Heterocyclic self-immolative linkers and conjugates
AssigneeSeattle Genetics, Inc.
InventorBainian Feng
Life of this patent
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Abstract
The present invention provides heterocyclic linker compounds useful for linking drug moieties to ligands. The compounds also include drug-ligand conjugates comprising a ligand capable of targeting a selected cell population, and a drug connected to the ligand by a heterocyclic linker moiety. The linker moiety comprises a peptide sequence that is a substrate for an intracellular enzyme, for example a cathepsin, that cleaves the peptide at an amide bond. The peptide further contains a self-immolating moiety which connects the drug and the protein peptide sequence. Upon cleavage of the peptide sequence by an intracellular enzyme the self-immolating moiety cleaves itself from the drug moiety such that the drug moiety is in an underivatized and active form.
Claims19
A drug-ligand conjugate compound comprising a cell-specific ligand and a drug moiety conjugated by a linker wherein said linker comprises a heterocyclic self-immolative moiety of Formula I
- where the wavy lines indicate the covalent attachment sites to the cell-specific ligand and the drug moiety, and wherein:
- U is O, S or NR6;
- Q is CR4 or N;
- T is NH, NR6, O or S pending from said drug moiety;
- R1, R2, R3 and R4 are independently selected from H, F, Cl, Br, I, OH, —N(R5)2, —N(R5)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R5, —S(═O)R5, —SR5, —SO2N(R5)2, —C(═O)R5, —CO2R5, —C(═O)N(R5)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 halosubstituted alkyl, polyethyleneoxy, phosphonate, phosphate, C1-C8 alkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl, C2-C8 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C1-C20 heterocycle, and C1-C20 substituted heterocycle;
- or when taken together, R2 and R3 form a carbonyl (═O), or spiro carbocyclic ring of 3 to 7 carbon atoms;
- and
- R5 and R6 are independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl, C2-C8 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C1-C20 heterocycle, and C1-C20 substituted heterocycle;
- where C1-C8 substituted alkyl, C2-C8 substituted alkenyl, C2-C8 substituted alkynyl, C6-C20 substituted aryl, and C2-C20 substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —N(R5)2, —N(R5)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R5, —S(═O)R5, —SR5, —SO2N(R5)2, —C(═O)R5, —CO2R5, —C(═O)N(R5)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1C8 trifluoroalkyl, C1-C8 alkyl, C3-C12 carbocycle, C6-C20 aryl, C2-C20 heterocycle, polyethyleneoxy, phosphonate, and phosphate.
Dependencies are inferred from the claim text.