Auristatins having an aminobenzoic acid unit at the N terminus
View Patent ↗Auristatin-type peptides are disclosed which are highly cytotoxic, synthetically accessible, and can be conjugated to antibodies and other ligands.
1. A Conjugate Compound having the Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein:
L- is a Ligand Unit;
-A a -W w — is a Linker Unit (LU), wherein:
-A- is a Stretcher Unit,
a is 0 or 1,
each —W— is independently an Amino Acid Unit,
w is an integer ranging from 0 to 12,
p is an integer ranging from 1 to about 20; and
-D is a Drug Unit of the formula
wherein independently at each location:
R 2 is selected from the group consisting of -hydrogen, —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, —NO 2 , —COOH, and —C(O)OR 11 ;
each R 3 is selected independently from the group consisting of -hydrogen and —C 1 -C 8 alkyl;
I is an integer ranging from 0-10;
R 4 is selected from the group consisting of -hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); and R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle, n is selected from the group consisting of 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
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, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(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, —O-alkyl-(C 1 -C 8 carbocycle) and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 10 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 — where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
2. The Conjugate Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the Linker Unit has the general Formula Ib:
wherein R 17 is selected from the group consisting of —C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, - arylene-, —C 1 -C 10 alkylene-arylene-, -arylene—C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 1 -C 8 carbocyclo)—C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)—C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1-100.
3. The Conjugate Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the Drug Unit has the following formula:
wherein independently at each location:
R 4 is selected from the group consisting of -hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); and R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle, n is selected from the group consisting of 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
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, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(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, —O-alkyl-(C 1 -C 8 carbocycle) and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 19 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 — where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
4. The Conjugate Compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the Drug Unit has the following formula:
wherein independently as each location:
R 10 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r—CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
5. The Conjugate Compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the Drug Unit has the following formula:
wherein Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —; where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
6. The Conjugate Compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the Drug Unit has the following formula:
7. The Conjugate Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit is an antibody that binds to an antigen.
8. The Conjugate Compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the antibody a chimeric antibody, a humanized antibody, or a functionally active fragment thereof.
9. The Conjugate Compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the antibody is attached to the Linker Unit through a cysteine residue of the antibody.
10. The Conjugate Compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein p is 2 to 8.
11. The Conjugate Compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein p is 4.
12. The Conjugate Compound of claim 7 , having the formula:
or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody, and S is a sulfur atom of the antibody.
13. The Conjugate Compound of claim 7 or a pharmaceutically acceptable salt thereof, having the formula:
wherein Ab is an antibody, and S is a sulfur atom of the antibody.
14. The Conjugate Compound of claim 7 , having the formula:
or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody, and S is a sulfur atom of the antibody.
15. The Conjugate Compound of claim 14 having the formula:
or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody, and S is a sulfur atom of the antibody.
16. The Conjugate Compound of claim 7 , wherein a Drug Linker Unit of the following formula or a pharmaceutically acceptable salt thereof is conjugated to the antibody:
17. The Conjugate Compound of claim 7 , wherein a Drug Linker Unit of the following formula or a pharmaceutically acceptable salt thereof is conjugated to the antibody:
18. A pharmaceutical composition, comprising
a Conjugate Compound of claim 1 or a pharmaceutically acceptable salt thereof;
a container; and
a package insert or label indicating that the compound can be used to treat cancer.
19. A Drug Compound having the Formula I:
or a pharmaceutically acceptable salt or solvate thereof; wherein, independently at each location:
R 2 is selected from the group consisting of -hydrogen —C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), -halogen, —NO 2 , —COOH, and —C(O)OR″;
each R 3 is selected independently from the group consisting of -hydrogen and —C 1 -C 8 alkyl;
I is an integer ranging from 0-10;
R 4 is selected from the group consisting of -hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 1 -C 8 heterocycle);
R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
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, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(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, —O-alkyl-(C 1 -C 8 carbocycle) and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 10 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —where R 12 is C 1 -C 8 alkyl; or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
20. The Drug Compound of claim 19 having the following formula:
or a pharmaceutically acceptable salt thereof; wherein independently at each location:
R 4 is selected from the group consisting of -hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 jointly have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle, n is selected from the group consisting of 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
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, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(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, —O-alkyl-(C 1 -C 8 carbocycle) and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 10 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
21. The Drug Compound of claim 20 having the following formula:
or a pharmaceutically acceptable salt thereof; wherein independently as each location:
R 10 is selected from the group consisting of aryl group and —C 3 -C 8 heterocycle;
Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —where R 12 is C 1 -C 8 alkyl or aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
22. The Drug Compound of claim 21 having the following formula:
or a pharmaceutically acceptable salt thereof; wherein Z is selected from the group consisting of —O—, —S—, —NH—, and —NR 12 —; where R 12 is C 1 -C 8 alkyl and aryl; and
R 11 is selected from the group consisting of —H, C 1 -C 8 alkyl, aryl, —C 3 -C 8 heterocycle, —(CH 2 CH 2 O) r —H, —(CH 2 CH 2 O) r —CH 3 , and —(CH 2 CH 2 O) r —CH 2 CH 2 C(O)OH;
wherein r is an integer ranging from 1-10.
23. The Drug Compound of claim 22 having the following formula:
or a pharmaceutically acceptable salt thereof.
24. A Linker Drug Conjugate having the following formula:
or a pharmaceutically acceptable salt thereof.
25. A Linker Drug Conjugate having the following formula:
or a pharmaceutically acceptable salt thereof.
26. A Linker Drug Conjugate having the following formula:
or a pharmaceutically acceptable salt thereof.
27. A Linker Drug Conjugate having the following formula:
or a pharmaceutically acceptable salt thereof.
28. A Conjugate Compound of claim 15 , having the following formula:
or a pharmaceutically acceptable salt thereof.