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 or solid tumor in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I to treat said leukemia or solid tumor, 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)-cycloalkyl, substituted —C(O)-aryl, substituted —C(O)-arylalkyl, substituted —C(O)-heteroaryl, substituted —C(O)-heteroarylalkyl, and an —C(O)-alkyl substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , —SR 60 , —CF 3 , —OS(O) 2 R 60 , —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 at least 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 method is to treating leukemia.
3. The method of claim 1 , wherein the method is to treating a solid tumor.
4. The method of claim 3 , wherein the solid tumor is breast cancer, renal cancer, brain cancer, colon cancer, colorectal cancer, prostate cancer, or lung cancer.
5. The method of claim 1 , wherein two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro; R 1 , R 2 , and R 3 are each independently hydrogen, alkyl, aryl, or nitro; and R 5 and R 6 each represent independently for each occurrence hydrogen, alkyl, aryl, or nitro.
6. The method of claim 1 , 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.
7. The method of claim 6 , wherein R 7 is —C(O)-cycloalkyl, —C(O)-arylalkyl, —C(O)-heteroarylalkyl, or —C(O)-alkyl, each of which is substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , and —OS(O) 2 R 60 .
8. The method of claim 6 , wherein R 7 is —C(O)-alkyl substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , and —OS(O) 2 R 60 ; and R 60 is alkyl, substituted alkyl, aryl, or substituted aryl.
9. The method of claim 6 , wherein R 7 is —C(O)-alkyl substituted with a halogen.
10. The method of claim 2 , wherein R 3 and R 4 are nitro; R 1 , R 2 , R 5 , and R 6 each represent independently for each occurrence hydrogen or alkyl; R 7 is —C(O)—CH 3 substituted with a halogen; and variable o is 1.
11. The method of claim 3 , wherein R 3 and R 4 are nitro; R 1 , R 2 , R 5 , and R 6 each represent independently for each occurrence hydrogen or alkyl; R 7 is —C(O)—CH 3 substituted with a halogen; and variable o is 1.
12. The method of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The method of claim 3 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 2 , wherein the compound is
15. The method of claim 3 , wherein the compound is
16. The method of claim 4 , wherein the compound is
17. The method of claim 1 , wherein the compound is administered in combination with radiation.
18. The method of claim 14 , wherein the compound is administered in combination with radiation.
19. The method of claim 15 , wherein the compound is administered in combination with radiation.
20. A method for treating cancer in a patient, comprising administering to the 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, brain 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)-cycloalkyl, substituted —C(O)-aryl, substituted —C(O)-arylalkyl, substituted —C(O)-heteroaryl, substituted —C(O)-heteroarylalkyl, and an —C(O)-alkyl substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , —SR 60 , —CF 3 , —OS(O) 2 R 60 , —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 at least two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is nitro.
21. The method of claim 20 , wherein the cancer is brain cancer.
22. The method of claim 20 , wherein the cancer is colon cancer or colorectal cancer.
23. The method of claim 20 , wherein two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro; R 1 , R 2 , and R 3 are each independently hydrogen, alkyl, aryl, or nitro; and R 5 and R 6 each represent independently for each occurrence hydrogen, alkyl, aryl, or nitro.
24. The method of claim 20 , 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.
25. The method of claim 21 , 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.
26. The method of claim 24 , wherein R 7 is —C(O)-alkyl substituted by one or more substituents independently selected from the group consisting of halogen, -OR 60 , and —OS(O) 2 R 60 ; and R 60 is alkyl, substituted alkyl, aryl, or substituted aryl.
27. The method of claim 25 , wherein R 7 is —C(O)-alkyl substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , and —OS(O) 2 R 60 ; and R 60 is alkyl, substituted alkyl, aryl, or substituted aryl.
28. The method of claim 24 , wherein R 7 is —C(O)—CH 3 substituted with a halogen; and variable o is 1.
29. The method of claim 25 , wherein R 7 is —C(O)—CH 3 substituted with a halogen; and variable o is 1.
30. The method of claim 20 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
31. The method of claim 21 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
32. The method of claim 20 , wherein the compound is
33. The method of claim 21 , wherein the compound is
34. The method of claim 22 , wherein the compound is
35. The method of claim 20 , wherein the compound is administered in combination with radiation.
36. The method of claim 32 , wherein the compound is administered in combination with radiation.
37. The method of claim 33 , wherein the compound is administered in combination with radiation.