Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules

A cell-binding agent-drug conjugate of formula (II):

• wherein:
• Cb represents a cell-binding agent;
• Drug represents a drug linked to the cell-binding agent via the hydrophilic linker by a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cycloheteroalkane, heteroaromatic, alkoxime or amide bond;
• Q and T are either —P(═O)(OM)-, or —S(O2)—, or —S(O)—;
• m and n are integer from 0 to 5, but not 0 at the same time;
• provided that when m=1, n=0, Q is not —P(═O)(OM)-;
• when n=1, m=0, T is not —P(═O)(OM)-;
• and when Q or T is —S(O)—, m and n are not 0:
• R1, R2, R3, and R4, are the same or different and are absent, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof,
• or R1, R2, R3 and R4 are respectively a chain of two or more atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug and among themselves (R1, R2, R3 and R4);
• R5 and R6, are the same or different and are absent, H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof;
• M is H, or Na, or K, or N+R1R2R3 or a pharmaceutical salt.

A compound of formula (III):

• wherein:
• Cb represents a cell-binding agent;
• Q and T are either —P(═O)(OM)-, or —S(O2)—, or —S(O)—;
• m and n are integer from 0 to 5, but not 0 at the same time;
• provided that when m=1, n=0, Q is not —P(═O)(OM)-;
• and when n=1, m=0, T is not —P(═O)(OM)-;
• q is an integer from 1 to 20;
• Z represents a functional group that enables linkage of the compound to a cytotoxic drug via a disulfide, thioether, thioester, hydrazone, ether, ester, carbamate, carbonate, secondary, tertiary, or quaternary amine, imine, cycloheteroalkane, heteroaromatic, alkoxime or amide bond;
• R1, R2, R3, and R4, are the same or different and are absent, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof,
• or R1, R2, R3 and R4 are respectively a chain of two or more atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug and among themselves (R1, R2, R3 and R4);
• R5 and R6, are the same or different and are absent, H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof;
• M is H, or Na, or K, or N+R1R2R3 or a pharmaceutical salt.

A compound of formula (IV):

• wherein:
• Y represents a functional group that enables reaction of the compound with a cell-binding agent;
• Q and T are either —P(═O)(OM)-, or —S(O2)—, or —S(O)—;
• m and n are integer from 0 to 5, but not 0 at the same time;
• provided that when m=1, n=0, Q is not —P(═O)(OM)-;
• and when n=1, m=0, T is not —P(═O)(OM)-;
• “Drug” represents a drug linked to the cell-binding agent via the hydrophilic linker by a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cycloheteroalkane, heteroaromatic, alkoxime or amide bond;
• R1, R2, R3, and R4, are the same or different and are absent, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof,
• or R1, R2, R3 and R4 are respectively a chain of two or more atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug and among themselves (R1, R2, R3 and R4);
• R5 and R6, are the same or different and are absent, H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or combination thereof;
• M is H or Na, or K or N+R1R2R3 or a pharmaceutical salt.