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US 2024/0350657 A1Published application
Sulfomaleimide-based linkers and corresponding conjugates
AssigneePierre Fabre Medicament
InventorsMichel PEREZ, Frédéric MARION, Jean-François HAEUW, Cyrille DREYFUS
Life of this patent
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Abstract
The present invention relates to a linker of the following formula (I) or a salt thereof: The present invention relates to a linker-drug conjugate of the following formula (II) or a salt thereof: The present invention relates also to a binding unit-drug conjugate, such as an antibody-drug conjugate, of the following formula (III) or (IV) or a salt thereof: as well as a pharmaceutical composition comprising such a binding unit-drug conjugate and its use in the treatment of cancer.
Claims20
A linker of the following formula (I):
- or a salt thereof,
- wherein:
- X1 and X2 represent, independently of each other, H, a halogen atom, a (C1-C6) alkoxy, an optionally substituted aryloxy, or —O—(CH2CH2O)rH, provided that X1 and X2 do not represent H at the same time;
- L1 represents a group of formula L1′-(CO—Z′)z;
- with L1′ being-(CH2)n—, —(CH2CH2O)m—CH2—CH2—, arylene, heteroarylene, cycloalkanediyl, —(CH2)n-arylene-, —(CH2)n-heteroarylene-, —(CH2)n-cycloalkanediyl-, -arylene-(CH2)p—, -heteroarylene-(CH2)p—, -cycloalkanediyl-(CH2)p—, —(CH2)n-arylene-(CH2)p—, —(CH2)n-heteroarylene-(CH2)p—, —(CH2)n-cycloalkanediyl-(CH2)p—, —(CH2CH2O)m—CH2—CH2-arylene-(CH2)p—, —(CH2CH2O)m—CH2—CH2-heteroarylene-(CH2)p—, —(CH2CH2O)m—CH2—CH2-cycloalkanediyl-(CH2)p—, —(CH2)n-arylene-CH2—CH2—(OCH2CH2)m—, —(CH2)n-heteroarylene-CH2—CH2—(OCH2CH2)m—, or —(CH2)n-cycloalkanediyl-CH2—CH2—(OCH2CH2)m—;
- each W independently represents an amino acid unit;
- Y is PAB—CO—(Z)z—, with PAB being the oxygen of the PAB unit being linked to CO—(Z)z;
- Z is —NR4—(CH2)u—NR5—, —NR4—(CH2)u—NR5—CO—, —NR4—(CH2)u—NR5—CO—(CH2)v—, or —NR4—(CH2)u—NR5—CO—(CH2)v—CO—, the NR4 group being linked to the CO group of PAB—CO;
- Z′ is-NR4—(CH2)u—NR5- or —NR4—(CH2)u—NR5—CO—(CH2)v—, the NR4 group being linked to the CO group of CO—Z′;
- R4 and R5 are independently H or a (C1-C6)alkyl group;
- c is 0 or 1;
- m is an integer from 1 to 15;
- n is an integer from 1 to 6;
- p is an integer from 1 to 6;
- q is 0, 1 or 2;
- r is an integer from 1 to 24;
- u is an integer from 1 to 6;
- v is an integer from 1 to 6;
- w is an integer from 0 to 5;
- y is 0 or 1;
- z is 0 or 1;
- z′ is 0 or 1;
- and
- X3 represents H when y=z=1 and Z is —NR4—(CH2)u—NR5- or when c=w=y=0, z′=1 and Z′ is-NR4—(CH2)u—NR5- and in the other cases, X3 represents OH, NH2 or a leaving group, wherein the leaving group is a halogen atom, a sulfonate of formula —OSO2—RLG, N-succinimidyloxy, 4-nitro-phenyloxy, pentafluorophenoxy or N-benzotriazoloxy, RLG representing a (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl or (C1-C6)alkyl-aryl group, the said group being optionally substituted with one or several halogen atoms such as fluorine atoms,
- with the proviso that it is not a compound of formula (I) for which:
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Cl, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Br;
- X1 is Cl, X2 is H, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is I;
- X1 is H, X2 is Cl, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is H, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is H, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Cl, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Cl, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Cl, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- X1 is Cl, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- or
- X1 is Br, X2 is Br, q is 0, L1 is
- c is 0, w is 0, y is 0 and X3 is Cl;
- wherein the dashed line indicates the point of attachment of L1 to the nitrogen atom of
- and the wavy line indicates the point of attachment of L1 to X3.
59 more elements
A binding unit-drug conjugate of the following formula (III) or (IV):
- or a salt thereof,
- wherein:
- the binding unit is a peptide, a protein, an antibody, or an antigen binding fragment thereof;
- L1 represents a group of formula L1′-(CO—Z′)z;
- with L1′ being-(CH2)n—, —(CH2CH2O)m—CH2—CH2—, arylene, heteroarylene, cycloalkanediyl, —(CH2)n-arylene-, —(CH2)n-heteroarylene-, —(CH2)n-cycloalkanediyl-, -arylene-(CH2)p—, -heteroarylene-(CH2)p—, -cycloalkanediyl-(CH2)p—, —(CH2)n-arylene-(CH2)p—, —(CH2)n-heteroarylene-(CH2)p—, —(CH2)n-cycloalkanediyl-(CH2)p—, —(CH2CH2O)m—CH2—CH2-arylene-(CH2)p—, —(CH2CH2O)m—CH2—CH2-heteroarylene-(CH2)p—, —(CH2CH2O)m—CH2—CH2—, cycloalkanediyl-(CH2)p—, —(CH2)n-arylene-CH2—CH2—(CH2CH2O)m—, —(CH2)n-heteroarylene-CH2—CH2—(CH2CH2O)m—, or —(CH2)n-cycloalkanediyl-CH2—CH2—(CH2CH2O)m—;
- each W independently represents an amino acid unit;
- Y is PAB—CO—(Z)z—, with PAB being
- the oxygen of the PAB unit being linked to CO—(Z)z;
- Z is-NR4—(CH2)u—NR5—, —NR4—(CH2)u—NR5—CO—, —NR4—(CH2)u—NR5—CO—(CH2)v—, or —NR4—(CH2)u—NR5—CO—(CH2)v—CO—, the NR4 group being linked to the CO group of PAB—CO;
- Z′ is-NR4—(CH2)u—NR5- or —NR4—(CH2)u—NR5—CO—(CH2)v—, the NR4 group being linked to the CO group of CO—Z′;
- R4 and R5 are independently H or a (C1-C6)alkyl group;
- Q represents a drug moiety;
- c is 0 or 1;
- m is an integer from 1 to 15;
- n is an integer from 1 to 6;
- p is an integer from 1 to 6;
- s is an integer from 1 to 8;
- u is an integer from 1 to 6;
- v is an integer from 1 to 6;
- w is an integer from 0 to 5;
- y is 0 or 1;
- z is 0 or 1;
- and
- z′ is 0 or 1.
21 more elements
Dependencies are inferred from the claim text.