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-10487091-B2
Application number	US-201715480220-A
Country	US
Kind code	B2
Filing date	Apr 5, 2017
Priority date	Oct 5, 2015
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

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 (VII):

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.

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 (VIII):

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 following formula:

6. A pharmaceutically acceptable salt of a compound having the following formula:

7. A compound according to claims 1 - 4 , wherein the compound is a pharmaceutically acceptable salt.

8. A pharmaceutical composition comprising a compound of any one of claim 1 - 4 , or 5 or a pharmaceutically acceptable salt thereof.

9. 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 claim 1 - 4 , 5 or 6 , or pharmaceutical composition of claim 8 .

10. The method of claim 9 , wherein the neurodegenerative disease is a proteinopathy.

11. The method of claim 10 , wherein the proteinopathy is a tauopathy.

12. The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease.

13. 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 - 4 , 5 or 6 , or pharmaceutical composition of claim 8 .

Assignees

• Univ Columbia
• Ny State Psychiatric Inst

Inventors

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

Classifications

• C07D401/12

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

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D239/86

  with hetero atoms directly attached in position 4 · 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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title