Conjugates of tumor necrosis factor inhibitors to functionalized polymers
AssigneeQuiaPEG Pharmaceuticals AB
InventorMarek Kwiatkowski
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Abstract
This document relates to conjugates of TNF inhibitors or derivatives thereof and functionalized (e.g., mono- or bi-functional) polymers (e.g., polyethylene glycol and related polymers) as well as methods and materials for making and using such conjugates.
Claims34
A method of making a TNF inhibitor conjugate, said method comprising reacting a TNF inhibitor with a preparation comprising a water-soluble, non-peptidic, and non-nucleotidic polymer backbone having at least one terminus covalently bonded to a structure of formula (1) under conditions suitable for group M or R to react with a TNF inhibitor:
- or a salt thereof,
- wherein:
- A is the point of covalent bonding to the terminus of the polymer backbone;
- E is O;
- P is phosphorous;
- K is selected from the group consisting of:
- alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
- G is selected from the group consisting of:
- hydrogen, alkoxy, and a hydrophobic separation handle;
- Z1 and Z2 are O;
- L is selected from the group consisting of:
- a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
- M is a protected group that when deprotected is reactive with a TNF inhibitor or is a group reactive with a TNF inhibitor;
- R is absent or selected from the group consisting of:
- hydrogen, a protecting group, a hydrophobic separation handle, or an activating group;
- R1 is absent or a hydrophobic separation handle;
- wherein when M is a protected group that when deprotected is reactive with a a TNF inhibitor, then R is a protecting group or a hydrophobic separation handle;
- wherein when M is a group reactive with a TNF inhibitor, R is absent, hydrogen, or an activating group;
- and
- wherein only one of R, R1, and G can be a hydrophobic separation handle.
A conjugate, or a pharmaceutically acceptable salt thereof, comprising a water-soluble, non-peptidic, and non-nucleotidic polymer backbone having at least one terminus covalently bonded to a structure of formula (9):
- or a salt thereof,
- wherein:
- A is the point of covalent bonding to the terminus of the polymer backbone;
- E is O;
- P is phosphorous;
- K is selected from the group consisting of:
- alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
- G is selected from the group consisting of:
- hydrogen, alkoxy, and a hydrophobic separation handle;
- Z1 and Z2 are O;
- L is selected from the group consisting of:
- a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
- R1 is absent or a hydrophobic separation handle, wherein only one of R1 and G can be a hydrophobic separation handle;
- L2 is a covalent linking moiety between L and B;
- and
- B is a TNF inhibitor.
Dependencies are inferred from the claim text.