Polymer-des-ethyl sunitinib conjugates

Patent metadata

Field	Value
Publication number	US-10220020-B2
Application number	US-201113995819-A
Country	US
Kind code	B2
Filing date	Dec 23, 2011
Priority date	Dec 23, 2010
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula I-C, multi-arm:

wherein:
Xr is a releasable linkage-containing spacer moiety;
POLY is a poly(ethylene oxide);
R, when taken with Q, is a residue of polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol or amino groups, respectively;
each Q is a linker selected from O, S, and NH; and
q is a positive integer from 3 to about 50;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Xr comprises a thioether, carbamate, ester, carbonate, urea, or enzyme-cleavable peptidic linkage.

3. The compound of claim 1 , wherein Xr is according to Formula III:
˜[X 1 ] a -Lr-[X 2 ] b ˜   (Formula III)

wherein:
a is zero or one;
b is zero or one;
X 1 , when present, is a first spacer;
Lr is a releasable linkage; and
X 2 , when present, is a second spacer.

4. A compound of claim 1 , wherein Xr comprises a structure selected from the group consisting of ˜C(O)O—,

wherein AASC 1 is a first amino acid side chain; AASC 2 is a second amino acid side chain; and AASC 1 and AASC 2 are selected such that the compound includes an enzymatically cleavable linkage.

5. The compound of claim 1 , wherein each POLY has a molecular weight of less than 2000 Daltons.

6. The compound of claim 1 , wherein each POLY has from about 1 to about 30 monomers.

7. The compound of claim 1 , wherein each POLY has from about 1 to about 10 monomers.

8. The compound of claim 1 , wherein each POLY has a molecular weight of from 2000 Daltons to about 150,000 Daltons.

9. The compound of claim 1 , wherein each POLY includes an alkoxy or hydroxy end-capping moiety.

10. The compound of claim 1 , wherein Q is oxygen and wherein R, when taken with Q, has a structure selected from:

wherein m is a positive integer from 0-40.

11. The compound of claim 1 , wherein q is 3.

12. The compound of claim 1 , wherein q is 4.

13. The compound of claim 1 , wherein q is 5.

14. The compound of claim 1 , wherein q is 6.

15. The compound of claim 1 , wherein q is 7.

16. The compound of claim 1 , wherein q is 9.

17. The compound of claim 1 , wherein q is 10.

18. A compound of claim 1 , wherein the compound is selected from the group consisting of
(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-(2-(4armPEG 20,000)acetamido)propanoate (Compound 14);
(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-(2-(4armPEG 20,000)acetamido)acetate (Compound 15); and
(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-((4armPEG 20,000)carbonylamino)-4-methylpentanoate (Compound 16).

19. A composition comprising:
(i) a compound of claim 1 ; and
(ii) a pharmaceutically acceptable excipient.

20. A dosage form comprising the composition of claim 19 .

21. A method of treating a subject having a condition that is mediated by abnormal protein kinase activity, the method comprising administering to the subject, a therapeutically effective amount of a compound of claim 1 .

Assignees

• Kozlowski Antoni
• Culbertson Sean M
• Shen Xiaoming
• Mcmanus Samuel P
• Wilson Mark A
• Nektar Therapeutics

Inventors

• Kozlowski Antoni
• Culbertson Sean M
• Shen Xiaoming
• Mcmanus Samuel P
• Wilson Mark A

Classifications

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title