Stabilized polymeric thiol reagents

A water-soluble polymeric reagent comprising the structure:

• PEG-[Y—S—W]x
• wherein:
• Y is a divalent linking group consisting of a saturated or unsaturated hydrocarbon backbone which is three to eight carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents as defined herein, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• S is a sulfur atom attached to an sp3 hybridized carbon of Y;
• S—W is a thiol, protected thiol, or thiol-reactive thiol derivative;
• x=1-25;
• and
• PEG has a molecular weight of at least 500 when PEG is linear, x=1, and Y is a linear alkyl chain.

A water-soluble polymeric reagent comprising the structure:

• POLY-[Y—S—W]x
• wherein:
• POLY is a water soluble polymer;
• Y is a divalent linking group, containing at least four carbon atoms, consisting of a saturated or unsaturated hydrocarbon backbone which is three to ten carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• S is a sulfur atom attached to an sp3 hybridized carbon of Y;
• x is 2-25;
• and
• S—W is a thiol, protected thiol, or thiol-reactive thiol derivative.

A water-soluble polymeric reagent comprising the structure:

• PEG-[Y—S—W]x
• wherein:
• Y is a divalent linking group consisting of a saturated or unsaturated hydrocarbon backbone which is three to ten carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents as defined herein, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• S is a sulfur atom attached to an sp3 hybridized carbon of Y;
• x is 2-25;
• and
• S—W is a thiol, protected thiol, or thiol-reactive thiol derivative.

A polymer conjugate comprising the structure:

• POLY-[Y—S—S-A]x
• wherein:
• POLY is a water soluble polymer;
• Y is a linking group having a saturated or unsaturated hydrocarbon backbone which is three to ten carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents as defined herein, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• S—S is a disulfide group attached to an sp3 hybridized carbon of Y;
• and
• A is a covalently linked residue of a pharmacologically active molecule;
• and
• x is 1-25.

A polymer conjugate comprising the structure:

• POLYA-L—S—S—Y-POLYB-Y—S—S-A
• wherein:
• each of POLYA and POLYB is a water soluble polymer segment, where POLYB has a molecular weight of 10 KDa or less, and the sum of the molecular weights of POLYA and POLYB is at least 3 KDa;
• each Y is independently a divalent linking group consisting of a saturated or unsaturated hydrocarbon backbone which is three to ten carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents as defined herein, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• L is a linker group;
• each S—S is a disulfide group attached to an sp3 hybridized carbon of the adjacent Y;
• and A is a covalently linked residue of a pharmacologically active molecule.

A method for delivering a pharmacologically active molecule to a subject, said method comprising administering to the subject, in a pharmaceutically acceptable carrier, a conjugate comprising the structure:

• POLY-[Y—S—S-A]x
• wherein:
• P1 POLY is a water soluble polymer;
• Y is a divalent linking group consisting of a saturated or unsaturated hydrocarbon backbone which is three to ten carbon atoms in length and has substituents which are independently selected from hydrogen, lower alkyl, lower alkenyl, and non-interfering substituents as defined herein, where two such alkyl and/or alkenyl substituents on different carbon atoms of the backbone may be linked so as to form a cycloalkyl, cycloalkenyl, or aryl group;
• S—S is a disulfide group attached to an sp3 hybridized carbon of Y;
• x is 1-25;
• and
• A is a covalently linked residue of said pharmacologically active molecule, wherein said molecule has a reactive thiol group in unconjugated form.