Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof

Patent metadata

Field	Value
Publication number	US-2016199346-A1
Application number	US-201514965062-A
Country	US
Kind code	A1
Filing date	Dec 10, 2015
Priority date	Aug 12, 2005
Publication date	Jul 14, 2016
Grant date	—

Abstract

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.

First claim

1 - 24 . (canceled)

25 . A method for treating a leukemia or solid tumor 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 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 two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro.

26 . The method of claim 25 , wherein the method is to treating leukemia.

27 . The method of claim 25 , wherein the method is to treating a solid tumor.

28 . The method of claim 26 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

29 . The method of claim 27 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

30 . The method of claim 25 , 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.

31 . The method of claim 28 , 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.

32 . The method of claim 29 , 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.

33 . 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, 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 two of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are nitro.

34 . The method of claim 33 , wherein the cancer is brain cancer.

35 . The method of claim 33 , wherein the cancer is colorectal cancer.

36 . The method of claim 33 , wherein the cancer is lung cancer.

37 . The method of claim 33 , wherein the cancer is colon cancer.

38 . The method of claim 33 , wherein the cancer is liver cancer.

39 . The method of claim 33 , 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.

40 . The method of claim 33 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

41 . The method of claim 34 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

42 . The method of claim 35 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

43 . The method of claim 36 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

44 . The method of claim 33 , wherein the compound is

45 . The method of claim 34 , wherein the compound is

46 . The method of claim 35 , wherein the compound is

47 . The method of claim 36 , wherein the compound is

48 . The method of claim 37 , wherein the compound is

Assignees

• Epicentrx Inc
• Orbital Atk Inc

Inventors

• Bednarski Mark D
• Knox Susan
• Cannizzo Louis
• Warner Kirstin
• Wardle Robert
• Velarde Stephen
• Ning Shoucheng

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title