Tartrate salts of quinazoline based EGFR inhibitors containing a zinc binding moiety
The present invention relates to tartrate salts of quinazoline containing zinc-binding moiety based derivatives of Formula II, below: These compounds are inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and may further act as HDAC inhibitors. The invention further relates to the use of these tartrate salts in the treatment of EGFR-TK related diseases and disorders such as cancer.
1. A method of treating a cancer selected from breast cancer, hepatocellular carcinoma, colon cancer, head and neck cancer, renal carcinoma, lung cancer, prostate cancer, gastric carcinoma, leukemia and pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a tartaric acid salt or complex of a compound represented by formula (II):
wherein B is a C 3 to C 9 alkylene;
R 1 is selected from hydrogen, C 1 to C 4 alkoxy or substituted C 1 to C 4 alkoxy;
each R 2 is independently selected from halogen, C 1 to C 4 alkyl, C 2 to C 4 alkenyl, and C 2 to C 4 alkynyl; and
n is 1, 2 or 3.
2. The method of claim 1 , wherein said cancer is non-small cell lung cancer.
3. The method of claim 1 , wherein B is a straight chain C 5 to C 7 alkylene.
4. The method of claim 1 , wherein B is a straight chain C 6 alkylene.
5. The method of claim 1 , wherein n is 1.
6. The method of claim 1 , wherein R 2 is ethynyl.
7. The method of claim 1 , wherein R 1 is methoxy.
8. The method of claim 1 , wherein the tartaric acid is the L-tartaric acid.
9. The method of claim 1 , wherein the tartaric acid is the D-tartaric acid.
10. The method of claim 1 , wherein the tartaric acid is D,L-tartaric acid.
11. The method of claim 1 , wherein the tartaric acid is meso-tartaric acid.
12. The method of claim 1 , wherein the compound is represented by formula (III):
13. The method of claim 12 , wherein B is a straight chain C 5 to C 7 alkylene.
14. The method of claim 12 , wherein R 1 is hydrogen or methoxy and B is a straight chain C 6 alkylene.
15. The method of claim 1 , wherein the compound is represented by formula (IV):
16. The method of claim 15 , wherein B is a straight chain C 5 to C 7 alkylene.
17. The method of claim 15 , wherein R 1 is methoxy and B is a straight chain C 6 alkylene.