Polymer-semaxanib moiety conjugates
Inventors
Riggs-Sauthier, Jennifer • Allums-Donald, Stephanie • Culbertson, Sean M.
Assignees
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Publication Number
US-11007270-B2
Publication Date
2021-05-18
Expiration Date
Abstract
The invention relates to (among other things) polymer-semaxanib moiety conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over the semaxanib moiety in unconjugated form.
Core Innovation
The disclosure relates to a compound having a formula, or pharmaceutically acceptable salts thereof, in which X is a spacer moiety selected from a single bond, an ether, an amide, a urethane, an amine, a thioether, a carbamate, an ester, a carbonate, and a urea linkage. The compound further includes POLY defined as a poly(alkylene oxide) having from about 3 to 10 monomer units.
The invention focuses on selecting the spacer linkage X and pairing it with a poly(alkylene oxide) (POLY) of a defined monomer-unit range. This defines a family of compounds in which the poly(alkylene oxide) portion is constrained to about 3 to 10 monomer units while maintaining the spacer moiety selection within the listed linkage types.
The disclosure relates to polymer-semaxanib moiety conjugates in which a semaxanib residue is covalently attached through a spacer moiety to a water-soluble, non-peptidic polymer. The polymer is a poly(alkylene oxide) designated as POLY, and the conjugates are intended to provide VEGFR/Flk-1/KDR inhibitory pharmacology while exhibiting improved properties relative to free semaxanib.
The polymer portion is described as water-soluble and non-peptidic, with PEG/mPEG structures and multi-attachment-point variants including two polymers. The description includes mPEGn-semaxanib conjugates and related spacer-linked derivatives, including mPEG3-semaxanib through mPEG9-semaxanib, an ethylene-glycol linked PEG semaxanib conjugate, and additional PEG-semaxanib ester derivatives, including a Compound 6k.
Claims Coverage
The independent claim covers a compound, or pharmaceutically acceptable salt, defined by a formula with two core structural parameters: spacer moiety X selected from a specified set of linkage types, and POLY as a poly(alkylene oxide) having from about 3 to 10 monomer units. The dependent claims refine the poly(alkylene oxide) identity, constrain the integer n range, specify X via a structural group shown in images, and further define certain oral dosage forms.
Selected spacer moiety with poly(alkylene oxide) conjugate
A compound having the formula, or pharmaceutically acceptable salts thereof, wherein X is a spacer moiety selected from a single bond, an ether, an amide, a urethane, an amine, a thioether, a carbamate, an ester, a carbonate, and a urea linkage; and POLY is a poly(alkylene oxide) having from about 3 to 10 monomer units.
Poly(ethylene oxide) variant of POLY
The compound has the poly(alkylene oxide) component specifically as poly(ethylene oxide).
Integer n constrained for polymer units
The compound is defined such that n is an integer from 3 to 10.
Narrowed integer n range
The compound is defined such that n is an integer between 3 and 9.
Image-defined spacer structural group
The compound is defined with the substituent X being a specific structural group shown in the provided image(s).
Oral dosage form types
The claimed composition is provided in one of several oral dosage forms including tablet, caplet, capsule, gel capsule, troche, dispersion, suspension, solution, elixir, or syrup.
Overall, the claim set focuses on semaxanib-poly(alkylene oxide) conjugate compounds characterized by the selection of spacer linkage X and a controlled poly(alkylene oxide) length (n), with further refinements to poly(ethylene oxide), narrower n ranges, image-defined X structures, and specified oral dosage form types.
Stated Advantages
Improved properties versus free semaxanib while retaining VEGFR/Flk-1/KDR inhibitory pharmacology.
Documented Applications
Therapeutic use for diseases mediated by abnormal protein kinase activity, particularly RTKs.
In vitro kinase inhibition assessment against c-Kit, VEGFR-2, and RET using Caliper-based enzymatic IC50 assays.
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