HYDANTOINS THAT MODULATE BACE-MEDIATED APP PROCESSING

摘要

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.

主权项

1. A compound of Formula I: wherein:
R7 is selected from the group consisting of C═O, C═S, C—NH2, and C═NH, and the bond represented by the wavy line is a single bond when R7 is C═O, C═S, or C═NH, and a double bond when R7 is C—NH2;R8 and R9 are independently selected from the group consisting of H, alkyl, cycloalkyl, and aryl, provided that when the bond represented by the wavy line is a double bond, then R9 is absent;R0 is selected from the group consisting of aryl, substituted aryl, disubstituted aryl, heteroaryl, substituted heteroaryl, disubstituted heteroaryl, alkyl, haloalkyl, cycloalkyl, alkenyl, and alkynyl;X1 is selected from the group consisting of CH, and N;R5 and R6 are independently selected from halogen;R3 and R4 are independently absent or selected from the group consisting of alkyl, cycloalkyl, alkoxy, thioalkyl; andwhen X1 is C, then R0 is not phenyl monosubstituted at the para position with —OCHF2, 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.