Chemical inhibition of the E3 ligase subunit FBXO7 confers neuroprotection and anti-inflammatory activity by stabilizing mitochondria

Patent metadata

Field	Value
Publication number	US-11242339-B2
Application number	US-201816624843-A
Country	US
Kind code	B2
Filing date	Jun 25, 2018
Priority date	Jun 30, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

A method for treating a neurodegenerative disease or an inflammatory disorder in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II:wherein each of R3-R7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy;R8 is an optionally-substituted heterocycloalkyl; anda is 0 to 3.

First claim

What is claimed is:

1. A method for treating a neurodegenerative disease or an inflammatory disorder in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II:

wherein each of R 3 -R 7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy;
R 8 is an optionally-substituted heterocycloalkyl; and
a is 0 to 3.

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

3. A method for treating frontotemporal dementia, a mitochondrial disease caused by mutations in nuclear DNA, a mitochondrial disease caused by mutations in mtDNA, or a disease of skeletal or cardiac muscle in a subject, comprising administering to the subject in need thereof, a compound, or a pharmaceutically acceptable salt thereof, of formula II:

wherein each of R 3 -R 7 is independently H, halogen, optionally-substituted alkyl, amino, alkoxy or hydroxy;
R 8 is an optionally-substituted heterocycloalkyl; and
a is 0 to 3.

4. The method of claim 1 , wherein the subject is in need of treatment for Parkinson's disease and the compound is:

5. The method of claim 1 , wherein the subject is need of treatment for a neurodegenerative disease.

6. The method of claim 1 , wherein at least one of R 3 -R 7 is an aminoalkyl.

7. The method of claim 1 , wherein the aminoalkyl is —(CH 2 ) b —NR 9 R 10 , wherein R 9 and R 10 are each independently H or alkyl and b is 1 to 5.

8. The compound of claim 1 , wherein at least one of R 3 -R 7 is an amino.

9. The method of claim 8 , wherein the amino is —NH 2 or an alkylamino.

10. The method of claim 9 , wherein the alkylamino is —NR 11 R 12 , wherein R 11 and R 12 are each independently H or alkyl.

11. The method of claim 1 , wherein at least one of R 3 -R 7 is an alkoxy.

12. The method of claim 1 , wherein R 5 is not H.

13. The method of claim 1 , wherein R 5 is alkoxy or alkylamino.

14. The method of claim 1 , wherein at least two of R 3 -R 7 are halogen.

15. The method of claim 1 , wherein at least one of R 3 -R 7 is not H.

16. The method of claim 1 , wherein each of R 3 -R 7 is H.

17. The method of claim 1 , wherein R 8 is a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl.

18. The method of claim 1 , wherein R 8 is a heterocycloalkyl that includes at least one oxygen heteroatom.

19. The compound of claim 1 , wherein the heterocycloalkyl is selected from oxetanyl, dioxetanyl, oxolanyl, dioxolanyl, oxanyl or dioxanyl.

20. The method of claim 1 , wherein the heterocycloalkyl is oxolanyl or oxanyl.

21. The method of claim 1 , wherein R 8 is:

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education
• Us Gov Veterans Affairs

Inventors

• Mallampalli Rama K
• Chen Beibei
• Chu Charleen T
• Liu Yuan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/517

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

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · 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