Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders
AssigneeThe Trustees of Columbia University in the City of New York
InventorsBrent R. Stockwell, Rachid Skouta, Scott Dixon
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Abstract
The present invention provides, inter alia, a compound having the structure of Formula (I). Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, and methods for treating or ameliorating the effects of a neurodegenerative disease.
Claims13
A compound according to formula (I):
- wherein:
- R1 and R2, are independently selected from the group consisting of no atom, H, D, ═O, —O−, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
- and
- R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof,
- with the proviso that:
- when R3 is ethyl, R1 and R2 cannot be both H, ═O, —O−, or
- and
- when R3 is ethyl and at least one of R1 or R2 is H, then the other of R1 or R2 cannot be
- R1 and R2 are not both “no atom”;
- and
- when R3 is H, then at least one of R1 and R2 is not H.
A compound having the structure of formula (II):
- wherein:
- R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
- R4 and R5 are independently selected from the group consisting of no atom, H, D, ═O, —O−, halo, aryl, heteroaryl, C1-6alkyl, C1-6alkyl-aryl, and C1-6alkyl-heteroaryl;
- and
- --- is an optional bond,
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A compound having the structure of formula (III):
- wherein the C2-4 alkyl is selected from the group consisting of ethyl, isopropyl, n-propyl, butyl, and t-butyl,
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of:
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (I):
- wherein:
- R1 and R2, are independently selected from the group consisting of no atom, H, D, ═O, —O−, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
- and
- R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof,
- with the proviso that:
- when R3 is ethyl, R1 and R2 cannot be both H, ═O, —O−,or
- and
- when R3 is ethyl and at least one of R1 or R2 is H, then the other of R1 or R2 cannot be
- R1 and R2 are not both “no atom”;
- and
- when R3 is H, then at least one of R1 and R2 is not H.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (II):
- wherein:
- R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
- R4 and R5 are independently selected from the group consisting of no atom, H, D, ═O, —O−, halo, aryl, heteroaryl, C1-6alkyl, C1-6alkyl-aryl, and C1-6alkyl-heteroaryl;
- and
- --- is an optional bond,
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (III):
- wherein the C2-4 alkyl is selected from the group consisting of ethyl, isopropyl, n-propyl, butyl, and t-butyl,
- or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound having a structure that is selected from the group consisting of:
- and combinations thereof, or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.
A compound having the formula:
Dependencies are inferred from the claim text.