Polyethylene glycol-conjugated glucocorticoid prodrugs and compositions and methods thereof

A method of preparing a glucocorticoid prodrug compound of formula (XII):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• n is an integer selected from 10 to 300;
• m is 1, 2, 3, or 4;
• w is 1 or 2;
• GC is a moiety of a glucocorticoid drug molecule;
• A is absent or C1-C6 alkylene;
• B is absent, NH, or C(O);
• D is absent, NH, O, or C(O);
• E is a linker selected from:
• where i and j are independently 0 or an integer selected from 1 to 5;
• G is NH;
• P is absent or C(O);
• Q is absent or C1-C6 alkylene;
• T is absent or C(O);
• X is absent, O, or NH;
• Y is absent, C(O), or C1-C6 alkylene;
• Z is absent, NR4, O, C1-C6 alkylene, or a linker comprising a branched structure capable of connecting to one or more glucocorticoid drug molecular moieties, said linker optionally comprising one or more heteroatoms independently selected from O, S, and N;
• and
• R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, each group except H optionally substituted;
• R4 at each occurrence is independently H or C1-C4 alkyl;
• wherein when any of A, B, D, E, G, P, Q, T, X, Y, and Z groups is absent, its two available adjacent groups are single-bonded to each other directly,
• the method comprising steps of:
• (a1) coupling a linker compound comprising a moiety of structure E with a glucocorticoid hydrazone derivative of formula (A) or (B) to form an intermediate;
• and
• (b1) coupling the intermediate with a polyethylene glycol derivative selected from PEG-OH, PEG-NH2, PEG-CO2H, and PEG-CO2R10 to form a precursor compound to the compound of structure (XII) comprising one or more OH-protecting groups;
• or
• alternatively, (a2) coupling a linker compound comprising a moiety of structure E with a polyethylene glycol derivative selected from PEG-OH, PEG-NH2, PEG-CO2H, and PEG-CO2R10 to form an intermediate;
• and
• (b2) coupling the intermediate with a glucocorticoid hydrazone derivative of formula (A) or (B) to form a precursor compound to the compound of structure (XII) comprising one or more OH-protecting groups;
• and
• (c) removing the OH-protecting groups from the precursor compound to obtain the compound of structure (XII),
• wherein R10 is C1-C4 alkyl.