Polymer-des-ethyl sunitinib conjugates
The invention relates to (among other things) polymer-des-ethyl sunitinib conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over des-ethyl sunitinib in unconjugated form.
1. A composition comprising (i) a compound comprising a des-ethyl sunitinib residue covalently attached via a releasable linkage-containing spacer moiety to a poly(ethylene oxide), and (ii) a pharmaceutically acceptable excipient.
2. A composition of matter comprising a compound comprising a des-ethyl sunitinib residue covalently attached via a releasable linkage-containing spacer moiety to a poly(ethylene oxide), wherein the compound is present in a dosage form.
3. A method of treatment of cancer comprising administering a compound comprising a des-ethyl sunitinib residue covalently attached via a releasable linkage-containing spacer moiety to a poly(ethylene oxide), to a subject in need thereof.
4. A compound having the formula
wherein:
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide),
and pharmaceutically acceptable salts thereof.
5. A compound having the formula
wherein:
PG 1 is H or an amine-protecting group;
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide),
and pharmaceutically acceptable salts thereof.
6. A compound having the formula
wherein:
PG 2 is H or an amine-protecting group;
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide),
and pharmaceutically acceptable salts thereof.
7. A compound having the formula
wherein:
PG 3 is H or an amine-protecting group;
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide),
and pharmaceutically acceptable salts thereof.
8. A compound having the formula
wherein:
PG 4 is H or an amine-protecting group;
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide),
and pharmaceutically acceptable salts thereof.
9. A compound having the formula
wherein:
PG 5 is H or an amine-protecting group;
Xr is a releasable linkage-containing spacer moiety; and
POLY is a poly(ethylene oxide);
and pharmaceutically acceptable salts thereof.
10. The compound of claim 4 , wherein Xr is selected from the group consisting of thioether, carbamate, ester, carbonate, urea and enzyme-cleavable peptidic linkages.
11. The compound of claim 4 , wherein Xr has the formula
˜[X 1 ] a -Lr-[X 2 ] b ˜ (Formula III)
wherein:
(a) is either zero or one;
(b) is either zero or one;
when present, is a first spacer;
Lr is the releasable linkage; and
X 2 , when present, is a second spacer.
12. The compound of claim 4 , wherein the poly(ethylene oxide) is a poly(ethylene glycol).
13. The compound of claim 4 , wherein the poly(ethylene oxide) is linear.
14. The compound of claim 4 , wherein the poly(ethylene oxide) is branched.
15. The compound of claim 14 , having the formula
wherein:
R is a residue of polyol, polythiol or polyamine bearing at from 3 to about 50 hydroxyl, thiol or amino groups;
each Q is a linker;
each Xr is a releasable linkage-containing spacer moiety;
each POLY is a poly(ethylene oxide); and
q is a positive integer from 3 to about 50,
and pharmaceutically acceptable salts thereof.
16. The compound of claim 4 , wherein the poly(ethylene oxide) has a molecular weight of less than 2000 Daltons.
17. The compound of claim 4 , wherein the poly(ethylene oxide) has from about 1 to about 30 monomers.
18. The compound of claim 4 , wherein the poly(ethylene oxide) has from about 1 to about 10 monomers.
19. The compound of claim 4 , wherein the poly(ethylene oxide) has a molecular weight of from 2000 Daltons to about 150,000 Daltons.
20. The compound of claim 4 , wherein the poly(ethylene oxide) includes an alkoxy or hydroxy end-capping moiety.