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US 8,609,105 B2Granted
Auristatin drug linker conjugates
AssigneeSeattle Genetics, Inc.
InventorsPeter Senter, Svetlana Doronina, Timothy Bovee
Life of this patent
Estimating the term…
Abstract
Drug Linker compounds and Drug Linker Ligand conjugates are provided that have auristatins linked via the C-terminus. The conjugates show efficacy without the need for a self-immolative group to release the drug.
Claims46
A compound having the formula:
- (D-LU)p-L
- or a pharmaceutically acceptable salt or solvate thereof;
- wherein L is Ligand Unit, LU is a Linker unit, and D is a Drug unit;
- L is a peptide, polypeptide or protein that specifically binds to a target cell population;
- LU has the formula -Ww-Aa,
- Ww is a sequence of w independently selected amino acid diradicals, wherein the W proximal to the Drug unit (W1) is a natural (L) amino acid linked via a peptide bond to the Drug unit and the remaining Ws are D-amino acids, provided that W1 cannot form secondary amide with C-terminal amino acid of D and that the peptide bond can be cleaved by an intracellular protease,
- w is an integer ranging from 1 to 12,
- A is Stretcher unit, and
- a is 1 or 2;
- p is an integer of from 1 to 20;
- and
- D has the formula:
- wherein the wavy line indicates the peptide bond to LU;
- R1 and R2 are independently selected from the group consisting of —H and —C1-C8 alkyl, with the proviso that both R1 and R2 are not —H;
- R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —X1—(C3-C8 carbocycle), —C3-C8 heterocycle and —X1—(C3-C8 heterocycle);
- R4 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —X1-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —X1-(C3-C8 heterocycle);
- R5 is selected from the group consisting of —H and methyl;
- or R4 and R5 jointly form a carbocyclic ring and have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H and —C1-C8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and —C1-C8 alkyl;
- R7 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —X1-aryl, —X1—(C3-C8 carbocycle), —C3-C8 heterocycle and —X1—(C3-C8 heterocycle);
- each R8 is independently selected from the group consisting of —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R12 is selected from —H, —C1-C8 alkyl, -aryl, —X1-aryl, —C3-C8 carbocycle, —X1—(C3-C8 heterocycle), —C1-C8 alkylene-NH2, —C3-C8 heterocycle and —X1-(C3-C8 heterocycle);
- and
- each X1 is independently —C1-C10 alkylene-.
21 more elements
A compound having the formula:
- D-LU
- or a pharmaceutically acceptable salt or solvate thereof;
- wherein LU- is a Linker unit and D is a Drug unit;
- LU has the formula Ww-Aa-,
- WW is a sequence of w independently selected amino acid diradicals, wherein the W proximal to the Drug unit (W1) is a natural (L) amino acid linked via a peptide bond to the Drug unit and the remaining Ws are D-amino acids, provided that W1 cannot form secondary amide with C-terminal amino acid of D and that the peptide bond can be cleaved by an intracellular protease,
- w is an integer ranging from 1 to 12,
- A is Stretcher unit, and
- a is 1 or 2;
- and
- D has the formula:
- wherein the wavy line indicates the peptide bond to LU;
- R1 and R2 are independently selected from the group consisting of —H and —C1-C8 alkyl;
- R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —X1- (C3-C8 carbocycle), —C3-C8 heterocycle and —X1- (C3-C8 heterocycle);
- R4 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —X1-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —X1- (C3-C8 heterocycle);
- R5 is selected from the group consisting of —H and -methyl;
- or R4 and R5 jointly form a carbocyclic ring and have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H and —C1-C8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and —C1-C8 alkyl;
- R7 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —X1-aryl, —X1—(C3-C8 carbocycle), —C3-C8 heterocycle and —X1—(C3-C8 heterocycle);
- each R8 is independently selected from the group consisting of —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R12 is selected from H, —C1-C8 alkyl, -aryl, —X1-aryl, —C3-C8 carbocycle, —X1—(C3-C8 heterocycle), —C1-C8 alkylene-NH2, —C3-C8 heterocycle and —X1—(C3-C8 heterocycle);
- and
- each X1 is independently —C1-C10 alkylene-.
19 more elements
Dependencies are inferred from the claim text.