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

Patent metadata

Field	Value
Publication number	US-2016297748-A1
Application number	US-201415100967-A
Country	US
Kind code	A1
Filing date	Dec 1, 2014
Priority date	Dec 2, 2013
Publication date	Oct 13, 2016
Grant date	—

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

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, halo, C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 alkenyl-heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 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 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;

or an N-oxide, crystalline form, 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, or

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

2 . A compound according to claim 1 having the structure of formula (II):

wherein:
R 3 is independently selected from the group consisting of H, 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, halo, aryl, heteroaryl, C 1-6 alkyl-aryl, and C 1-6 alkyl-heteroaryl; and
is an optional bond,

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

3 . A compound according to claim 1 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, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

4 . A compound according to claim 1 , which is selected from the group consisting of:

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

5 . A compound according to claim 1 , which is selected from the group consisting of:

and combinations thereof, or an N-oxide, crystalline form, 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, halo, C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 alkenyl-heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 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 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;

or an N-oxide, crystalline form, 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, or

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

7 . A pharmaceutical composition according to claim 6 , wherein the compound has the structure of formula (II):

wherein:
R 3 is independently selected from the group consisting of H, 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, halo, aryl, heteroaryl, C 1-6 alkyl-aryl, and C 1-6 alkyl-heteroaryl; and
is an optional bond,

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

8 . A pharmaceutical composition according to claim 6 , wherein the compound has 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, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

9 . A pharmaceutical composition according to claim 6 , wherein the compound has a structure that is selected from the group consisting of:

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

10 . A pharmaceutical composition according to claim 6 , wherein the compound has a structure that is selected from the group consisting of:

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

11 . A kit comprising a compound according to claim 1 together with instructions for the use of the compound.

12 . A kit comprising a pharmaceutical composition according to claim 6 together with instructions for the use of the pharmaceutical composition.

13 . A method for treating or ameliorating the effects of a 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:
R 1 and R 2 , are independently selected from the group consisting of no atom, H, D, O, halo, C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 alkenyl-heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkyl-heteroaryl, C 1-6 alkenyl, C 1-6 alkenyl-aryl, and C 1-6 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 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl;

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
with the proviso that:
when R 3 is ethyl, R 1 an

Assignees

• Univ Columbia

Inventors

• Stockwell Brent R
• Skouta Rachid
• Dixon Scott

Classifications

• A61K31/196

  the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil · CPC title

• C07C271/16

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title

• C07C2603/74

  Adamantanes · CPC title

• C07C271/28

  to a carbon atom of a non-condensed six-membered aromatic ring · CPC title

• C07C2601/18

  with a ring being at least seven-membered · CPC title