Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof
The present invention provides cyclic nitro compound, pharmaceutical compositions of cyclic nitro compounds and methods of using cyclic nitro compounds and/or pharmaceutical compositions thereof to treat or prevent diseases or disorders characterized by abnormal cell proliferation, such as cancer, inflammation, cardiovascular disease and autoimmune disease.
1. A method for treating a leukemia in a human patient, comprising intravenously administering to a human patient in need of such treatment a therapeutically effective amount of a compound of Formula I to treat said leukemia, wherein Formula I is represented by:
or a salt thereof, wherein:
R 1 , R 2 , R 3 and R 4 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halogen, hydroxy, or nitro;
R 5 and R 6 each represent independently for each occurrence hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halogen, hydroxy, or nitro;
R 7 is a substituted acyl selected from the group consisting of substituted —C(O)-arylalkyl, substituted —C(O)— heteroaryl, and substituted —C(O)-heteroarylalkyl; or R 7 is —C(O)-alkyl or —C(O)-cycloalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of halogen, —CF 3 , —OP(O)(OR 60 )(OR 61 ), and —OP(O)(OH) 2 ;
R 60 represents independently for each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 61 represents independently for each occurrence hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
o is 0, 1, 2, 3 or 4; and
provided that two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro.
2. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
4. The method of claim 2 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
5. A method for treating cancer in a human patient, comprising intravenously administering to the human patient in need of such treatment a therapeutically effective amount of a compound of Formula I to treat said cancer, wherein the cancer is breast cancer, renal cancer, colon cancer, colorectal cancer, prostate cancer, lung cancer, ovarian cancer, pancreatic cancer, testicular cancer, liver cancer, uterine cancer, or bladder cancer, and Formula I is represented by:
or a salt thereof, wherein:
R 1 , R 2 , R 3 and R 4 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halogen, hydroxy, or nitro;
R 5 and R 6 each represent independently for each occurrence hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halogen, hydroxy, or nitro;
R 7 is a substituted acyl selected from the group consisting of substituted —C(O)-aryl, substituted —C(O)-arylalkyl, substituted —C(O)— heteroaryl, and substituted —C(O)-heteroarylalkyl; or R 7 is —C(O)-alkyl or —C(O)-cycloalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of halogen, —CF 3 , —OP(O)(OR 60 )(OR 61 ), and —OP(O)(OH) 2 ;
R 60 represents independently for each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 61 represents independently for each occurrence hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
o is 0, 1, 2, 3 or 4; and
provided that two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro.
6. The method of claim 5 , wherein the cancer is colorectal cancer.
7. The method of claim 5 , wherein the cancer is lung cancer.
8. The method of claim 5 , wherein the cancer is colon cancer.
9. The method of claim 5 , wherein the cancer is liver cancer.
10. The method of claim 5 , wherein R 3 and R 4 are nitro; and R 1 , R 2 , R 5 , and R 6 each represent independently for each occurrence hydrogen or alkyl; and R 7 is —C(O)-alkyl substituted with a halogen.
11. The method of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
12. The method of claim 6 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The method of claim 7 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 5 , wherein the compound is
15. The method of claim 6 , wherein the compound is
16. The method of claim 7 , wherein the compound is
17. The method of claim 8 , wherein the compound is
18. The method of claim 9 , wherein the compound is
19. The method of claim 5 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
20. The method of claim 14 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
21. The method of claim 15 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
22. The method of claim 16 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
23. The method of claim 17 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.
24. The method of claim 18 , wherein the method comprises intravenously administering to the human patient in need of such treatment a therapeutically effective amount of said compound in combination with radiation.