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 cancer in a patient, the method comprising:
administering to a patient in need of such treatment a therapeutically effective amount of a compound of structural Formula (I):
or a salt thereof,
wherein:
R 1 , R 2 , R 3 and R 4 are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halo, hydroxyl, or nitro;
each of R 5 and R 6 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, halo, hydroxy or nitro;
o is 0, 1, 2, 3 or 4;
R 7 is a substituted acyl selected from the group consisting of: —C(O)-cycloalkyl, —C(O)-aryl, —C(O)-arylalkyl, —C(O)-heteroaryl, —C(O)-heteroarylalkyl, and —C(O)-alkyl, each of which is substituted by one or more substituents independently selected from the group consisting of halogen, —OR 60 , —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;
provided that at least two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro; and
the cancer is selected from the group consisting of: stomach cancer, laryngeal cancer, esophageal cancer, parotid cancer, biliary tract cancer, cervical cancer, endometrial cancer, thyroid cancer, squamous cell carcinoma, adenocarcinoma, melanoma, angiosarcoma, chondrosarcoma, small cell carcinoma, glioblastoma multiforme, and neuroendocrine cancer.
2. The method of claim 1 , wherein the cancer comprises tumor cells with a reduced and hypoxic intracellular environment.
3. The method of claim 1 , wherein:
each of R 1 , R 2 , R 3 and R 4 are independently hydrogen, alkyl, or nitro, and
each of R 5 and R 6 are independently hydrogen, alkyl, or nitro.
4. The method of claim 1 , wherein R 7 is —C(O)-alkyl, —C(O)— cycloalkyl, —C(O)-aryl, —C(O)-arylalkyl, —C(O)-heteroaryl, or —C(O)-heteroarylalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of: halogen, —OR 60 and —CF 3 .
5. The method of claim 1 , wherein R 7 is —C(O)-alkyl substituted with a halogen or —CF 3 .
6. The method of claim 1 , wherein each of R 3 and R 4 are nitro.
7. The method of claim 1 , wherein:
each of R 1 , R 2 , R 3 and R 4 are independently hydrogen, alkyl or nitro,
each of R 5 and R 6 are independently, hydrogen and alkyl, and
R 7 is —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-aryl, —C(O)-arylalkyl, —C(O)-heteroaryl, or —C(O)-heteroarylalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of: halogen and —OR 60 .
8. The method of claim 1 , wherein:
each of R 1 , R 2 , R 3 and R 4 are independently hydrogen, alkyl or nitro,
each of R 5 and R 6 are independently hydrogen, alkyl or nitro,
R 7 is —C(O)-alkyl or —C(O)-arylalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of: halogen and —CF 3 , and
R 8 is alkyl, substituted alkyl, aryl, or substituted aryl.
9. The method of claim 1 , wherein:
each of R 1 and R 2 are independently hydrogen, alkyl or nitro,
R 3 and R 4 are nitro,
each of R 5 and R 6 are independently hydrogen, alkyl or nitro, and
R 7 is —C(O)-alkyl or —C(O)-arylalkyl, each of which is substituted by one or more substituents independently selected from the group consisting of: halogen and —OR 60 .
10. The method of claim 1 , wherein:
each of R 1 and R 2 are independently, hydrogen, alkyl or nitro,
R 3 and R 4 are nitro,
each of R 5 and R 6 are independently hydrogen, alkyl or nitro,
R 7 is —C(O)-alkyl substituted with a halogen or —CF 3 , and
R 8 is alkyl, substituted alkyl, aryl or substituted aryl.
11. The method of claim 1 , wherein o is 1.
12. The method of claim 1 , wherein:
each of R 1 and R 2 are independently, hydrogen, alkyl or nitro,
R 3 and R 4 are nitro,
each of R 5 and R 6 are independently, hydrogen, alkyl or nitro,
R 7 is —C(O)-alkyl substituted with a halogen, and
o is 1.
13. The method of claim 1 , wherein:
R 1 and R 2 are hydrogen,
R 3 and R 4 are nitro,
R 5 and R 6 are hydrogen,
R 7 is —C(O)—CH 3 substituted with a halogen, and
o is 1.
14. The method of claim 1 , wherein:
the compound comprises the structure:
each X is independently —F, —Cl 5 —Br, —I or —OS(O) 2 R 8 ,
R 8 is methyl, CF 3 , phenyl or tolyl, and
each p is independently 1, 2, 3, or 4.
15. The method of claim 1 , wherein:
the compound has the structure:
X is —F, —Cl, —Br, —I or —OS(O) 2 R, and
R is methyl, CF 3 , phenyl or tolyl.
16. The method of claim 1 , wherein the cancer is neuroendocrine cancer.
17. The method of claim 1 , wherein the cancer is glioblastoma multiforme.
18. The method of claim 1 , wherein the cancer is small cell carcinoma.
19. A method for treating cancer in a patient, the method comprising:
administering to a patient in need of such treatment a therapeutically effective amount of the compound:
or a salt thereof,
wherein the cancer is selected from the group consisting of: stomach cancer, laryngeal cancer, esophageal cancer, parotid cancer, biliary tract cancer, cervical cancer, endometrial cancer, thyroid cancer, squamous cell carcinoma, adenocarcinoma, melanoma, angiosarcoma, chondrosarcoma, small cell carcinoma, glioblastoma multiforme, and neuroendocrine cancer.
20. The method of claim 19 , wherein the cancer is neuroendocrine cancer.
21. The method of claim 19 , wherein the cancer is glioblastoma multiforme.
22. The method of claim 19 , wherein the cancer is small cell carcinoma.