CONJUGATES OF BIOLOGICALLY ACTIVE MOLECULES TO FUNCTIONALIZED POLYMERS
This document relates to conjugates of a biologically active molecule or a derivative 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 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising a structure of formula (10):
or a salt form thereof, wherein:
polymer is poly(ethylene glycol), wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da, wherein each linking group is bonded at a different terminus of said polymer;
E is O;
E 1 is O;
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;
Z 1 is O;
Z 2 is O;
Z 3 is O;
Z 4 are O;
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;
L 2 is a covalent linking moiety between L on the polymer backbone and B;
L 3 is a covalent linking moiety between L on the polymer backbone and B 1 ;
B is a TNF inhibitor or a derivative thereof; and
B 1 is a TNF inhibitor or a derivative thereof.
2 . The conjugate of claim 1 , wherein B is a TNF inhibitor.
3 . The conjugate of claim 1 , wherein B 1 is a TNF inhibitor.
4 . The conjugate of claim 1 , 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.
5 . The conjugate of claim 1 , 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.
6 . The conjugate of claim 1 , wherein G is substituted or unsubstituted trityloxy.
7 . The conjugate of claim 1 , wherein G is alkoxy.
8 . The conjugate of claim 1 , wherein G 1 is substituted or unsubstituted trityloxy.
9 . The conjugate of claim 1 , wherein G 1 is alkoxy.
10 . The conjugate of claim 1 , wherein L is a divalent radical of a nucleoside.
11 . The conjugate of claim 1 , wherein L 1 is a divalent radical of a nucleoside.
12 . The conjugate of claim 1 , wherein L is alkylene.
13 . The conjugate of claim 1 , wherein L 1 is alkylene.
14 . The conjugate of claim 1 , wherein:
B is a TNF inhibitor;
B 1 is a TNF inhibitor;
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;
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;
G is alkoxy;
G 1 is alkoxy;
L is alkylene; and
L 1 is alkylene.
15 . The conjugate of claim 1 , wherein:
B is a TNF inhibitor;
B 1 is a TNF inhibitor;
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;
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;
G is substituted or unsubstituted trityloxy;
G 1 is substituted or unsubstituted trityloxy;
L is a divalent radical of a nucleoside; and
L 1 is a divalent radical of a nucleoside.
16 . A composition comprising the conjugate of claim 1 , and a pharmaceutically acceptable excipient.
17 . A method of treating a patient diagnosed with an inflammatory disease, said method comprising administering to said patient an effective amount of the conjugate of claim 1 .
18 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising a compound of formula (11):
or a salt form thereof,
wherein:
polymer is poly(ethylene glycol wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da, wherein L 4 and the phosphonate-derived functional group are bonded at a different terminus of said polymer;
E and E 1 are O;
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;
Z 1 and Z 2 are independently 0;
L is selected from the group consisting of: a divalent radical of nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
L 2 is a covalent linking moiety between L on the polymer backbone and B;
L 4 is a covalent linking moiety between L on the polymer backbone and B 1 ; and
B and B 1 are independently a TNF inhibitor, a derivative of a TNF inhibitor, a biologic other than a TNF inhibitor, a drug, a detectable group, a separation moiety, wherein at least one of B and B 1 is a TNF inhibitor or a derivative of a TNF inhibitor.
19 . A composition comprising the conjugate of claim 18 , and a pharmaceutically acceptable excipient.
20 . A method of treating a patient diagnosed with an inflammatory disease, said method comprising administering to said patient an effective amount of the conjugate of claim 18 .