Metabolically programmed metal chelators and uses thereof
View Patent ↗The present invention provides compounds of Formula (I), which are “metabolically programmed” metal chelators, e.g., lipophilic, absorbable (e.g., orally absorbable), and effective metal chelators that are converted in vivo to their hydrophilic, nontoxic metabolites. The present invention also provides compounds of Formula (II), which are also “metabolically programmed” metal chelators. The invention also provides pharmaceutical compositions, kits, methods, and uses that include a compound described herein. The compounds, pharmaceutical compositions, kits, and methods may be useful in treating or preventing a disease (e.g., metal overload, oxidative stress, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, reperfusion injury, metal poisoning, or infectious disease).
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group,
each instance of R′ is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group;
each instance of x is independently 0;
each instance of y is independently 0;
each instance of p is independently an integer between 1 and 10, inclusive;
q is 0 or 1, provided that when q is 0, then R 1 is of the formula:
each instance of R 2 is independently —C(═O)OH, or —C(═O)OR 2a , wherein each instance of R 2a is independently substituted or unsubstituted alkyl or an oxygen protecting group;
each instance of R 3 is independently halogen, substituted or unsubstituted alkyl, or —OR 8 , wherein each instance of R 8 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group,
k is 0, 1, 2, 3, or 4;
R 4 is hydrogen or substituted or unsubstituted alkyl;
R 5 is hydrogen or substituted or unsubstituted alkyl;
R 6 is hydrogen or substituted or unsubstituted alkyl;
Z is —O— or —S—; and
R 9 is hydrogen, substituted or unsubstituted alkyl,
an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
2. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein at least one instance of p is 1, 2, 3, 4, or 5.
7. The compound of claim 1 , wherein at least one instance of R 2 is —C(═O)OH.
8. The compound of claim 1 , wherein at least one instance of R 2 is —C(═O)OR 2a .
9. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable alkali or alkaline earth metal salt.
11. A pharmaceutical composition comprising a compound of claim 1 and optionally a pharmaceutically acceptable excipient.
12. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 , wherein the disease is iron overload, aluminum overload, lanthanide overload, actinide overload, oxidative stress, transfusional iron overload, thalassemia, primary hemochromatosis, secondary hemochromatosis, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, reperfusion injury, an infectious disease, or metal poisoning.
13. A method of reducing the formation of biofilms in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .
14. The compound of claim 2 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein each of R 4 and R 5 is hydrogen.
16. The compound of claim 1 , wherein Z is —O—.
17. The compound of claim 1 , wherein R 6 is substituted or unsubstituted C 1-6 alkyl.
18. The compound of claim 1 , wherein p is 3.
19. The compound of claim 1 , wherein R 9 is hydrogen.
20. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group,
each instance of R′ is independently hydrogen, substituted or unsubstituted alkyl, or an oxygen protecting group;
each instance of x is independently 0;
each instance of y is independently 0;
each instance of p is independently 5, 6, 7, 8, 9, or 10;
q is 0 or 1, provided that when q is 0, then R 1 is of the formula:
each instance of R 2 is independently —CH 2 OH, —C(═O)OH, or —C(═O)OR 2a , wherein each instance of R 2a is independently substituted or unsubstituted alkyl or an oxygen protecting group;
each instance of R 3 is independently halogen, substituted or unsubstituted alkyl, or —OR 8 , wherein each instance of R 8 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, an oxygen protecting group,
k is 0, 1, 2, 3, or 4;
R 4 is hydrogen or substituted or unsubstituted alkyl;
R 5 is hydrogen or substituted or unsubstituted alkyl;
R 6 is hydrogen or substituted or unsubstituted alkyl;
Z is —O— or —S—; and
R 9 is hydrogen, substituted or unsubstituted alkyl,
an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.