Conjugation method for carrier-linked prodrugs

A compound of formula (II)

• Z-(L2′-B0)b (II),
• wherein
• —Z is a carrier comprising a C8-24 alkyl moiety or a polymeric moiety;
• -L2′- is a chemical bond or a spacer;
• —B0 is —Y0;
• b is an integer of at least 1;
• and
• —Y0 is a substituted hydroxylamine.

A method of synthesizing a carrier-linked prodrug, the method comprising the step of reacting a compound of formula (I)

• D-(L1-L2-A)a (I),
• wherein
• -D is a drug moiety;
• each -L1- is independently a reversible prodrug linker, which is covalently conjugated to -D through a reversible linkage that is cleavable in the absence of enzymes in aqueous buffer at pH 7.4 and 37° C.;
• each -L2- is independently a chemical bond or a spacer;
• each -A is —X0 or —Y0;
• a is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;
• —X0 is a substituted acyl borate;
• and
• —Y0 is a substituted hydroxylamine;
• under aqueous conditions with a compound of formula (II)
• Z-(L2′-B0)b (II),
• wherein
• —Z is a carrier comprising a C8-24 alkyl moiety or a polymeric moiety;
• -L2′- is a chemical bond or a spacer;
• —B0 is —Y0;
• b is an integer of at least 1;
• and
• —Y0 is a substituted hydroxylamine;
• with -A being —X0 and —B0 being —Y0, and forming an amide bond between moiety -A and a moiety —B0.