Stable 4-isoxazoline conjugates
AssigneeSynaffix B.V.
InventorsElias POST, Remon VAN GEEL, Sander Sebastiaan VAN BERKEL, Floris Louis VAN DELFT
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Abstract
Disclosed herein are nitrones that are capable of forming 4-isoxazoline compounds by strain-promoted alkyne-nitrone cycloaddition (SPANC), which have improved stability. The 4-isoxazoline compounds do not disintegrate by rearrangement into two molecules. The nitrone compounds disclosed herein are suitable for preparing bioconjugates by SPANC reaction. Also disclosed herein are the thus obtained bioconjugates, as well as the application thereof in targeting cells and treating cancer.
Claims14
A process for preparing an isoxazoline compound by strain-promoted alkyne nitrone cycloaddition (SPANC), comprising reacting a nitrone compound with a (hetero)cycloalkyne compound to obtain the isoxazoline compound, wherein the nitrone compound has structure (1):
- wherein
- R1 is L10XR4, wherein:
- L10 is a linker of structure (C(R3)2)z, wherein z is 2 or 3, and each R3 is individually selected from H and C1-4 alkyl, or two occurrences of R3 may be joined together to form an oxo group, a C3-6 (hetero)cycloalkyl group;
- R4 is selected from H and C1-4 alkyl;
- X is S, O or NH,
- R2a is selected from H and C1-6 (cyclo)alkyl;
- R2b is selected from the group consisting of C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR14 wherein R14 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, or wherein R2b is L(D)r, wherein D is a payload, r is an integer in the range of 1-10, and L is a linker covalently connecting D with the nitrone group, or R2b is L6(B), wherein B is a biomolecule and L6 is a linker covalently connecting B with the nitrone group;
- wherein when R2a and R2b are different, the configuration of the C=N double bond in the nitrone group may be E or Z,
- or a salt thereof.
A bioconjugate having structure (3), (4), (5) or (6), or a salt thereof:
- wherein:
- B is a biomolecule;
- D is a payload;
- L6 is a linker covalently connecting B with the isoxazoline group;
- L is a linker covalently connecting the isoxazoline group with (D)r;
- r is an integer in the range of 1-10;
- x is an integer in the range of 1-4;
- y is an integer in the range of 1-10;
- R1 is L10XR4;
- L10 is a linker of structure (C(R3)2)z, wherein z is 2 or 3, and each R3 is individually selected from H and C1-4 alkyl, wherein two occurrences of R3 may be joined together to form a C3-6 (hetero)cycloalkyl group;
- R4 is selected from H and C1-4 alkyl;
- X is S, O or NH,
- R2 is selected from H and C1-4 alkyl.
A nitrone compound of structure (1):
- wherein
- R1 is L10XR4, wherein:
- L10 is a linker of structure (C(R3)2)z, wherein z is 2 or 3, and each R3 is individually selected from H and C1-4 alkyl, or two occurrences of R3 may be joined together to form an oxo group, a C3-6 (hetero)cycloalkyl group;
- R4 is selected from H and C1-4 alkyl;
- X is S, O or NH,
- R2a is selected from H and C1-6 (cyclo)alkyl;
- R2b is selected from the group consisting of C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR14 wherein R14 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, or wherein R2b is L(D)r, wherein D is a payload, r is an integer in the range of 1-10, and L is a linker covalently connecting D with the nitrone group, or R2b is L6(B), wherein B is a biomolecule and L6 is a linker covalently connecting B with the nitrone group;
- wherein when R2a and R2b are different, the configuration of the C=N double bond in the nitrone group may be E or Z,
- or a salt thereof.
Dependencies are inferred from the claim text.