Reversible pegylated drugs

摘要

Reversible pegylated drugs are provided by derivatization of free functional groups of the drug selected from amino, hydroxyl, mercapto, phosphate and/or carboxyl with groups sensitive to mild basic conditions such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), to which group a PEG moiety is attached. In these pegylated drugs, the PEG moiety and the drug residue are not linked directly to each other, but rather both residues are linked to different positions of the scaffold Fmoc or FMS structure that is highly sensitive to bases and is removable under physiological conditions. The drugs are preferably drugs containing an amino group, most preferably peptides and proteins of low or medium molecular weight. Similar molecules are provided wherein a protein carrier or another polymer carrier replaces the PEG moiety.

主权项

1. A method for preparation of a conjugate of the formula:herein designated (PEG-FMS)n-drug when R2 is —SO3H at position 2 of the fluorene ring or (PEG-Fmoc)n-drug when R2 is H at position 2 of the fluorene ring, wherein n is an integer from 1 to 3, PEG is a linear or branched PEG moiety of molecular weight in the range of 200 to 200,000, and the drug is a peptide or a protein drug of low or medium molecular weight, said method comprising:
(i) reacting a peptide or protein drug of low or medium molecular weight with at least one equivalent of N-[2 maleimido-propionylamino)-7-sulfo-fluoren-9-yl-methoxy-carbonyloxy]succinimide or N-[2 (maleimidopropionylamino)fluoren-9-yl-methoxycarbonyloxy]succinimide, herein identified MAL-FMS-NHS or MAL-Fmoc-NHS, thus obtaining a conjugate (MAL-FMS)n-drug or (MAL-Fmoc)n-drug, respectively; and (ii) reacting the conjugate (MAL-FMS)n-drug or (MAL-Fmoc)n-drug with PEG-SH, thus obtaining the conjugate (PEG-FMS)n-drug or (MAL-Fmoc)n-drug, respectively.