Polymer-des-ethyl sunitinib conjugates

Inventors

Kozlowski, Antoni • Culbertson, Sean M. • Shen, Xiaoming • McManus, Samuel P. • Wilson, Mark A.

Assignees

Nektar Therapeutics

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.

Core Innovation

The invention relates to compounds in which a des-ethyl sunitinib residue is covalently attached via a releasable linkage-containing spacer moiety to a poly(ethylene oxide). The disclosure includes mPEG-based and multi-arm PEG-based polymer conjugates, including related pharmaceutical compositions and dosage forms, with the drug attached through the terminal amine and pharmaceutically acceptable salts also contemplated.

The disclosure describes specific PEG conjugate structures including mPEG-Gly-Des-ethyl sunitinib, successive des-ethyl sunitinib PEG conjugates, mPEG-5K-Gly-Des-ethyl sunitinib (CACE), and corresponding amino-acid variants such as Leu and Val. It also includes 4-arm PEG-constructed derivatives and multi-arm species in which q ranges from 3 to about 50 arms, with polymer repeat unit ranges including n ranges such as 100–32000 and each n independently 2–32000.

The patent further characterizes the PEG conjugates by release or hydrolysis behavior and by compositional characterization criteria for four-arm PEG compositions, in which at least 90% of arms are Sun and at least 90% of arms satisfy specified structural criteria. It also references plasma hydrolysis rates under rat plasma, dog plasma, phosphate buffer pH 8.5, and phosphate buffer pH 7.5, together with in vivo plasma/tumor sampling and concentration-time plots in an NCr nu/nu mice HCT116 tumor model.

Claims Coverage

The supplied claim coverage centers on a des-ethyl sunitinib residue covalently attached to poly(ethylene oxide) through a releasable linkage-containing spacer moiety. Across the independent claims, the inventive features cover compositions, dosage forms, cancer treatment, and formula-defined compounds with Xr as the releasable linkage-containing spacer moiety and POLY as poly(ethylene oxide), including pharmaceutically acceptable salts.

The claims collectively cover compositions and compounds in which a des-ethyl sunitinib residue is covalently attached to poly(ethylene oxide) through a releasable linkage-containing spacer moiety, including versions in a dosage form and pharmaceutically acceptable formulations. They also cover a cancer-treatment method by administering the specified compound and formula-defined compound classes characterized by Xr and POLY, with additional PG definitions as H or an amine-protecting group.

Stated Advantages

Documented Applications