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/molecule;
• Drug represents the drug linked to the cell-binding agent via the hydrophilic linker by a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cycloheteroalkyane, 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;
• In addition, when m=1, n=0, Q is not —P(═O)(OM)-;
• or when n=1, m=0, T is not —P(═O)(OM)-;
• R1, R2, R3, R4, R5 and R6, are the same or different and are 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 1-6 carbon atoms of esters, ether, amide, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or combination thereof.
• Additionally R1, R2, R3 and R4 are respectively a chain of atoms selected from C, N, O, S, Si, and P that covalently connects the cell-surface binding ligand, the phosphinate or sulfonyl group, the conjugated drug and among themselves (R1, R2, R3 and R4). The atoms used in forming the hydrophilic linker may be combined in all chemically relevant ways, such as forming alkylene, alkenylene, and alkynylene, ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or combination thereof.
• M is H, or Na, or K, or N+R1R2R3 or a pharmaceutical salt. R1, R2 and R3 are described above.

A compound of formula (III):

• wherein:
• Cb represents a cell-binding agent/molecule;
• Z represents a functional group that enables reaction with a cytotoxic drug;
• 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;
• In addition, when m=1, n=0, Q is not —P(═O )(OM)-;
• or when n=1, m=0, T is not —P(═O )(OM)-;
• Z represents a functional group that enables linkage of a cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quartary), imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond;
• R1, R2, R3, R4, R5 and R6, are the same or different and are 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 1-6 carbon atoms of esters, ether, amide, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or combination thereof.
• Additionally R1, R2, R3 and R4 are respectively a chain of atoms selected from C, N, O, S, Si, and P that covalently connects the cell-surface binding ligand, the phosphinate or sulfonyl group, the conjugated drug and among themselves (R1, R2,R3 and R4). The atoms used in forming the hydrophilic linker may be combined in all chemically relevant ways, such as forming alkylene, alkenylene, and alkynylene, ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or combination thereof.
• M is H, or Na, or K, or N+R1R2R3 or a pharmaceutical salt. R1, R2 and R3 are described above.

A compound of formula (IV):

• W herein:
• Y represents a functional group that enables reaction 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;
• In addition, when m=1, n=0, Q is not —P(═O )(OM)-;
• or when n=1, m=0, T is not —P(═O )(OM)-;
• “Drug” represents the drug linked to the cell-binding agent via the hydrophilic linker by a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond;
• R1, R2, R3, R4, R5 and R6, are the same or different and are 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 1-6 carbon atoms of esters, ether, amide, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or combination thereof.
• Additionally R1, R2, R3 and R4 are respectively a chain of atoms selected from C, N, O, S, Si, and P that covalently connects the cell-surface binding ligand, the phosphinate or sulfonyl group, the conjugated drug and among themselves (R1, R2, R3 and R4). The atoms used in forming the hydrophilic linker may be combined in all chemically relevant ways, such as forming alkylene, alkenylene, and alkynylene, ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or combination thereof.
• M is H, or Na, or K, or N+R1R2R3 or a pharmaceutical salt. R1, R2 and R3 are described above.