Method of modulating stress-activated protein kinase system
View Patent ↗Disclosed are methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of at least one p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the at least one p38 MAPK by the compound. Also disclosed are derivatives of pirfenidone. These derivatives can modulate a stress activated protein kinase (SAPK) system.
1. A compound of Genus 1a:
wherein
R 2 is selected from the group consisting of C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 1 -C 10 nitroalkyl, C 1 -C 10 thioalkyl, C 1 -C 10 hydroxyalkyl, hydroxyl, C 1 -C 10 alkoxyalkyl, C 1 -C 10 carboxy, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO-polysaccharide;
R 3 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 1 -C 10 nitroalkyl, C 1 -C 10 thioalkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxy, phenyl, substituted phenyl, halogen, hydroxyl, C 1 -C 10 alkoxyalkyl, C 1 -C 10 carboxy, C 1 -C 10 alkoxycarbonyl, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO-polysaccharide;
R 1 is hydrogen;
R 4 is hydrogen; and
X 1 X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of hydrogen, halogen, and hydroxyl, provided that at least one of X 1 X 2 , X 3 , X 4 and X 5 is not H.
2. The compound of claim 1 , wherein R 2 is selected from the group consisting of C 1 -C 10 haloalkyl, hydroxyalkyl, and hydroxyl.
3. The compound of claim 2 , wherein R 2 is selected from C 1 -C 10 haloalkyl.
4. The compound of claim 1 , wherein R 3 is selected from hydrogen or C 1 -C 10 alkyl.
5. The compound of claim 1 , wherein X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from H and halogen.
6. A compound selected from the group consisting of:
7. A pharmaceutical composition comprising a compound of claim 1 , and pharmaceutically acceptable excipients.
8. A method for treating or ameliorating fibrosis comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.
9. A method of treating or ameliorating fibrosis in a subject in need of, comprising administering an effective amount of a compound has the structure of Genus Ia:
wherein
R 1 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 1 -C 10 nitroalkyl, C 1 -C 10 thioalkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxy, phenyl, substituted phenyl, halogen, hydroxyl, C 1 -C 10 alkoxyalkyl, C 1 -C 10 carboxy, C 1 -C 10 alkoxycarbonyl, CO-uronide, CO-monosaccharide, CO-oligosaccharide, and CO-polysaccharide;
R 2 is selected from the group consisting of C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 1 -C 10 nitroalkyl, C 1 -C 10 thioalkyl, C 1 -C 10 alkoxy, phenyl, substituted phenyl, halogen, hydroxyl, C 1 -C 10 alkoxyalkyl; and
X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkoxy, and hydroxyl.
10. The method of claim 9 , wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is not H.
11. The method of claim 9 , wherein R 2 is selected from the group consisting of C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, phenyl, substituted phenyl, halogen, and hydroxyl.
12. The method of claim 9 , wherein R 2 is selected from the group consisting of C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy, phenyl, and substituted phenyl.
13. The method of claim 12 , wherein R 2 is substituted phenyl.
14. The method of claim 13 , wherein R 2 is phenyl substituted with one or more halogens.
15. The method of claim 9 , wherein R 3 is H or C 1 -C 10 alkyl.
16. The method of claim 15 , wherein R 3 is H.
17. The method of claim 9 , wherein both R 1 and R 4 are H.
18. The method of claim 9 , wherein X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from H or halogen.
19. The method of claim 9 , wherein X 1 and X 5 are each independently selected from H or halogen.
20. The method of claim 9 , wherein X 2 and X 4 are each independently selected from H, halogen, or C 1 -C 10 alkoxy.
21. The method of claim 9 , wherein X 3 is selected from H, halogen, or C 1 -C 10 alkoxy.
22. The method of claim 9 , wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, liver fibrosis, and renal fibrosis.
23. The method of claim 22 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
24. The method of claim 9 , wherein the compound is administered by inhalation.