Novel peptidic linkers and cryptophycin conjugates, their preparation and their therapeutic use

A Compound of formula (I):

• RCG1-L-P (I)
• wherein
• RCG1 represents a reactive chemical group that is reactive towards a chemical group present on a polypeptide such as an antibody;
• P represents a hydrogen atom, —OH or an activated O;
• L represents a linker of formula (II):
• wherein:
• L1 is of formula (III):
• wherein:
• when P represents a hydrogen atom, then x=0 or 1 and y=1 and z=0;
• when P represents —OH, then x=y=z=0;
• when P represents an activated O, then x=1 and y=z=0, or x=y=z=1;
• J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;
• ALK represents a (C1-C12)alkylene group;
• A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group wherein L1 is bonded directly to P;
• (AA)w is a sequence of w amino acids connected together via peptide bonds, wherein the amino acids, (AA)w, are non-substituted amino acids (AAns);
• w represents an integer ranging from 1 to 12;
• wherein:
• L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i—NA7-(C1-C6)alkyl group, a C(═O)—NA7-(C1-C6)alkyl group, a C(═O)—(C1-C6)alkyl-NA7 group, a C(═O)—NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(═O)—NA7-aryl group, a C(═O)—NA7-heteroaryl group, a C(═O)—(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl group, a C(═O)—(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl-(OCH2CH2)i group, a C(═O)—(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl group, a C(═O)—(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(═O)—(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(═O)—(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(═O)—(C1-C6)alkyl-(OCH2CH2)i—NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i—NA7-(C1-C6)alkyl group, a C(═O)—NA8-(C1-C6)alkyl-NA7 group, a C(═O)—NA8-(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl group, a C(═O)—NA8-(C1-C6)alkyl-NA7C(═O)—(C1-C6)alkyl-(OCH2CH2)i group, a C(═O)—NA8-(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl group, a C(═O)—NA8-(C1-C6)alkyl-C(═O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(═O)—NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(═O)—NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(═O)—NA8-(C1-C6)alkyl-(OCH2CH2)i—NA7-(C1-C6)alkyl group;
• A7 represents a straight or branched, saturated or unsaturated, C1-C160 hydrocarbon chain wherein the C1-C160 hydrocarbon is optionally substituted by 1 or more substituents independently selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl), and further wherein 1 or more —CH2— units of the C1-C160 hydrocarbon are optionally and independently replaced by 1 or more atoms or groups independently selected from the group consisting of —CH(OH)—, —CH(SO3H)—, —CH(SO3−M+)-, —C(O)—, —C(O)NH—, —C(O)N(alkyl)-, —C(O)O—, —NHC(O)—, —N(alkyl)C(O)—, —NHS(O)2—, —N(alkyl)S(O)2—, —P(O)(OH)—, —P(O)(OH)O—, —O—, —OC(O)—, —OC(O)O—, —OP(O)(OH)—, —OP(O)(OH)O—, —S(O)—, —S(O)2—, —S(O)2NH—, —S(O)2N(alkyl)-, and heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl);
• A8 represents a hydrogen atom or a (C1-C6)alkyl group;
• M+ is an alkali metal;
• i represents an integer ranging from 1 to 50;
• and
• wherein L2 is bonded to RCG1.