Disulfur bridge linkers for conjugation of a cell-binding molecule

A bridge linker compound of Formula (I)

• wherein:
• Y1 and Y2 are the same or different and represent a functional group that enables reaction of the bridge linker compound with a pair of sulfur atoms of a cell-binding agent, to form disulfide, thioether, or thioester bonds, the function group for Y1 and Y2 being a N-hydroxysuccinimide ester, maleimide, disulfide, haloacetyl, ethenesulfonyl, acryl(acryloyl), 2-(tosyloxy)acetyl, 2-(mesyloxy)acetyl, 2-(nitrophenoxy)acetyl, 2-(dinitrophenoxy)acetyl, 2-(fluorophenoxy)-acetyl, 2-(difluorophenoxy)-acetyl, 2-(pentafluorophenoxy)acetyl, 2-(((trifluoromethyl)-sulfonyl)oxy)-acetyl, or acid anhydride group, as shown below:
• N-hydroxysuccinimide ester;
• maleimide;
• disulfide;
• haloacetyl;
• ethenesulfonyl;
• acryl (acryloyl);
• 2-tosyloxy)acetyl;
• 2-mesyloxy)acetyl;
• 2-nitrophenoxy)acetyl;
• 2-(dinitrophenoxy)acetyl;
• 2-(fluorophenoxy)-acetyl;
• 2-(difluorophenoxy)-acetyl;
• 2-(pentafluorophenoxy)acetyl;
• methylsulfone phenyloxadiazole (ODA);
• (((trifluoromethyl)-sulfonyl)oxy)acetyl;
• acid anhydride,
• wherein X1 is F, Cl, Br, I or Lv;
• X;
• is O, NH, N(R1′), or CH2;
• R5 is R1′, aromatic, heteroaromatic, or aromatic group wherein one or several H atoms are replaced independently by —R1′, -halogen, —OR1′, —SR1′, —NR1′R1′, —NO2, —S(O)R1′, —S(O)2R1′, or —COOR1′;
• Lv is a leaving group selected from the group consisting of nitrophenol;
• N-hydroxysuccinimide (NHS);
• phenol;
• dinitrophenol pentafluorophenol;
• tetrafluorophenol;
• difluorophenol;
• monofluorophenol;
• pentachlorophenol;
• triflate;
• imidazole;
• dichlorophenol;
• tetrachlorophenol;
• 1-hydroxybenzotriazole;
• tosylate;
• mesylate;
• and 2-ethyl-5-phenylisoxazolium-3′-sulfonate;
• R1′ and R2′ are the same or different, and are H, a linear alkyl having from 1 to 8 carbon atoms, branched or cyclic alkyl having from 3 to 8 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 8 carbon atoms, or an ester, ether or amide having 2 to 8 carbon atoms;
• Z1 and Z2 are the same or different and represent a function group of a thiol, disulfide, amino, carboxy, aldehyde, ketone, maleimido, haloacetyl, hydrazine, alkoxyamino, or hydroxy group;
• R1, R2, R3 and R4 are the same or different, and are one or more linker components selected from the group consisting of 6-maleimidocaproyl (MC)
• maleimido propanoyl (MP)
• valine-citrulline (val-cit), alanini-phenylalanine (ala-phe), lysine-phenylalanine (lys-Phe), p-amidobenzyloxycarbonyl (PAB)
• 4-thio-pentanoate (SPP)
• 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (MCC)
• 4-thio-butyrage (SPDB)
• maleimidoethyl (ME)
• 4-thio-2-hydroxysulfonyl-butyrate (2-Sulfo-SPDB)
• alkoxy amino (AOA), ethyleneoxy (EO) —CH2CH2O—, 4-methyl-4-dithio-pentanoic (MPDP)
• alkynyl —C═C—, dithio —S—S—, peptides containing 1˜25 aminoacids, and (4-acetyl)aminobenzoate (SIAB)