Hydantoins that modulate bace-mediated app processing
AssigneeBuck Institute for Research on Aging
InventorsVARGHESE JOHN, Dale E. BREDESEN
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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.
Claims36
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;
- and
- when 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.
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8-10. (canceled)
12-13. (canceled)
15-17. (canceled)
A compound of Formula VI:
- 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.
19-20. (canceled)
24-27. (canceled)
30-50. (canceled)
52-60. (canceled)
62-63. (canceled)
65-67. (canceled)
69-78. (canceled)
80-93. (canceled)
96-97. (canceled)
99-101. (canceled)
Dependencies are inferred from the claim text.