Auristatin tyramine phosphate salts and auristatin aminoquinoline derivatives and prodrugs thereof
The present invention relates to new auristatin compounds and prodrugs thereof, compositions comprising them and uses thereof.
1. A compound of formula (I):
wherein R is selected from the group consisting of:
R 1 and R 2 are independently selected from the group consisting of H, methyl and a Linker Unit;
R 3 and R 4 are independently selected from the group consisting of lithium (Li + ), sodium (Na + ), potassium (K + ), hydrogen (H), morpholine, quinine, tris(hydroxymethyl)aminomethane (TRIS), serine, nitroarginine and a Linker Unit; and
each R 5 is selected from H or a Linker Unit.
2. The compound of claim 1 , wherein R 1 is methyl.
3. The compound of claim 1 or 2 , wherein R 2 is a Linker Unit.
4. The compound of claim 1 , wherein R is:
5. The compound of claim 4 , wherein R 3 and R 4 are sodium.
6. The compound of claim 5 , wherein R 5 is H.
7. The compound of claim 1 , wherein R is
8. The compound of claim 1 , wherein R is
9. The compound of claim 3 , wherein the Linker Unit comprises an antibody.
10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising a combination of compounds of claim 1 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 10 or claim 11 , further comprising a therapeutically effective amount of chemotherapeutic agent selected from the group consisting of a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.
13. A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating tumor cells or cancer cells with a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in an amount effective to kill or inhibit the proliferation of the tumor cells or cancer cells.
14. A method for treating cancer in a patient comprising administering to the patient a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is administered in an amount effective to treat cancer.
15. The method of claim 14 , further comprising administering an effective amount of a chemotherapeutic agent.
16. A method of inhibiting the growth of tumor cells that overexpress a tumor-associated antigen comprising administering to a patient the compound of claim 1 conjugated to an antibody that is specific for said tumor-associated antigen, and optionally a chemotherapeutic agent wherein the compound and said chemotherapeutic agent are each administered in amounts effective to inhibit growth of tumor cells in the patient.
17. The method of claim 16 , wherein the cancer is selected from the group consisting of breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, colorectal, thyroid, pancreatic, prostate and bladder cancer.
18. The compound of claim 1 or 2 , wherein R 2 is H.
19. A compound having the formula:
wherein the compound is selected from:
Compd.
No.
R
R 1
R 2
R 3
R 4
R 5
3a
CH 3
CH 3
Li +
Li +
H
3b
CH 3
CH 3
Na +
Na +
H
3c
CH 3
CH 3
K +
K +
H
3d
CH 3
CH 3
H
morpholine
H
3e
CH 3
CH 3
H
quinine
H
3f
CH 3
CH 3
H
TRIS
H
3g
CH 3
CH 3
H
serine
H
3h
CH 3
CH 3
H
nitro- arginine
H
4
CH 3
CH 3
—
—
—
5
CH 3
CH 3
—
—
—.