Methods for increasing the stabilization of hypoxia inducible factor-α
View Patent ↗Disclosed herein are methods for controlling the activity of hypoxia-inducible transcription factor 1-alpha (HIF-1α) and diseases, conditions, or syndromes related thereto, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia. Further disclosed are pharmaceutical compositions comprising HIF-1α prolyl hydroxylase inhibitors useful in treating diseases, conditions, and/or syndromes related thereto the activity of HIF-1α.
1. A method for treating a wound in a subject, comprising administering to a subject in need thereof an effective amount of a compound having the formula:
wherein wherein Z has the formula:
R represents a halogen, and n is an integer from 0 to 5;
R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl;
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 , wherein R 4 is tert-butyl.
3. The method according to claim 1 , wherein Z is 4-chlorophenyl.
4. The method according to claim 1 , wherein the one or more compounds is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.
5. The method according to claim 1 , wherein the wound is infected with methicillin resistant Staphylococcus aureus.
6. The method according to claim 1 , wherein the wound is infected with bacteria.
7. The method according to claim 6 , wherein the compound is co-administered with an antimicrobial.
8. A method for treating peripheral vascular disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a HIF-1α prolyl hydroxylase inhibitor having the formula:
wherein Z has the formula:
R represents a halogen, and n is an integer from 0 to 5;
R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl;
or a pharmaceutically acceptable salt thereof.
9. The method according to claim 8 , wherein the compound is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures.
10. A method for up regulation of phosphoglycerate kinase (PGK) in a subject in need thereof, comprising administering to the subject in need thereof a compound of the formula:
wherein Z has the formula:
R represents a halogen, and n is an integer from 0 to 5;
R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or
a pharmaceutically acceptable salt thereof.
11. The method according to claim 10 , wherein R 4 is tert-butyl.
12. The method according to claim 10 , wherein Z is 4-chlorophenyl.
13. The method according to claim 10 , wherein the one or more compounds is tert-butyl4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.