Autophagy inducers for treatment of CNS conditions

Patent metadata

Field	Value
Publication number	US-11241436-B2
Application number	US-201816480885-A
Country	US
Kind code	B2
Filing date	Jan 25, 2018
Priority date	Jan 25, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

The invention provides a compound of formula (I): wherein R1, R2, R3, and R4 are as defined herein, ginsenoside Rg2 of structure (II): or a combination thereof, for use in treating or preventing a condition responsive to the induction of autophagy in a brain of a mammal in need thereof.

First claim

The invention claimed is:

1. A method of treating a condition responsive to induction of autophagy in a brain of a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (I):

wherein R 1 is selected from the group consisting of thioalkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, hydroxycycloalkyl, hydroxycycloalkylalkyl, thiocycloalkyl, alkoxycycloalkyl, alkylthiocycloalkyl, dialkylaminoalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, arylalkyl, arylalkylpiperidin-4-yl, arylpiperazinylalkyl, and heteroarylalkyl,
R 2 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl,
R 3 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl, and
R 4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and arylalkyl,
or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , R 3 , and R 4 , other than H, are optionally substituted on the aryl and/or alkyl portion with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, alkylenedioxy, and alkylcarbonyl,
wherein the condition is a decrease in a level or activity of cannabinoid receptor 1 (CB1R) wherein the decrease in the levels or activity of CB1R results from repeated administration of at least one CB1R receptor agonist to the mammal.

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

3. The method of claim 1 , wherein the method results in reduction of cannabinoid tolerance and enhancement of the analgesic effects of cannabinoids.

4. The method of claim 1 , wherein the condition is Alzheimer's disease.

5. The method of claim 4 , wherein the induction of autophagy results in reduction of amyloid β (Aβ) peptides, wherein the Aβ peptides comprise Aβ42 peptide.

6. The method according to claim 1 , wherein the CB1R receptor agonist is a cannabinoid.

7. The method according to claim 6 , wherein the method results in reduction of cannabinoid tolerance and enhancement of the analgesic effects of cannabinoids.

8. The method according to claim 1 , wherein the CBR1 receptor agonist is tetrahydrocannabinol.

9. The method according to claim 1 , wherein the heterocyclylalkyl is (tetrahydrofuran 3 yl)methyl, (tetrahydrofuran 2 yl)methyl, or (tetrahydro 2H pyran 4yl)methyl.

Assignees

• Univ Northwestern
• Us Health
• Univ Kansas
• The United States Of Americans Represented By The Sec Dep Of Health And Human Services

Inventors

• He Congcong
• Huang Sui
• Wang Chen
• Rocchi Altea
• Marugan Juan Jose
• Ferrer Marc
• Patnaik Samarjit
• Chen Yuchi
• Frankowski Kevin
• Schoenen Frank J

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P43/00

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

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · 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

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title