Monomethylvaline compounds having phenylalanine carboxy modifications at the C-terminus
View Patent ↗Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine 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.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof;
wherein:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl;
R 4 is selected from the group consisting of C 1 -C 8 alkyl;
R 5 is H;
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 and C 1 -C 8 alkyl;
each R 8 is independently selected from the group consisting of H, OH,and O—(C 1 -C 8 alkyl);
and
the moiety —NR 9 Z 1 is a bioisostere having Formula A
wherein:
R 9 is selected from the group consisting of H and an amino protecting group;
R 10 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH 2 —(C 3 -C 8 carbocycle), CH 2 -aryl and CH 2 —(C 3 -C 8 heterocycle); and
Z 2 is selected from the group consisting of:
2. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 9 is H; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 10 is CH 2 -aryl; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein Formula A is
or a pharmaceutically acceptable salt thereof.
6. A compound having the formula:
LU-D
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 selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl;
R 4 is selected from the group consisting of C 1 -C 8 alkyl;
R 5 is H;
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 and C 1 -C 8 alkyl;
each R 8 is independently selected from the group consisting of H, OH, and O—(C 1 -C 8 alkyl;
and
the moiety —NR 9 Z 1 is phenylalanine bioisostere having Formula A
wherein:
R 9 is selected from the group consisting of H and an amino protecting group;
R 10 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH 2 —(C 3 -C 8 carbocycle), CH 2 -aryl and CH 2 —(C 3 -C 8 heterocycle); and
Z 2 is selected from the group consisting of:
7. A compound having Formula Ia′:
Ab-(A a -W w -Y y -D) p Ia′
or a pharmaceutically acceptable salt thereof, wherein:
Ab is an antibody that specifically binds to an antigen,
(A a -W w -Y y ) is a Linker unit, 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,
Y is a Spacer unit and
y is 0, 1 or 2,
p ranges from 1 to about 20, and
D is a drug moiety having Formula D:
wherein:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of C 1 -C 8 alkyl;
R 4 is selected from the group consisting of C 1 -C 8 alkyl;
R 5 is H;
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 and C 1 -C 8 alkyl;
each R 8 is independently selected from the group consisting of H, OH, and O—(C 1 -C 8 alkyl);
and
the moiety —NR 9 Z 1 is a phenylalanine bioisostere having Formula A
wherein:
R 9 is selected from the group consisting of H and an amino protecting group;
R 10 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH 2 —(C 3 -C 8 carbocycle), CH 2 -aryl and CH 2 —(C 3 -C 8 heterocycle); and
Z 2 is selected from the group consisting of:
8. A compound according to claim 7 having the formulae:
wherein Z is the phenylalanine bioisostere moiety
having Formula A
wherein:
R 9 is selected from the group consisting of H and an amino protecting group;
R 10 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH 2 —(C 3 -C 8 carbocycle), CH 2 -aryl and CH 2 —(C 3 -C 8 heterocycle); and
Z 2 is selected from the group consisting of:
9. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the Linker unit comprises:
-A a -W w -Y y -
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,
-Y- is a Spacer unit, and
y is 0, 1 or 2.
10. A pharmaceutical composition comprising an effective amount of the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.
11. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof.