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

Patent metadata

Field	Value
Publication number	US-10259775-B2
Application number	US-201415100967-A
Country	US
Kind code	B2
Filing date	Dec 1, 2014
Priority date	Dec 2, 2013
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

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.

First claim

What is claimed is:

1. A compound according to formula (I):

wherein:
R 1 and R 2 , are independently selected from the group consisting of no atom, H, D, ═O, —O − , halo, C 1-6 alkyl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, C 2-6 alkenyl, C 2-6 alkenyl-aryl, and C 2-6 alkenyl-heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, C 2-6 alkenyl, C 2-6 alkenyl-aryl, and C 2-6 alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C 1-4 alkyl, CF 3 , and combinations thereof; and
R 3 is independently selected from the group consisting of H, C 1-12 aliphatic, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;
or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof,
with the proviso that:
when R 3 is ethyl, R 1 and R 2 cannot be both H, ═O, —O − , or

 and
when R 3 is ethyl and at least one of R 1 or R 2 is H, then the other of R 1 or R 2 cannot be

R 1 and R 2 are not both “no atom”; and
when R 3 is H, then at least one of R 1 and R 2 is not H.

2. A compound having the structure of formula (II):

wherein:
R 3 is independently selected from the group consisting of H, C 1-12 aliphatic, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;
R 4 and R 5 are independently selected from the group consisting of no atom, H, D, ═O, —O − , halo, aryl, heteroaryl, C 1-6 alkyl, C 1-6 alkyl-aryl, and C 1-6 alkyl-heteroaryl; and
--- is an optional bond,
or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.

3. A compound having the structure of formula (III):

wherein the C 2-4 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.

4. A compound selected from the group consisting of:

or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.

5. A compound according to claim 3 , which is selected from the group consisting of:

and combinations thereof, or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (I):

wherein:
R 1 and R 2 , are independently selected from the group consisting of no atom, H, D, ═O, —O − , halo, C 1-6 alkyl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, C 2-6 alkenyl, C 2-6 alkenyl-aryl, and C 2-6 alkenyl-heteroaryl, wherein the C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, C 2-6 alkenyl, C 2-6 alkenyl-aryl, and C 2-6 alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C 1-4 alkyl, CF 3 , and combinations thereof; and
R 3 is independently selected from the group consisting of H, C 1-12 aliphatic, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;
or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof,
with the proviso that:
when R 3 is ethyl, R 1 and R 2 cannot be both H, ═O, —O − ,or

 and
when R 3 is ethyl and at least one of R 1 or R 2 is H, then the other of R 1 or R 2 cannot be

R 1 and R 2 are not both “no atom”; and
when R 3 is H, then at least one of R 1 and R 2 is not H.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (II):

wherein:
R 3 is independently selected from the group consisting of H, C 1-12 aliphatic, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;
R 4 and R 5 are independently selected from the group consisting of no atom, H, D, ═O, —O − , halo, aryl, heteroaryl, C 1-6 alkyl, C 1-6 alkyl-aryl, and C 1-6 alkyl-heteroaryl; and
--- is an optional bond,
or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (III):

wherein the C 2-4 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.

9. 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.

10. A pharmaceutical composition according to claim 8 , wherein the compound has a structure that is selected from the group consisting of:

and combinations thereof or an N-oxide, hydrate, or pharmaceutically acceptable salt thereof.

11. A kit comprising a compound according to claim 3 together with instructions for the use of the compound.

12. A kit comprising a pharmaceutical composition according to claim 8 together with instructions for the use of the pharmaceutical composition.

13. A compound having the formula:

Assignees

• Univ Columbia

Inventors

• Stockwell Brent R
• Skouta Rachid
• Dixon Scott

Classifications

• C07C2601/02

  with a three-membered ring · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C229/56 Primary

  with amino and carboxyl groups bound in ortho-position · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• C07C2603/72

  Ethanonaphthalenes; Hydrogenated ethanonaphthalenes · CPC title