Compounds for the treatment of acute and chronic kidney disease

Patent metadata

Field	Value
Publication number	US-11623918-B2
Application number	US-202117529201-A
Country	US
Kind code	B2
Filing date	Nov 17, 2021
Priority date	Nov 18, 2020
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

Abstract

The present disclosure is concerned with thioquinolinone compounds for the treatment of disorders associated with heme oxygenase-1 (HO-1) signaling dysfunction such as, for example, kidney diseases (e.g., chronic kidney disease, acute kidney injury). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein n is 1 or 2;
wherein each of R 1a , R 1b , and R 1c is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R 1a , R 1b , and R 1c is —OH, C1-C4 alkoxy, or C1-C4 alkylamino;
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and
wherein each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,
provided that at least two of R 1a , R 1b , R 1c , R 2a , and R 2b are non-hydrogen groups, and
provided that when n is 1, Z is —S—, and R 1a is —OH or C1-C4 alkoxy, then exactly two of R 1a , R 1b , R 1c , R 2a , and R 2b are non-hydrogen groups,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein n is 1.

3. The compound of claim 1 , wherein n is 2.

4. The compound of claim 1 , wherein one of R 1a , R 1b , and R 1c is —OH or C1-C4 alkoxy.

5. The compound of claim 1 , wherein R 1c is —OH or C1-C4 alkoxy.

6. The compound of claim 1 , wherein R 1c is —OH or —OMe.

7. The compound of claim 1 , wherein one of R 1a , R 1b , and R 1c is —OH or C1-C4 alkoxy, and two of R 1a , R 1b , and R 1c are independently selected from hydrogen and halogen.

8. The compound of claim 1 , wherein each of R 2a and R 2b is independently selected from hydrogen and halogen.

9. The compound of claim 1 , wherein each of R 3a , R 3b , R 3c , R 3d , R 3e , and R 3f is hydrogen.

10. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

11. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

12. The compound of claim 1 , wherein the compound is not:

13. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

15. A method for treating a disorder associated with heme oxygenase-1 (HO-1) signaling dysfunction, wherein the disorder associated with HO-1 is a kidney disease, in a subject in need thereof, the method comprising administering to the subject an effective amount of compound having a structure represented by a formula.

16. The method of claim 15 , wherein the kidney disease is chronic kidney disease or acute kidney injury (AKI).

17. The method of claim 15 , wherein the subject is a human.

18. A method for modifying HO-1 signaling in a subject, the method comprising administering to the subject an effective amount of compound having a structure represented by a formula:

wherein n is 1 or 2;
wherein each of R 1a , R 1b , and R 1c is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R 1a , R 1b , and R 1c is —OH, C1-C4 alkoxy, or C1-C4 alkylamino;
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and
wherein each of R 3a , R 3b , R 3e , R 3d , R 3e , and R 3f is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,
or a pharmaceutically acceptable salt thereof, thereby modifying HO-1 signaling in the subject.

19. The method of claim 18 , wherein modifying is activating.

Assignees

• Southern Res Inst
• Uab Research Foundation
• Us Gov Veterans Affairs

Inventors

• Suto Mark J
• Mathew Bini
• Agarwal Anupam
• Traylor Amie M

Classifications

• A61P13/12

  of the kidneys · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D213/70

  Sulfur atoms · CPC title

• C07D215/36 Primary

  Sulfur atoms (C07D215/24 takes precedence) · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title