Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders

Patent metadata

Field	Value
Publication number	US-10233171-B2
Application number	US-201715442475-A
Country	US
Kind code	B2
Filing date	Feb 24, 2017
Priority date	Apr 2, 2012
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

The present invention provides, inter alia, a compound having the structure:

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.

First claim

The invention claimed is:

1. A compound having the structure of formula (I):

wherein
X is N;
Y is H, halo, or C 1-4 alkyl;
R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;
R 2 is NR 6 R 7 ;
R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;
R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;
R 10 and R 11 are independently selected from H and Boc; and
R 12 is a C 1-4 alkyl optionally substituted with aryl,
with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

2. A compound according to claim 1 having the structure selected from the group consisting of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

3. A compound according to claim 1 having the structure of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

4. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

5. A method for treating or ameliorating the effects of an excitotoxic disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound having the structure of formula (I):

wherein
X is N;
Y is H, halo, or C 1-4 alkyl;
R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;
R 2 is NR 6 R 7 ;
R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;
R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;
R 10 and R 11 are independently selected from H and Boc; and
R 12 is a C 1-4 alkyl optionally substituted with aryl,
with the proviso that:
when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

6. The method according to claim 5 , wherein the compound is selected from the group consisting of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

7. The method according to claim 5 , wherein the compound has the structure of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

8. The method according to claim 5 , wherein the excitotoxic disorder is a disease involving oxidative cell death.

9. The method according to claim

Assignees

• Univ Columbia

Inventors

• Stockwell Brent R
• Dixon Scott J
• Skouta Rachid

Classifications

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D295/30

  non-acylated · CPC title

• C07D295/088

  to an acyclic saturated chain · CPC title

• C07D213/80

  in position 3 · CPC title