c-Kit kinase inhibitor
It was discovered that a compound represented by the general formula (I) shows strong c-Kit kinase inhibitory activity, and it inhibits proliferation of c-Kit kinase activated-cancer cells in vitro and in vivo. A novel anticancer agent showing c-Kit kinase inhibitory activity was discovered. The general formula (I): (wherein R 1 represents methyl etc., R 2 represents cyano etc., R 3 represents hydrogen etc., R 4 represents hydrogen etc.).
1. A method for treating a cancer that express c-kit in a patient, comprising:
a) determining if the patient's cancer expresses c-Kit kinase or a mutant c-Kit kinase; and
b) if the cancer is determined to express c-Kit kinase or a mutant c-Kit kinase, administering to the patient a pharmacologically effective dose to inhibit c-Kit activity of said cKit kinase or mutant c-Kit kinase of a compound selected from the group consisting of:
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the cancer is acute myelogenous leukemia, a small cell lung cancer, or gastorintestinal stromal tumor (GIST).
3. A method for treating mastocytosis, allergy, or asthma comprising administering to a patient suffering from one or more of the diseases a pharmacologically effective dose to inhibit c-Kit activity of said cKit kinase or mutant c-Kit kinase of a compound selected from the group consisting of:
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmaceutically acceptable salt thereof:
4. A method of inhibiting c-kit activity in a cancer cell in a patient comprising:
a) determining if a cell expresses c-Kit kinase or a mutant c-Kit kinase; and
b) if the cell is determined to express c-Kit kinase or a mutant c-Kit kinase, applying to the cell a pharmacologically effective dose to inhibit c-Kit activity of said cKit kinase or mutant c-Kit kinase of a compound selected from the group consisting of:
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide;
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide; and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 or 4 wherein the compound is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 or 4 , wherein the compound) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
7. The method of claim 1 , wherein the cancer is mast cell leukemia, testicular cancer, ovarian cancer, breast cancer, brain cancer, neuroblastoma, or colorectal cancer.
8. The method of claim 1 , wherein the c-Kit kinase or mutant c-Kit kinase is activated.
9. The method of claim 1 , wherein the c-Kit kinase or mutant c-Kit kinase is phosphorylated.
10. The method of claim 1 , wherein the expression of c-Kit kinase or mutant c-Kit kinase is excessive.
11. The method of claim 1 , wherein the determining step comprises extracting cells from the patient.
12. The method of claim 11 , wherein the extracted cells comprise cancer cells.
13. The method of claim 4 , wherein the cancer cell is a mast cell leukemia, testicular cancer, ovarian cancer, breast cancer, brain cancer, neuroblastoma, or colorectal cancer cell.
14. The method of claim 4 , wherein the cancer cell is a myelogenous leukemia, a small cell lung cancer or a GIST cancer cell.
15. The method of claim 1 , wherein the compound is administered orally or parenterally.
16. The method of claim 4 , wherein the c-Kit kinase or mutant c-Kit kinase is activated.
17. The method of claim 4 , wherein the c-Kit kinase or mutant c-Kit kinase is phosphorylated.
18. The method of claim 4 , wherein the expression of c-Kit kinase or mutant c-Kit kinase is excessive.
19. The method of claim 4 , wherein the determining step comprises extracting cells from the patient.
20. The method of claim 1 , wherein the compound is administered orally or parenterally.
21. The method of claim 1 , wherein the cancer is determined to express a mutant c-Kit kinase.
22. The method of claim 4 , wherein the cell is determined to express a mutant c-Kit kinase.