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-10865214-B2
Application number	US-201816027990-A
Country	US
Kind code	B2
Filing date	Jul 5, 2018
Priority date	Oct 5, 2015
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

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 having the formula (IV):

wherein X is halide;
wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, 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.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a salt thereof.

3. A compound having the formula (V):

wherein X is H;
wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, 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.

4. The compound of claim 3 , wherein the compound is selected from the group consisting of:

or a salt thereof.

5. A compound having the formula (VI):

wherein X is H;
wherein R 1 is selected from the group consisting of optionally substituted thioheteroaryl, halide, 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.

6. The compound of claim 5 , wherein the compound is selected from the group consisting of:

or a salt thereof.

7. A pharmaceutical composition comprising a compound of any one of claims 1 , 3 or 5 or a pharmaceutically acceptable salt thereof.

8. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 , 3 or 5 , wherein the neurodegenerative disease is a proteinopathy.

9. The method of claim 8 , wherein the proteinopathy is a tauopathy.

10. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 , 6 or 5 , wherein the neurodegenerative disease is Alzheimer's disease.

11. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of a compound of any one of claims 1 , 3 or 5 .

12. A method of treating a proteinopathy comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 , 3 or 5 .

13. A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 , 3 or 5 .

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 7 , wherein the neurodegenerative disease is a proteinopathy.

15. The method of claim 14 , wherein the proteinopathy is a tauopathy.

16. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 7 , wherein the neurodegenerative disease is Alzheimer's disease.

17. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of the pharmaceutical composition of claim 7 .

18. A method of treating a proteinopathy comrising administering to a subject in need thereof an effective amount of the pharmaceutical composition of cliam 7 .

19. A method of treating a tauopathy comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 7 .

Assignees

• Univ Columbia
• Ny State Psychiatric Inst
• The Trustees Of Columbia Univ In They City Of New York

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