Multi-arm polymeric prodrug conjugates of pemetrexed-based compounds
Inventors
Cheng, Lin • Riggs-Sauthier, Jennifer
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11612662-B2
Publication Date
2023-03-28
Expiration Date
Abstract
Among other aspects, provided herein are multi-arm polymeric prodrug conjugates of pemetrexed-based compounds. Methods of preparing such conjugates as well as methods of administering the conjugates are also provided. Upon administration to a patient, release of the pemetrexed-based compound is achieved.
Core Innovation
The document describes multi-arm polymeric prodrugs of pemetrexed, where pemetrexed is conjugated to a multi-arm water-soluble non-peptidic polymer (POLY1) through a releasable spacer (X) and an optional hydrolytically stable linker (Q). The resulting conjugates are q-arm prodrugs that provide a defined structural architecture in which pemetrexed is connected to the polymer arms by linkage structures designed for in vivo cleavage and release.
The structural scope includes a polymer arm core (R) that comprises a polyol-, polythiol-, or polyamine residue bearing a plurality of functional groups, together with substituent options for R1/R2/R3 and a scope for POLY1 including poly(alkylene glycol), such as PEG. The document also describes a conjugate according to Formula I in which R, taken with Q, is a residue of pentaerythritol, with Q defined as —CH2O, and q fixed at 4.
The document further emphasizes that the multi-arm architecture supports multiple release events and cleavage/release of pemetrexed in vivo. It includes pharmaceutical composition and administration discussion for conjugates encompassed by the structural definitions, including forms such as pharmaceutically acceptable salts and solvates.
Claims Coverage
The claim coverage centers on two independent themes: a multi-arm polymeric pemetrexed prodrug and a Formula I conjugate/cancer-treatment method. The coverage combines a releasable multi-arm polymer architecture for pemetrexed with a defined pentaerythritol-derived residue, POLY1 as a poly(alkylene glycol), specified linker moieties X, and q fixed at 4.
Multi-arm polymeric pemetrexed prodrug
Pemetrexed is conjugated to a multi-arm water-soluble non-peptidic polymer (POLY1) through a releasable spacer (X) and an optional hydrolytically stable linker (Q), forming a q-arm prodrug architecture designed for in vivo cleavage and release.
Formula I conjugate with pentaerythritol residue, poly(alkylene glycol), and defined linker X
A conjugate according to Formula I where R, taken with Q, is a residue of pentaerythritol (Q = —CH2O), POLY1 is a poly(alkylene glycol), X is one of the specified linker moieties, R1 is selected from H, halo, methyl, methoxy and trifluoromethyl, R2 is selected from H and methyl, R3 is selected from H, lower alkyl and amino, R4 is selected from H, —CH3, —CH(CH3)2, —CH2CH(CH3)2, or —CH(CH3)CH2CH3, and q is 4, including pharmaceutically acceptable salts and solvates.
Cancer treatment by administering the Formula I conjugate
A method of treating cancer comprising administering to a subject in need thereof a conjugate according to formula I defined by the same selections for R (with Q as —CH2O), POLY1 as a poly(alkylene glycol), X as one of the specified linker moieties, q fixed at 4, and substituent selections R1, R2, and R3 as stated, including pharmaceutically acceptable salts and solvates thereof.
Across the independent claims, coverage is focused on a multi-arm pemetrexed prodrug architecture and a defined Formula I conjugate/cancer-treatment method, both using releasable linkage structures and specified polymer and substituent selections.
Stated Advantages
Supports in vivo cleavage/release of pemetrexed.
Provides multiple release events from the multi-arm architecture.
Documented Applications
Cancer treatment by administering a conjugate according to Formula I with q=4 and a releasable linkage.
Use in pharmaceutical compositions for administration of the multi-arm pemetrexed prodrugs, including embodiments with four-arm conjugates encompassed by Formula I.
Interested in licensing this patent?