO 2 , —C(O)CH 3 , —C(O)OCH 3 , —C(O)NH—CH 3 , —C(O)N(CH 3 ) 2 , —OC(O)CH 3 , or —NH—C(O)CH 3 .

9. The compound of claim 8 , wherein R 4 is —CF 3 .

10. The compound of claim 1 , wherein a is 1.

11. The compound of claim 1 , wherein R 5 is methyl.

12. The compound of claim 1 , wherein Q is a hydrolytically stable linker.

13. The compound of claim 1 , wherein X is spacer moiety that includes a releasable linkage.

14. The compound of claim 13 , wherein the releasable linkage is a hydrolysable linkage.

15. The compound of claim 13 , wherein the releasable linkage is an enzymatically degradable linkage.

16. The compound of claim 1 , wherein R is a residue of a polyol bearing from 3 to 6 hydroxyl groups.

17. The compound of claim 1 , wherein R is a residue of pentaerythritol.

18. A compound according to Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

n is an integer from 10 to about 500;

is 3-methoxyphenyl, 3-chlorophenyl or 1-naphthyl;

each R 4 is independently —H, —F, —Cl, —Br, —I, phenyl, —CF 3 , —CF 2 H, —CFH 2 , lower alkyl, —O-lower alkyl, —OCH 2 CF 3 , —OH, —CN, —C(O)-lower alkyl, —C(O)NH-lower alkyl, —C(O)N-(lower alkyl) 2 , —OC(O)-lower alkyl, or —NH—C(O)-lower alkyl;

a is an integer from 1 to 5;

R 5 is lower alkyl;

X is —(CR x R y ) a′ —K w —(CR x R y ) b —(CH 2 CH 2 O) c —(CR x R y ) d —K z —, an amino acid residue, or combination thereof;

each of R x and R y , in each occurrence, is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or substituted aryl;

each of K w and K z is independently —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —O—, —S—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)NH—, or —NHC(O)O—;

each a′ is independently an integer from 0 to 12;

each b is independently an integer from 0 to 12;

each c is independently an integer from 0 to 25;

each d is independently an integer from 0 to 12;

with the proviso that X is not —O—O—, —NH—O—, or —NH—NH—; and

AA is an amino acid residue.

19. The compound of claim 18 , according to Formula IV:

or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 18 , according to Formula V:

or a pharmaceutically acceptable salt or solvate thereof.