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US 7,498,298 B2Granted
Monomethylvaline compounds capable of conjugation to ligands
AssigneeSeattle Genetics, Inc.
InventorsSvetlana O. Doronina, Peter D. Senter, Brian E. Toki
Life of this patent
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Abstract
Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.
Claims22
A compound having the formula:
- wherein:
- R2 is selected from —H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb), wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- Z is —S—, —NH—, or —NR12—, wherein R12 is C1-C8 alkyl;
- R11 is selected from —H, C1-C20 alkyl, aryl, —C3-C8 heterocycle, —(R13O)m—R14, and —(R13O)m—CH(R15)2;
- m is an integer ranging from 1 to 1000;
- R13 is —C2-C8 alkyl;
- R14 is —H or —C1-C8 alkyl;
- each occurrence of R15 is independently —H, —COOH, —(CH2)n—N(R6)2, —(CH2)n—SO3H, or —(CH2)n—SO3—C1-C8 alkyl;
- each occurrence of R16 is independently —H, —C1-C8 alkyl, or —(CH2)n—COOH;
- and
- n is an integer ranging from 0 to 6;
- or a pharmaceutically acceptable salt thereof.
17 more elements
A compound having the formula:
- wherein the wavy line indicates H or a covalent linkage to a Linker Unit or a Ligand unit selected from the group consisting of a protein, a polypeptide and a peptide,
- and independently at each location:
- R2 is selected from —H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from —H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A compound having the formula:
- wherein,
- independently at each location:
- R2 is selected from H and —C1-C8 alkyl;
- R3 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —H and -methyl;
- or R4 and R5 jointly have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
- R6 is selected from —H and —C1-C8 alkyl;
- R7 is selected from —H, —C1-C8 alkyl, —C3-C8 carbocycle, aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from —H and —C1-C8 alkyl;
- R10 is selected from aryl group and —C3-C8 heterocycle;
- or a pharmaceutically acceptable salt thereof.
9 more elements
Dependencies are inferred from the claim text.