Small molecule ferroptosis inducers

Patent metadata

Field	Value
Publication number	US-10947188-B2
Application number	US-201916445104-A
Country	US
Kind code	B2
Filing date	Jun 18, 2019
Priority date	Dec 19, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

The present invention provides, inter alia, a compound according to formula (I):

Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for regulating GPX4 in a cell and methods for inducing ferroptosis in a cell.

First claim

What is claimed is:

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

wherein:
R 1 is selected from the group consisting of H, and —(OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 2 , R 2 ′, R 3 , and R 3 ′ independently are selected from the group consisting of H, C 3-8 cycloalkyl, and combinations thereof, or R 2 and R 2 ′ may be joined together to form a pyridinyl or pyranyl and R 3 and R 3 ′ may be joined together to form a pyridinyl or pyranyl;

or an N-oxide, or pharmaceutically acceptable salt thereof;
with the proviso that the compound is not

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

wherein:
R 1 is —(OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 4 and R 5 are independently selected from the group consisting of CH 2 and O;

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

wherein:
R 1 is OH and (1) R 4 and R 5 are both O; or (2) R 4 is CH 2 and R 5 is O; or (3) R 4 is O and R 5 is CH 2 ;
or an N-oxide, or pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 , which is selected from the group consisting of:

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

4. A composition comprising a compound according to any one of claims 1 - 3 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

5. A pharmaceutically acceptable salt of a compound according to any one of claims 1 - 3 .

6. A composition comprising a pharmaceutically acceptable salt of a compound according to any one of claims 1 - 3 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

7. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound having the structure of formula (I):

wherein:
R 1 is selected from the group consisting of H, OH, and (OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 2 , R 2 ′, R 3 , and R 3 ′ independently are selected from the group consisting of H, C 3-8 cycloalkyl, and combinations thereof, or R 2 and R 2 ′ may be joined together to form a pyridinyl or pyranyl and R 3 and R 3 ′ may be joined together to form a pyridinyl or pyranyl;

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

8. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound having the structure of formula (II):

wherein:
R 1 is selected from the group consisting of OH and —(OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 4 and R 5 are independently selected from the group consisting of CH 2 and O;

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

9. A method for inducing ferroptosis in a cell comprising contacting the cell with an effective amount of a compound selected from the group consisting of:

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

10. The method according to claim 7 , wherein the compound is FIN56:

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

11. The method according to any one of claims 7 - 10 , wherein the cell is a mammalian cell.

12. The method according to claim 11 , wherein the cell is a human cell.

13. The method according to any one of claims 7 - 10 , wherein the cell is from a laboratory animal.

14. The method according to any one of claims 7 - 10 , which is carried out in vitro, or ex vivo.

15. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound having the structure of formula (I):

wherein:
R 1 is selected from the group consisting of H, OH, and —(OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 2 , R 2 ′, R 3 , and R 3 ′ independently are selected from the group consisting of H, C 3-8 cycloalkyl, and combinations thereof, or R 2 and R 2 ′ may be joined together to form a pyridinyl or pyranyl and R 3 and R 3 ′ may be joined together to form a pyridinyl or pyranyl;

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

16. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound having the structure of formula (II):

wherein:
R 1 is selected from the group consisting of OH and —(OCH 2 CH 2 ) x OH;
X is an integer from 1 to 6; and
R 4 and R 5 are independently selected from the group consisting of CH 2 and O;

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

17. A method for decreasing GPX4 in a cell, comprising contacting the cell with an effective amount of a compound selected from the group consisting of:

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

18. The method according to claim 15 , wherein the compound is FIN56:

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

19. The method according to any one of claims 15 - 18 , wherein the cell is a mammalian cell.

Assignees

• Univ Columbia

Inventors

• Stockwell Brent R
• Shimada Kenichi
• Skouta Rachid

Classifications

• C07C311/21

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D401/12

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

• C07C311/20 Primary

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C311/15 Primary

  Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07D407/12

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