Activators of autophagic flux and phospholipase D and clearance of protein aggregates including tau and treatment of proteinopathies

Patent metadata

Field	Value
Publication number	US-11230558-B2
Application number	US-201816027951-A
Country	US
Kind code	B2
Filing date	Jul 5, 2018
Priority date	Oct 5, 2015
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present application discloses compounds which are activators of autophagic flux and pharmaceutical compositions comprising said activators. It further discloses use of said compounds and pharmaceutical compositions in the treatment of neurodegenerative diseases, particularly proteinopathies and tauopathies such as Alzheimer's disease. It further discloses methods of enhancing autophagic flux.

First claim

What is claimed is:

1. A compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

2. The compound of claim 1 , wherein the compound is:

or a salt thereof.

3. A compound having the formula (XV):

wherein X is halide;
wherein Z 1 is O;
wherein R 4 is selected from the group consisting of unsubstituted alkyl, Et, CF 3 , optionally substituted cycloalkyl, optionally substituted heteroaryl, and

4. The compound of claim 3 , wherein:
X is selected from group consisting of F, Cl, and Br; and
R 4 is selected from the group consisting of CH 3 , Et, CF 3 , cycloalkyl, heteroaryl, and

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

5. A pharmaceutical composition comprising a compound of claim 1 or claim 3 , or a pharmaceutically acceptable salt thereof.

6. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or claim 3 , wherein the neurodegenerative disease is a proteinopathy.

7. The method of claim 6 , wherein the proteinopathy is a tauopathy.

8. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or claim 3 , wherein the neurodegenerative disease is Alzheimer's disease.

9. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of a compound of claim 1 or claim 3 .

10. A method of treating a proteinopathy comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or claim 3 .

11. A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or claim 3 .

12. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 5 , wherein the neurodegenerative disease is a proteinopathy.

13. The method of claim 12 , wherein the proteinopathy is tauopathy.

14. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 5 , wherein the neurodegenerative disease is Alzheimer's disease.

15. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of the pharmaceutical composition of claim 5 .

16. A method of treating a proteinopathy comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 5 .

17. A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 5 .

18. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound having the following formula:

wherein X is H or halide;
wherein Z 1 is O;
wherein R 4 is selected from the group consisting of H, optionally substituted alkyl, Et, CF 3 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and

and
wherein the neurodegenerative disease is a proteinopathy.

19. The method of claim 18 , wherein the proteinopathy is a tauopathy.

20. The method of claim 18 , wherein the proteinopathy is Alzheimer's disease.

21. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (II):

wherein Y 1 and Y 2 are N;
wherein X is selected from the group consisting of H, halide, and aryl;
wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, and optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof,
wherein the neurodegenerative disease is Alzheimer's disease.

22. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of formula (II):

wherein Y 1 and Y 2 are N;
wherein X is selected from the group consisting of H, halide, and aryl;
wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, and optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof,
wherein the neurodegenerative disease is a proteinopathy.

23. The method of claim 22 , wherein the proteinopathy is a tauopathy.

Assignees

• Univ Columbia
• Ny State Psychiatric Inst

Inventors

• Rinderspacher Kirsten Alison
• Yu Wai
• Duff Karen
• Landry Donald
• Deng Shi-Xian

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title