PROLYL HYDROXYLASE INHIBITORS
Disclosed herein are prolyl hydroxylase inhibitors that can stabilize hypoxia inducible factor-1 alpha (HIF-1α), as well as hypoxia inducible factor-2 (HIF-2). Also disclosed herein are pharmaceutical compositions comprising one or more of the disclosed compounds. Yet further disclosed are methods for stimulating the cellular immune response in a mammal such as increasing phagocytosis, for example, prolonging the life of phagocytes, inter alia, kerotyiocytes, neutrophils. As such the disclosed compounds provide methods for treating diseases that relate to the body's immune response.
1 . A compound having the formula:
wherein:
R 1 and R 2 taken together form a substituted or unsubstituted C 4 -C 11 heterocyclic ring or a substituted or unsubstituted C 4 -C 11 heteroaryl ring;
each R is independently a substituent for hydrogen;
L is CH 2 or SO 2 ; and
n is an integer from 0 to 5; or
a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 , wherein R 1 and R 2 taken together form a substituted C 4 -C 11 heterocyclic ring.
3 . The compound according to claim 1 , wherein R 1 and R 2 taken together form a substituted piperazine ring.
4 . The compound according to claim 1 , wherein R 1 and R 2 taken together form a 4-(piperazine-1-carboxylate).
5 . The compound according to claim 1 , wherein the compound is a pharmaceutically acceptable salt of an anion chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogensulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate, or citrate.
6 . The compound according to claim 1 , wherein the compound is tert-butyl 4-((1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate.
7 . A compound chosen from:
Methyl 4-((1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate;
Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;
Methyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate;
Ethyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate; and
tert-Butyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate.
8 . A method for treating an infection, comprising administering to a subject in need thereof a therapeutically-effective amount of a composition comprising:
a) one or more compounds having the formula:
wherein:
R 1 and R 2 taken together form a substituted or unsubstituted C 4 -C 11 heterocyclic ring or a substituted or unsubstituted C 4 -C 11 heteroaryl ring;
each R is independently a substituent for hydrogen;
L is CH 2 or SO 2 ; and
n is an integer from 0 to 5; or
a pharmaceutically acceptable salt thereof; and
b) one or more pharmaceutically acceptable excipients.
9 . The method according to claim 8 , wherein R 1 and R 2 taken together form a substituted C 4 -C 11 heterocyclic ring.
10 . The method according to claim 8 , wherein R 1 and R 2 taken together form a substituted piperazine ring.
11 . The method according to claim 8 , wherein R 1 and R 2 taken together form a 4-(piperazine-1-carboxylate).
12 . The method according to claim 8 , wherein the compound is a pharmaceutically acceptable salt of an anion chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogensulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate, or citrate.
13 . The method according to claim 8 , wherein the compound is chosen from:
Methyl 4-((1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate;
Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;
tert-Butyl-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;
Methyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate;
Ethyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate; and
tert-Butyl 4-((3-hydroxy-2-oxo-1-(phenylsulfonyl)-1,2-dihydropyridin-4-yl)methyl)piperazine-1-carboxylate.
14 . The method according to claim 8 , wherein the infection is caused by a pathogen chosen from bacteria, viruses, yeasts, fungi, or parasites.
15 . The method according to claim 14 , wherein the infection is caused by bacteria.
16 . The method according to claim 15 , wherein the bacteria is Staphylococcus aureus.
17 . The method according to claim 16 , wherein the bacteria is methicillin resistant Staphylococcus aureus.
18 . The method according to claim 15 , wherein the bacteria is Streptococcus pyogenes.
19 . The method according to claim 15 , wherein the bacteria is Pseudomonas aeruginosa.