Nitrated lipids and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-9522156-B2
Application number	US-201615040376-A
Country	US
Kind code	B2
Filing date	Feb 10, 2016
Priority date	Apr 28, 2004
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

Described herein are nitrated lipids and methods of making and using the nitrated lipids.

First claim

What is claimed:

1. A method for treating inflammatory disease in a subject comprising administering to a subject in need thereof an effective amount of a lipid having the structure:

wherein:
R 1 is selected from the group consisting of C 1 -C 24 alkyl, C 1 -C 24 alkenyl, and C 1 -C 24 alkynyl;
R 2 , R 3 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, NO 2 , OH, and OOH, wherein at least one of R 2 , R 3 , R 7 , and R 8 is NO 2 ;
R 4 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkenyl, wherein R 4 comprises a terminal COOR 6 and R 6 is hydrogen, C 1 -C 24 alkyl, or a pharmaceutically acceptable counterion;
R 5 is hydrogen or R 4 and R 5 collectively form ═C(R 9 )(R 10 ), wherein R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkynyl and R 10 is hydrogen, NO 2 , OH, or OOH; and
n is from 1 to 24,
and a therapeutic agent.

2. The method of claim 1 , wherein the therapeutic agent is selected from a group consisting of antibodies, antivirals, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, cytokines, chemokines, and growth factors.

3. The method of claim 1 , wherein the lipid comprises a fatty acid.

4. The method of claim 1 , wherein the lipid is selected from the group consisting of glycolipids, glycerolipids, phospholipids, and cholesterol.

5. The method of claim 1 , wherein the lipid is selected from the group consisting of oleic acid (18:1), 22:6, and docosahexanoic acid.

6. The method of claim 1 , wherein the lipid comprises 10-nitro-9-cis,12-cis-octadecadienoic acid.

7. The method of claim 1 , wherein the lipid is selected from the group consisting of linoleic acid (18:2), linolenic acid (18:3), and cholesterol linoleate.

8. The method of claim 1 , wherein the lipid comprises arachidonic acid (20:4).

9. The method of claim 1 , the lipid having the formula:

wherein:
R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkenyl and includes a terminal COOR 6 ; and
R 10 is hydrogen, NO 2 , OH, or OOH,
wherein at least one of R 2 , R 3 , R 7 , R 8 , and R 10 is NO 2 .

10. The method of claim 1 , wherein R 1 is C 4 -C 10 alkyl; R 2 , R 8 , and R 10 are hydrogen; R 7 is NO 2 ; and R 9 is C 6 -C 12 alkyl.

11. The method of claim 1 , wherein R 3 and R 8 are cis to one another, and R 7 and R 10 are cis to one another.

12. The method of claim 1 , wherein R 1 is C 4 -C 10 alkyl; R 2 , R 3 , and R 7 are hydrogen; R 8 is NO 2 ; and R 4 is C 6 -C 12 alkyl.

13. The method of claim 1 , wherein the lipid comprises 12-nitro-9-cis,12-cis-octadecadienoic acid.

14. The method of claim 1 , wherein R 9 is C 6 -C 12 alkyl.

15. The method of claim 1 , wherein the lipid is 10-nitro-9-cis-octadecaenoic acid.

16. The method of claim 1 , wherein the lipid and the therapeutic agent are administered from a group consisting of concomitantly, simultaneously, and sequentially.

17. The method of claim 1 , wherein the lipid and the therapeutic agent are administered selected from a group consisting of topically, orally, by inhalation, parenterally, intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally, intratracheally, and extracorporeally.

18. The method of claim 1 , wherein the inflammatory disease is selected from a group consisting of systemic lupus erythematosus, Hashimoto's disease, rheumatoid arthritis, graft versus-host disease, Sjogren's syndrome, pernicious anemia, Addison disease, scleroderma, Goodpasture's syndrome, Crohn's disease, autoimmune hemolytic anemia, myasthenia gravis, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Basedow's disease, thrombopenia purpura, insulin-dependent diabetes mellitus, allergy, asthma, inflammatory bowel disease, cancer, ulcerative colitis, scleroderma, cardiomyopathy, atherosclerosis, hypertension, sickle cell disease, and respiratory distress syndrome.

19. A method for treating a nitric oxide-related condition in a subject comprising administering to a subject in need thereof an effective amount of a lipid having the structure:

wherein:
R 1 is selected from the group consisting of C 1 -C 24 alkyl, C 1 -C 24 alkenyl, and C 1 -C 24 alkynyl;
R 2 , R 3 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, NO 2 , OH, and OOH, wherein at least one of R 2 , R 3 , R 7 , and R 8 is NO 2 ;
R 4 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkenyl, wherein R 4 comprises a terminal COOR 6 and R 6 is hydrogen, C 1 -C 24 alkyl, or a pharmaceutically acceptable counterion;
R 5 is hydrogen or R 4 and R 5 collectively form ═C(R 9 )(R 10 ), wherein R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkynyl and R 10 is hydrogen, NO 2 , OH, or OOH; and
n is from 1 to 24,
and a therapeutic agent.

20. The method of claim 19 , wherein the therapeutic agent is selected from a group consisting of chemotherapeutic agents, antibodies, antivirals, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, cytokines, chemokines, and growth factors.

21. The method of claim 19 , wherein the lipid comprises a fatty acid.

22. The method of claim 19 , wherein the lipid is selected from the group consisting of glycolipids, glycerolipids, phospholipids, and cholesterol.

23. The method of claim 19 , wherein the lipid is selected from the group consisting of oleic acid (18:1), 22:6, and docosahexanoic acid.

24. The method of claim 19 , wherein the lipid comprises 10-nitro-9-cis,12-cis-octadecadienoic acid.

25. The method of claim 19 , wherein the lipid is selected from the group consisting of linoleic acid (18:2), linolenic acid (18:3), and cholesterol linoleate.

26. The method of claim 19 , wherein the lipid comprises arachidonic acid (20:4).

27. The method of claim 19 , the lipid having the formula:

wherein:
R 9 is C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkenyl and includes a terminal COOR 6 ; and
R 10 is hydrogen, NO 2 , OH, or OOH,
wherein at least one of R 2 , R 3 , R 7 , R 8 , and R 10 is NO 2 .

28. The method of claim 19 , wherein R 1 is C 4 -C 10 alkyl; R 2 , R 8 , and R 10 are hydrogen; R 7 is NO 2 ; and R 9 is C 6 -C 12 alkyl.

29. The method of claim 19 , wherein R 3 and R 8 are cis to one another, and R 7 and R 10 are cis to one another.

30. The method of claim 19 , wherein R 1 is C 4 -C 10 alkyl; R 2 , R 3 , and R 7 are hydrogen; R 8 is NO 2 ; and R 4 is C 6 -C 12 alkyl.

31. The method of claim 19 , wherein the lipid comprises 12-nitro-9-cis,12-cis-octadecadienoic acid.

32. The method of claim 19 , wherein R 9 is C 6 -C 12 alkyl.

33. The method of claim 19 , wherein the lipid is 10-nitro-9-cis-octadecaenoic acid.

34. The method of claim 19 , wherein the lipid

Assignees

• Uab Res Found
• State Of Oregon Acting By And Through The Board Of Education On Behalf Of The Univ Of Oregon
• Univ College Cardiff Consultants Ltd
• Morehouse School Of Medicine Inc
• The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The Univ

Inventors

• Freeman Bruce A
• Schopfer Francisco
• O'Donnell Valerie
• Baker Paul
• Chen Yuqing E
• Branchaud Bruce

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title