Hydantoins that modulate BACE-mediated app processing

Patent metadata

Field	Value
Publication number	US-11091444-B2
Application number	US-202016740110-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Feb 12, 2013
Publication date	Aug 17, 2021
Grant date	Aug 17, 2021

Abstract

In certain embodiments hydantoin compounds are provided herein that are effective to inhibit BACE activity against APP. Without being bound to a particular theory, it is believed the activity of the hydantoins identified herein appears to be associated with binding to BACE and/or to APP particularly when these moieties form a BACE/APP complex. Accordingly, it is believed the compounds described herein represent a new class of compounds designated herein as APP-Binding-BACE Inhibitors (ABBIs) and provide a new mechanism to modulate APP processing. The hydantoins described herein appear to show improved brain permeability and functional BACE inhibition.

First claim

What is claimed is:

1. A compound corresponding in structure to Formula III:

wherein:
R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl;
X 1 is selected from the group consisting of CH, and N;
R 5 and R 6 are independently selected from Cl and F;
R 3 and R 4 are independently absent or selected from the group consisting of alkyl, cycloalkyl, alkoxy, and thioalkyl;
R 1 and R 2 are independently absent or selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
X 2 , Y, and Z are independently CH or N;

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt of an enantiomer thereof.

2. The compound of claim 1 , wherein said compound is a compound of Formula IV:

3. The compound of claim 1 , wherein said compound is capable of binding to APP and/or to the enzyme BACE and/or to an APP/BACE complex.

4. The compound of claim 1 , wherein said compound is capable of binding to APP and inhibits the enzyme BACE.

5. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

6. A kit comprising one or more containers containing a compound of claim 1 .

7. A compound corresponding in structure to the formula:

8. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of claim 7 .

9. A kit comprising one or more containers containing a compound of claim 7 .

10. A compound corresponding in structure to Formula FAH-8:

11. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of claim 10 .

12. A kit comprising one or more containers containing a compound of claim 10 .

Assignees

• Buck Inst Res Aging

Inventors

• John Varghese
• Bredesen Dale E

Classifications

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title

• A61K31/4166

  having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D233/70 Primary

  One oxygen atom · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title