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US 2017/0360952 A1Published application
Biomolecule conjugates
AssigneeCelgene Corporation
InventorsEric Schwartz, Laura Akullian D'Agostino, Hernan Cuervo, Wesley Austin
Life of this patent
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Abstract
The present invention relates to biomolecule conjugates which comprise a biomolecule wherein at least one non-natural amino acid (NNAA) is integral to the structure of the biomolecule and wherein the NNAA is a point of attachment of a linker to which a payload, particularly a cytotoxic agent, is attached. More specifically, this invention relates to conjugates of cell-binding agents and active release products comprising cytotoxic agents wherein the conjugates are produced by means of a cycloaddition reaction. Methods of production, pharmaceutical compositions and methods of use are provided.
Claims20
An isolated compound of Formula I
- wherein
- A is a strained alkyne ring or a strained alkene ring wherein the ring is carbocyclyl or heterocyclyl;
- D is a payload;
- Each E is independently selected from the group consisting of —CO—, —CR1R2—, —NR3—, —S—S—, —S—, —SO—, —SO2—, —O—, —CR3═N—NR3—, —CR3═N—O—, —CR3═N—NR3—CO—, —N═N—CO—, alkyl, C3-C8 carbocyclyl, —O—(CR1R2)a—, aryl, —(CR1R2)a-aryl, heteroaryl, —(CR1R2)a-heteroaryl, —(CR1R2)a—C3-C8 carbocyclyl, heterocyclyl, —(CR1R2)a-heterocyclyl, —(CH2CH2O)a—, —(CH2CH2O)a—(CH2)b, —(CH2)aC(O)—, amino acid, and peptide;
- R1 and R2 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R3, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, polyethyleneoxy, phosphonate, phosphate, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- or, when taken together, R1 and R2 form a carbonyl (═O), or spiro carbocyclic ring of 3 to 7 carbon atoms;
- and,
- R3 is selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C3-C12 carbocycle, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, C2-C20 heterocyclyl, polyethyleneoxy, phosphonate, and phosphate;
- m is an integer from 1 to 100;
- and,
- a and b are each an integer from 1 to 100.
9 more elements
An isolated conjugate of Formula III or Formula III′
- wherein:
- CB is a cell-binding agent;
- M is a non-natural amino acid;
- A′ is a carbocyclyl or heterocyclyl D is a payload;
- Each E is independently selected from the group consisting of —CO—, —CR1R2—, —NR3—, —S—S—, —S—, —SO—, —SO2—, —O—, —CR3═N—NR3—, —CR3═N—O—, —CR3═N—NR3—CO—, —N═N—CO—, alkyl, C3-C8 carbocyclyl, —O—(CR1R2)a—, aryl, —(CR1R2)a-aryl, heteroaryl, —(CR1R2)a-heteroaryl, —(CR1R2)a—C3-C8 carbocyclyl, heterocyclyl, —(CR1R2)a-heterocyclyl, —(CH2CH2O)a—, —(CH2CH2O)a—(CH2)b, —(CH2)aC(O)—, amino acid, and peptide;
- R1 and R2 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R3, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, polyethyleneoxy, phosphonate, phosphate, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- or, when taken together, R1 and R2 form a carbonyl (═O), or spiro carbocyclic ring of 3 to 7 carbon atoms;
- and,
- R3 is selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C3-C12 carbocycle, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, C2-C20 heterocyclyl, polyethyleneoxy, phosphonate, and phosphate;
- m is an integer from 1 to 100;
- and,
- a and b are each an integer from 1 to 100.
10 more elements
An isolated conjugate of Formula III or Formula III′ produced by the process of reacting a compound of Formula I with a compound of Formula II
- wherein, with reference to Formula I,
- A is a strained alkyne ring or a strained alkene ring wherein the ring is carbocyclyl or heterocyclyl;
- D is a payload;
- Each E is independently selected from the group consisting of —CO—, —CR1R2—, —NR3—, —S—S—, —S—, —SO—, —SO2—, —O—, —CR3═N—NR3—, —CR3═N—O—, —CR3═N—NR3—CO—, —N═N—CO—, alkyl, C3-C8 carbocyclyl, —O—(CR1R2)a—, aryl, —(CR1R2)a-aryl, heteroaryl, —(CR1R2)a-heteroaryl, —(CR1R2)a—C3-C8 carbocyclyl, heterocyclyl, —(CR1R2)a-heterocyclyl, —(CH2CH2O)a—, —(CH2CH2O)a—(CH2)b, —(CH2)aC(O)—, amino acid, and peptide;
- R1 and R2 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R3, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, polyethyleneoxy, phosphonate, phosphate, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- or, when taken together, R1 and R2 form a carbonyl (═O), or Spiro carbocyclic ring of 3 to 7 carbon atoms;
- and,
- R3 is selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, and C1-C20 heterocyclyl;
- alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl are optionally independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, —N(R3)2, —N(R3)3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —S(═O)R3, —SR3, —SO2N(R3)2, —C(═O)R3, —CO2R3, —C(═O)N(R3)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C3-C12 carbocycle, C6-C20 aryl, C6-C20 heteroaryl, C3-C8 carbocyclyl, C2-C20 heterocyclyl, polyethyleneoxy, phosphonate, and phosphate;
- m is an integer from 1 to 100;
- a and b are each an integer from 1 to 100;
- and,
- with reference to Formula II,
- CB is a cell-binding agent;
- M is a non-natural amino acid;
- T is an azide group or a tetrazine group;
- and,
- with reference to Formula III and Formula III′,
- A′ is a carbocyclyl or heterocyclyl.
16 more elements
Dependencies are inferred from the claim text.