Quinstatin compounds
View Patent ↗The present disclosure relates to Quinstatin compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.
1. A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, a Protecting Group or a Linker Unit;
R 2 is selected from H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or (C 2 -C 6 ) alkynyl;
R 3 is H or (C 1 -C 6 ) alkyl; and
X is a bicyclic heterocyclic ring system selected from quinolinyl, isoquinolinyl, 1,5-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 2,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl, phthalazinyl, 2H-chromenyl, 1H-1,5-benzodiazepinyl, 1,2,3-benzotriazinyl and 2,5-benzodiazocinyl, wherein the bicyclic heterocyclic ring system is unsubstituted or substituted with 1, 2 or 3 substituent(s) selected from (C 1 -C 6 ) alkoxy, methylene dioxy, hydroxyl, O-Protecting Group and O-Linker Unit.
2. The compound of claim 1 , wherein the compound has formula (Ia):
3. The compound of claim 1 , wherein the compound has formula (Ib):
4. The compound of claim 1 , wherein the compound has formula (Ic):
5. The compound of claim 1 , wherein the compound has formula (Id):
6. The compound of claim 1 , wherein the compound has formula (Ie):
7. The compound of claim 1 , wherein the compound has formula (If):
8. The compound of claim 1 , wherein the compound has formula (Ig):
9. The compound of claim 1 , wherein R 1 is H, (C 1 -C 6 ) alkyl or a Linker Unit.
10. The compound of claim 1 , wherein R 2 is H or (C 1 -C 6 ) alkyl.
11. The compound of claim 1 , wherein the Linker Unit has formula:
A a W w Y y , wherein
A a is maleimidocaproyl, W w is Valine-Citrulline and Y y is p-aminobenzyloxycarbonyl.
12. A compound selected from the group consisting of:
and
pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
14. An article of manufacture comprising the compound of claim 1 , a container, and a package insert or label indicating that the compound can be used to treat cancer characterized by the overexpression of at least one tumor-associated antigen.
15. A method for killing or inhibiting the proliferation of tumor cells or cancer cells comprising treating the tumor cells or cancer cells with a compound of claim 1 , or a pharmaceutical composition of claim 13 , in an amount effective to kill or inhibit the proliferation of the tumor cells or cancer cells.
16. A method for treating cancer in a patient in need thereof comprising administering to the patient a compound of claim 1 , or a pharmaceutical composition of claim 13 , wherein the compound or pharmaceutical composition is administered in an amount effective to treat cancer.
17. A method of determining inhibition of cellular proliferation by a compound, comprising contacting cells in a cell culture medium with the compound of claim 1 and measuring the cytotoxic activity of the compound, whereby proliferation of the cells is inhibited.
18. 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 second therapeutic agent wherein the compound and the second therapeutic agent are each administered in amounts effective to inhibit the growth of tumor cells in the patient.