CONJUGATES OF TUMOR NECROSIS FACTOR INHIBITORS TO FUNCTIONALIZED POLYMERS
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.
1 . (canceled)
2 . A preparation comprising a compound of formula (2):
or a salt thereof, wherein:
polymer is a linear, water-soluble, non-peptidic, and non-nucleotidic polymer backbone, wherein each linking group is bonded at a different terminus of said polymer;
E and E 1 are independently O or S;
K and K 1 are independently selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
G and G 1 are independently absent or are selected from the group consisting of: alkoxy and a hydrophobic separation handle;
each pair of Z 1 and Z 2 and Z 3 and Z 4 are independently selected from O and NH, wherein only one of each pair of Z 1 and Z 2 and Z 3 and Z 4 can be NH;
L and L 1 are independently selected from the group consisting of: a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
M and M 1 are independently selected from a protected group that when deprotected is reactive with a TNF inhibitor or said derivative or a group reactive with a TNF inhibitor or said derivative, wherein M and M 1 are different; and
R and R 1 are independently absent, hydrogen, a protecting group, or an activating group;
wherein when M is a protected group that when deprotected is reactive with a TNF inhibitor or said derivative, then R is a protecting group or a hydrophobic separation handle;
wherein when M is a group reactive with a TNF inhibitor or said derivative, R is absent, hydrogen, or an activating group;
wherein when M 1 is a protected group that when deprotected is reactive with a TNF inhibitor or said derivative, then R 1 is a protecting group or a hydrophobic separation handle; and
wherein when M 1 is a group reactive with a TNF inhibitor or said derivative, R 1 is absent, hydrogen, or an activating group.
3 . The preparation of claim 2 , wherein said polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(α-hydroxy acid), poly(vinyl alcohol), polyoxazoline, and copolymers.
4 . The preparation of claim 2 , wherein said polymer backbone is poly(ethylene glycol).
5 . The preparation of claim 4 , wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da.
6 . The preparation of claim 2 , wherein E is O.
7 . The preparation of claim 2 , wherein E 1 is O.
8 . The preparation of claim 2 , wherein Z 1 is O and Z 2 is NH.
9 . The preparation of claim 2 , wherein both Z 1 and Z 2 are O.
10 . The preparation of claim 2 , wherein Z 3 is O and Z 4 is NH.
11 . The preparation of claim 2 , wherein both Z 3 and Z 4 are O.
12 . The preparation of claim 2 , wherein K is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol.
13 . The preparation of claim 2 , wherein K 1 is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol.
14 . The preparation of claim 2 , wherein G is a substituted or unsubstituted trityloxy.
15 . The preparation of claim 2 , wherein G 1 is a substituted or unsubstituted trityloxy.
16 . The preparation of claim 2 , wherein L is a substituted or unsubstituted C 1 -C 12 alkylene.
17 . The preparation of claim 2 , wherein L 1 is a substituted or unsubstituted C 1 -C 12 alkylene.
18 . The preparation of claim 2 , wherein M, when deprotected, is selected from the group consisting of: hydroxyl, amine, thiol, carboxyl, aldehyde, glyoxal, dione, alkenyl, alkynyl, alkedienyl, azide, acrylamide, vinyl sulfone, hydrazide, aminoxy, maleimide, dithiopyridine, and iodoacetamide.
19 . The preparation of claim 2 , wherein M 1 , when deprotected, is selected from the group consisting of: hydroxyl, amine, thiol, carboxyl, aldehyde, glyoxal, dione, alkenyl, alkynyl, alkedienyl, azide, acrylamide, vinyl sulfone, hydrazide, aminoxy, maleimide, dithiopyridine, and iodoacetamide.
20 . The preparation of claim 2 , wherein said TNF inhibitor is selected from the group consisting of a fusion protein, a monoclonal antibody, and an antibody fragment.
21 . The preparation of claim 2 , wherein said TNF inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.