Compounds for modulating mitochondrial function

Patent metadata

Field	Value
Publication number	US-10774045-B2
Application number	US-201916433254-A
Country	US
Kind code	B2
Filing date	Jun 6, 2019
Priority date	Mar 3, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Compounds and compositions that can modulate mitochondrial function in neuronal cells are provided herein, as are methods for using the compounds and compositions to treat or prevent conditions such as Alzheimer's disease. For example, compounds of Formula I, compositions containing the compounds, and methods for using the compounds and compositions are provided herein:

wherein X is absent, CH 2 , or C(O); R 1 is H, OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, or di(C 1-3 alkyl)amino; R 2 is H or C 1-6 alkyl; R 3 is H, C 1-6 alkyl, —C(O)(C 1-3 alkyl), or —C(O)O(C 1-3 alkyl); R 4 is C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 5 groups; and R 5 is OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, or di(C 1-3 alkyl)amino.

First claim

What is claimed is:

1. A method for treating a neurodegenerative disorder in a subject, wherein the neurodegenerative disorder is Alzheimer's disease (AD), and wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is absent or selected from the group consisting of CH 2 and C(O);
R 1 is selected from the group consisting of H, OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino;
R 2 is selected from the group consisting of H and C 1-6 alkyl;
R 3 is selected from the group consisting of H, C 1-6 alkyl, —C(O)(C 1-3 alkyl), and —C(O)O(C 1-3 alkyl);
R 4 is selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 5 groups; and

R 5 is selected from the group consisting of OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the subject has a mutation in a PS1, PS2, or APP gene that is associated with AD.

4. The method of claim 1 , wherein X is CH 2 .

5. The method of claim 4 , wherein R 1 is C 1-3 alkyl.

6. The method of claim 5 , wherein R 2 is C 1-6 alkyl.

7. The method of claim 6 , wherein R 3 is H.

8. The method of claim 7 , wherein R 4 is unsubstituted 5-10 membered heteroaryl.

9. The method of claim 7 , wherein R 4 is aryl and R 5 is halo or OH.

10. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of H, OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino;
R 2 is selected from the group consisting of H and C 1-6 alkyl;
R 3 is selected from the group consisting of H, C 1-6 alkyl, —C(O)(C 1-3 alkyl), and —C(O)O(C 1-3 alkyl);
R 4 is selected from the group consisting of C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 5 groups; and
R 5 is selected from the group consisting of OH, CN, NO 2 , halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-7 cycloalkyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

12. The method of claim 11 , wherein R 1 is C 1-3 alkyl.

13. The method of claim 12 , wherein R 2 is C 1-6 alkyl.

14. The method of claim 13 , wherein R 3 is H.

15. The method of claim 14 , wherein R 4 is unsubstituted 5-10 membered heteroaryl.

16. The method of claim 14 , wherein R 4 is aryl and R 5 is halo or OH.

17. The method of claim 11 , wherein the compound of Formula (II) is a compound of Formula (IIa)

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Mayo Found Medical Education & Res

Inventors

• Trushina Eugenia
• Greenhouse Robert
• Greenman Kevin
• Thomas William

Classifications

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D213/36 Primary

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title