METHODS OF PRODUCING CONJUGATES Russian patent published in 2017 - IPC A61K47/50 C07D487/04 C07D519/00 A61P35/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a process for preparing a conjugate comprising an agent that binds to cells (CBA) and conjugated to a cytotoxic compound by a binding group, where the said process comprises reacting of the modified cytotoxic compound with modified CBA at pH from about 4 to about 9, wherein the modified CBA includes a residue of a bifunctional crosslinking agent associated with CBA and the said residue includes a binding group and a group capable of reacting with a thiol, wherein CBA is an antibody and the modified CBA is represented by the formulas set forth in the claims, the modified cytotoxic compound comprises a thiol group and is obtained by reacting of imine-containing cytotoxic compound (carrying a thiol group) with a reagent capable of reacting with imines, and wherein the imine-containing cytotoxic compound is represented by the formula:

,

wherein X' is -H, Y' is -H or oxo-group, W' represents -N(R^e)-, R^e is -(CH₂-CH₂-O)_n-R^k, wherein R^k is -H, a linear, branched or cyclic alkyl having from 1 to 6 carbon atoms, n is an integer from 1 to 24, R^x is a linear or branched alkyl having from 1 to 6 carbon atoms, A and A' are-O-, R₆ is -OR, R, in each case, is a linear or branched alkyl having from 1 to 6 carbon atoms, G is a -CH-, and the reagent capable of reacting with imines is selected from the group consisting of sulfite, metabisulfite and dithionite. The invention also relates to other methods of producing conjugate.

EFFECT: herein there is a description of new methods of obtaining a conjugate using a reagent capable of reacting and imines for modifying the imine-containing cytotoxic compounds.

54 cl, 28 dwg, 16 tbl, 16 ex