Patent ID: 8735350

Claim:
A method for treatment of diabetes mellitus or hyperglycemia comprising administering to an individual in need an effective amount of a conjugate of the formula: (X) n —Y wherein Y is insulin; and X is a radical of the formula (i): wherein R 1 is a radical of the formula —R 5 —R 6 -PEG, wherein PEG is a linear or branched polyethylene glycol (PEG) moiety; R 2 is selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8) alkoxy, (C1-C8)alkoxyalkyl, (C6-C10)aryl, (C1-C8)alkaryl, (C6-C10)ar(C1-C8)alkyl, halogen, nitro, —SO 3 H, —SO 2 NHR, amino, ammonium, carboxyl, PO 3 H 2 , and OPO 3 H 2 , and R is selected from the group consisting of hydrogen, (C1-C8)alkyl and (C6-C10)aryl; R 3 and R 4 , the same or different, are each selected from the group consisting of hydrogen, (C1-C8)alkyl and (C6-C10)aryl; R 5 is selected from the group consisting of —NH—, —S—, —CO—, —CH 2 —, —SO 2 —, and —PO 2 —; and A is OCO— linked to an amino group of the insulin; and n is an integer of at least one, provided that: (i) when R 5 is —NH—, R 6 is —CO—, —COO—, —CH 2 —, —CH(CH 3 )—, —CO—NH—, —CS—NH, —CO—CH 2 —NH—CO—, —CO—CH(CH 3 )—NH—CO—, —CO—CH 2 —NH—CO—NH, Z is O, S or NH that is linked to the PEG moiety; and R 7 is selected from the group consisting of C 1 -C 18 straight or branched alkylene, phenylene, an oxyalkylene radical having 3-18 carbon atoms in the backbone, a residue of a peptide containing 2-10 amino acid residues, and a residue of a saccharide containing 1-10 monosaccharide residues; (ii) when R 5 is —S—, R 6 is and Z is O, S or NH; (iii) when R 5 is —CO—, R 6 is —O—, —NH—, —NH—R 7 —COO—, —NH—R 7 —NH, —NH—R 7 —CO—NH, Z is O, S or NH; and R 7 is selected from the group consisting of C1-C18 straight or branched alkylene, phenylene, an oxyalkylene radical having 3-18 carbon atoms in the backbone, a residue of a peptide containing 2-10 amino acid residues, and a residue of a saccharide containing 1-10 monosaccharide residues; (iv) when R 5 is —CH 2 —, R 6 is —(CH 2 ) n —S— or —(CH 2 ) n —NH—, wherein n is 0 to 18; (v) when R 5 is —SO 2 —, R 6 is —O—; —NH— or —CH 2 —CH 2 —S; and (vi) when R 5 is —PO 2 —, R 6 is —O— or —NH—.