Monomethylvaline compounds having phenylalanine side-chain replacements at the C-terminus
View Patent ↗Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) are provided having C-terminal phenylalanine residue side chain replacements or modifications which are provided alone or attached to ligands through various linkers. The related conjugates can target specific cell types to provide therapeutic benefit.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is C 1 -C 8 alkyl;
R 3 is C 1 -C 8 alkyl;
R 4 is C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and methyl;
R 6 is C 1 -C 8 alkyl;
R 7 is C 1 -C 8 alkyl;
each R 8 is independently selected from O—(C 1 -C 8 alkyl); and
the moiety —NR 9 Z 1 is a phenylalanine bioisostere moiety selected from the group consisting of,
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is isopropyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is isopropyl.
5. The compound of claim 1 , wherein the phenylalanine bioisostere moiety is
6. A compound having the formula:
L-((LU)-(D) 1-4 ) p
or a pharmaceutically acceptable salt thereof
wherein,
L- is a Ligand Unit selected from the group consisting of a protein, polypeptide and peptide;
LU is a Linker Unit;
p is an integer of from 1 to about 20; and
D is a drug moiety having Formula D:
wherein,
R 2 is C 1 -C 8 alkyl;
R 3 is C 1 -C 8 alkyl;
R 4 is C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and methyl;
R 6 is C 1 -C 8 alkyl;
R 7 is C 1 -C 8 alkyl;
each R 8 is independently selected from O—(C 1 -C 8 alkyl); and
the moiety —NR 9 Z 1 is a phenylalanine bioisostere moiety selected from the group consisting of
7. A compound of claim 6 , having the formula:
L-[LU-D] p
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
L is an antibody (Ab),
LU is a Linker Unit having the formula -A a -W w —Y y —, wherein
A is a Stretcher unit,
a is 0or 1,
each W is independently an Amino Acid unit,
w is an integer ranging from 0 to 12,
Y is a Spacer unit, and
y is 0, 1 or 2.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof having the formula:
10. The compound of claim 8 having the formula:
11. The compound of claim 8 having the formula:
12. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein w is an integer ranging from 2 to 12.
13. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein w is 2.
14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein W W is -valine-citrulline-.
15. The compound of claim 8 wherein W W is selected from the group consisting of 5-aminovaleric acid, homophenylalanine-lysine, tetraisoquinolinecarboxylate-lysine, cyclohexylalanine-lysine, isonepecotic acid-lysine, beta-alanine-lysine, glycine-serine-valine-glutamine (SEQ ID NO:1) and isonepecotic acid.
16. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the antibody is a monoclonal antibody.
17. The compound of claim 8 , wherein the antibody is an antibody fragment.
18. The compound of claim 8 having the formulae:
or a pharmaceutically acceptable salt thereof
wherein mAb is a monoclonal antibody and
is a phenylalanine bioisostere moiety selected from the group consisting of
19. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the antibody specifically binds to CD20, CD30, CD33, CD40, CD70, or Lewis Y antigen.
20. A pharmaceutical composition comprising an effective amount of the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
21. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein y is 1 or 2.
22. The compound of claim 6 , wherein the phenylalanine bioisostere moiety is
23. The compound of claim 8 , wherein the phenylalanine bioisostere moiety is
24. The compound of claim 18 , wherein the phenylalanine bioisostere moiety is
25. A compound having the formula:
LU-(D) 1-4
or a pharmaceutically acceptable salt thereof
wherein,
LU- is a Linker Unit; and
D is a drug moiety having the Formula D:
wherein
R 2 is C 1 -C 8 alkyl;
R 3 is C 1 -C 8 alkyl;
R 4 is C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and methyl;
R 6 is C 1 -C 8 alkyl;
R 7 is C 1 -C 8 alkyl;
each R 8 is independently selected from O—(C 1 -C 8 alkyl); and
the moiety —NR 9 Z 1 is a phenylalanine bioisostere selected from the group consisting of
26. The compound of claim 25 , wherein the phenylalanine bioisostere moiety is