Conjugates of tumor necrosis factor inhibitors to functionalized polymers

A method of preparing a compound 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 or S;
• Y represents an optionally substituted residue selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• Z1 and Z2 are independently selected from O and NH, wherein only one of Z1 and Z2 can be NH;
• L is selected from the group consisting of:
• a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
• L2 is a covalent linking moiety between L on the polymer backbone and B;
• and
• B is a TNF inhibitor or a derivative thereof,
• comprising the steps of:
• (a) providing a composition comprising a compound of formula (8):
• wherein
• A is the point of covalent bonding to the terminus of the polymer backbone;
• E is O or S;
• Y represents an optionally substituted residue selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• Z1 and Z2 are independently selected from O and NH, wherein only one of Z1 and Z2 can be NH;
• L is selected from the group consisting of:
• a divalent radical of a nucleoside, an unsubstituted or substituted alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and an unsubstituted or substituted arylene;
• M is a protected group that when deprotected is reactive with a TNF inhibitor or a derivative thereof;
• R is a hydrophobic separation handle;
• R1 is absent or a hydrophobic separation handle;
• and
• (b) removing the hydrophobic separation handle(s);
• (c) optionally reacting the compound obtained in step (b) with an activating agent;
• and
• (d) reacting the compound obtained in step (b), or, optionally in step (c), with a TNF inhibitor or a derivative thereof.