Radiomitigating pharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-9783515-B2
Application number	US-201414889719-A
Country	US
Kind code	B2
Filing date	May 7, 2014
Priority date	May 7, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present disclosure relates to compounds of Formula (I) and (II), compositions containing the compounds (alone or in combination with other agents), and their use to prevent, mitigate or treat a) damage induced by ionizing radiation, b) inflammation or c) cancer.

First claim

We claim:

1. A method of mitigating an effect of ionizing radiation on a cell, organ, tissue, or organism, comprising contacting the cell, organ, tissue, or organism with a compound having the structure of Formula I:

wherein:
A 5 is a secondary or tertiary amino substituent, and
A 6 is a substituted or unsubstituted aryl group.

2. The method of claim 1 , wherein the compound contacts the cell before, during, or after exposure to ionizing radiation.

3. A method of treating inflammation in an organism, comprising administering to the organism a compound having the structure of Formula I:

wherein:
A 5 is a secondary or tertiary amino substituent, and
A 6 is a substituted or unsubstituted aryl group.

4. A method of treating lung cancer in an organism, comprising administering to the organism a compound having the structure of Formula I:

wherein:
A 5 is a secondary or tertiary amino substitutent, and
A 6 is a substituted or unsubstituted aryl group.

5. The method of claim 4 , wherein the organism is a mammal.

6. A method of claim 1 , wherein the aryl group of A 6 bears at least one substituent including a nitro substitutent.

7. The method of claim 6 , wherein the nitro substituent is disposed at a position on A 6 distal to the sulfonyl.

8. The method of claim 7 , wherein A 6 is optionally substituted 4-nitrophenyl.

9. The method of claim 1 , wherein A 5 is a heterocyclic amine.

10. The method of claim 1 , wherein A 5 is NR 15 R 16 , wherein each of R 15 and R 16 , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, provided that R 15 and R 16 are not both H.

11. A method of claim 1 , having the structure of Formula II:

wherein:
X is N; and
Y 1 and Y 2 are each independently lower alkyl or Y 1 and Y 2 taken together with X form a heterocyclyl ring.

12. The method of claim 11 , wherein Y 1 and Y 2 are each ethyl.

13. The method of claim 11 , wherein Y 1 and Y 2 taken together form a piperazine ring.

14. The method of claim 11 , wherein Y 1 and Y 2 taken together with X form:

wherein
X is N;
G is selected from N or —C(H)—;
Z is absent or selected from substituted or unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl;
R 4 is absent or selected from substituted or unsubstituted aryl and heteroaryl; and
R 5 and R 6 are each independently absent or lower alkyl.

15. The method of claim 14 , wherein G is N and R 4 is selected from phenyl, 4-fluorophenyl and 3-chlorophenyl.

16. The method of claim 14 , wherein Z is absent.

17. The method of claim 14 , wherein Z is prop-2-en-1-yl and R 4 is phenyl.

18. The method of claim 1 , wherein the compound is selected from

19. A method of claim 3 , wherein the aryl group of A 6 bears at least one substituent including a nitro substitutent.

20. The method of claim 19 , wherein the nitro substituent is disposed at a position on A 6 distal to the sulfonyl.

21. The method of claim 20 , wherein A 6 is optionally substituted 4-nitrophenyl.

22. The method of claim 3 , wherein A 5 is a heterocyclic amine.

23. The method of claim 3 , wherein A 5 is NR 15 R 16 , wherein each of R 15 and R 16 , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, provided that R 15 and R 16 are not both H.

24. A method of claim 3 , having the structure of Formula II:

wherein:
X is N; and
Y 1 and Y 2 are each independently lower alkyl or Y 1 and Y 2 taken together with X form a heterocyclyl ring.

25. The method of claim 24 , wherein Y 1 and Y 2 are each ethyl.

26. The method of claim 24 , wherein Y 1 and Y 2 taken together form a piperazine ring.

27. The method of claim 24 , wherein Y 1 and Y 2 taken together with X form:

wherein
X is N;
G is selected from N or —C(H)—;
Z is absent or selected from substituted or unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl;
R 4 is absent or selected from substituted or unsubstituted aryl and heteroaryl; and
R 5 and R 6 are each independently absent or lower alkyl.

28. The method of claim 27 , wherein G is N and R 4 is selected from phenyl, 4-fluorophenyl and 3-chlorophenyl.

29. The method of claim 27 , wherein Z is absent.

30. The method of claim 27 , wherein Z is prop-2-en-1-yl and R 4 is phenyl.

31. The method of claim 3 , wherein the compound is selected from

32. A method of claim 4 , wherein the aryl group of A 6 bears at least one substituent including a nitro substitutent.

33. The method of claim 32 , wherein the nitro substituent is disposed at a position on A 6 distal to the sulfonyl.

34. The method of claim 33 , wherein A 6 is optionally substituted 4-nitrophenyl.

35. The method of claim 34 , wherein A 5 is a heterocyclic amine.

36. The method of claim 4 , wherein A 5 is NR 15 R 16 , wherein each of R 15 and R 16 , independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, provided that R 15 and R 16 are not both H.

37. A method of claim 4 , having the structure of Formula II:

wherein:
X is N; and
Y 1 and Y 2 are each independently lower alkyl or Y 1 and Y 2 taken together with X form a heterocyclyl ring.

38. The method of claim 37 , wherein Y 1 and Y 2 are each ethyl.

39. The method of claim 37 , wherein Y 1 and Y 2 taken together form a piperazine ring.

40. The method of claim 37 , wherein Y 1 and Y 2 taken together with X form:

wherein
X is N;
G is selected from N or —C(H)—;
Z is absent or selected from substituted or unsubstituted alkyl, heteroalkyl, alkenyl, or alkynyl;
R 4 is absent or selected from substituted or unsubstituted aryl and heteroaryl; and
R 5 and R 6 are each independently absent or lower alkyl.

41. The method of claim 40 , wherein G is N a

Assignees

• Univ California

Inventors

• Mcbride William
• Micewicz Ewa

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• C07D211/96

  Sulfur atom · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D215/54

  attached in position 3 · CPC title