Auristatin drug linker conjugates

Patent metadata

Field	Value
Publication number	US-9463252-B2
Application number	US-201314061261-A
Country	US
Kind code	B2
Filing date	Oct 23, 2013
Priority date	Mar 18, 2008
Publication date	Oct 11, 2016
Grant date	Oct 11, 2016

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.

First claim

What is claimed is:

1. 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 an antigen;
LU has the formula —W w -A a -,
W w is a sequence of w independently selected amino acid diradicals, wherein the W proximal to the Drug unit (W 1 ) is a non-natural amino acid linked via a peptide bond to the Drug unit and the remaining Ws are D -amino acids, provided that W 1 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 ranging from 1 to 20; and
D has the formula:

wherein the wavy line indicates the peptide bond to LU;
R 1 and R 2 are independently selected from the group consisting of —H and —C 1 -C 8 alkyl, with the proviso that both R 1 and R 2 are not —H;
R 3 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —X 1 —(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —X 1 -aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of —H and methyl,

or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of —H and —C 1 -C 8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —X 1 -aryl, —X 1 —(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);
R 12 is the side chain of a natural (L) amino acid selected from the group consisting of arginine, glutamine, tyrosine, lysine, methionine, glycine, alanine, histidine, serine, glutamic acid, aspartic acid, threonine, leucine, asparagine, isoleucine, tryptophan, phenylalanine and valine; and
each X 1 is independently —C 1 -C 10 alkylene-.

2. 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 W w -A a -,
W w is a sequence of w independently selected amino acid diradicals, wherein the W proximal to the Drug unit (W 1 ) is a non-natural amino acid linked via a peptide bond to the Drug unit and the remaining Ws are D -amino acids, provided that W 1 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;
R 1 and R 2 are independently selected from the group consisting of —H and —C 1 -C 8 alkyl, with the proviso that both R 1 and R 2 are not —H;
R 3 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —X 1 —(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —X 1 -aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of —H and methyl,

or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of —H and —C 1 -C 8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —X 1 -aryl, —X 1 —(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —X 1 —(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);
R 12 is the side chain of a natural ( L ) amino acid selected from the group consisting of arginine, glutamine, tyrosine, lysine, methionine, glycine, alanine, histidine, serine, glutamic acid, aspartic acid, threonine, leucine, asparagine, isoleucine, tryptophan, phenylalanine and valine; and
each X 1 is independently —C 1 -C 10 alkylene-.

3. The compound of claim 1 or 2 , wherein R 12 is the side chain of tryptophan or methionine.

4. The compound of claim 3 , wherein R 1 and R 2 are —CH 3 .

5. The compound of claim 1 or 2 , wherein w is an integer ranging from 2 to 12 and the remaining W's are D -isomers of natural amino acids.

6. The compound of claim 1 or 2 , wherein a is 1.

7. The compound of claim 1 or 2 , wherein a is 2.

8. The compound of claim 6 , wherein A has the formula —NH—R 9 —R 11 wherein R 9 —R 11 have the formula:

wherein R 9 is selected from the group consisting of —C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 1 -C 30 heteroalkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, and —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-.

9. The compound of claim 6 , wherein —NH—R 9 is selected from the group consisting of —NH—C 1 -C 10 alkylene-, —NH—C 1 -C 10 alkylene-NH—C(O)—C 1 -C 10 alkylene-, —NH—C 1 -C 10 alkylene-C(O)—NH—C 1 -C 10 alkylene-, —NH—(CH 2 CH 2 O) r —, —NH—(CH 2 CH 2 O) r —CH 2 —, —NH—C 1 -C 10 alkylene-, —NH—C 1 -C 10 alkylene-NH—C(O)—C 1 -C 10 alkylene-, —NH—(C 3 -C 8 carbocyclo)-, —NH-(arylene-)-, —NH—C 1 -C 10 alkylene-NH—C(O)-(arylene-)-, and —NH—(C 3 -C 8 heterocyclo-)-, wherein r is an integer ranging from 1 to 10.

10. The compound of claim 9 , wherein —NH—R 9 is selected from the group consisting of:

wherein the bar line indicates the point of attachment to a W of W w and the wavy line indicates the point of attachment to the remainder of A.

11. The compound of claim 9 , wherein —NH—R 9 is:

wherein the bar line indicates the point of covalent attachment to a W of W w and the wavy line indicates covalent attachment to the remainder of A.

12. The compound of claim 10 , having the formula:

13. The compound of claim 1 or 2 , wherein W 1 is selected from the group consisting of orni

Assignees

• Seattle Genetics Inc

Inventors

• Senter Peter
• Doronina Svetlana
• Bovee Timothy

Classifications

• A61K47/6861

  the tumour determinant being from kidney or bladder cancer cell · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• A61K47/6865

  the tumour determinant being from skin, nerves or brain cancer cell · CPC title

• A61K38/08 Primary

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title