# US 10,766,867 B2 · Hydantoins that modulate BACE-mediated APP processing > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,766,867 B2 - Document ID: US10766867B2 - Status: Granted - Kind: B2 - Application number: 15/833,862 - Filed: 2017-12-06 - Published: 2018-07-12 - Granted: 2020-09-08 - Earliest claimed: 2013-02-12 - Assignees: Buck Institute for Research on Aging - Applicants: Buck Institute for Research on Aging - Inventors: Varghese John; Dale E. Bredesen - Web page: https://patentgrep.com/patent/US10766867B2 ## CPC - C07D 233/76: with substituted hydrocarbon radicals attached to the third ring carbon atom - A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin - A61K 31/4168: having a nitrogen attached in position 2, e.g. clonidine - A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) - A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/02: for peripheral neuropathies - A61P 25/28: 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 - A61P 27/02: Ophthalmic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 233/70: One oxygen atom - C07D 233/88: Nitrogen atoms, e.g. allantoin - C07D 401/04: directly linked by a ring-member-to-ring-member bond - C07D 401/10: linked by a carbon chain containing aromatic rings - C07D 403/10: linked by a carbon chain containing aromatic rings - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## 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. ## Claims ### Claim 1 A method of ameliorating one or more symptoms of a pre-Alzheimer's condition and/or cognitive dysfunction, or delaying the progression of a pre-Alzheimer's condition or cognitive dysfunction to Alzheimer's disease, said method comprising: administering to a subject in need thereof a hydantoin in an amount sufficient to ameliorate one or more symptoms of a pre-Alzheimer's cognitive dysfunction, and/or to delay the progression of a pre-Alzheimer's cognitive dysfunction to Alzheimer's disease, wherein said hydantoin is a compound having a formula selected from the group consisting of or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) The method of claim 1, wherein said method is a method of delaying the progression of a pre-Alzheimer's cognitive dysfunction to Alzheimer's disease. ### Claim 3 (depends on 1) The method of claim 1, wherein: said administration produces a reduction in the CSF of levels of one or more components selected from the group consisting of Aβ42, sAPPβ, total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and/or an increase in the CSF of levels of one or more components selected from the group consisting of Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPβ/sAPPβ ratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio; and/or said administration produces a reduction of the plaque load in the brain of the subject; and/or said administration produces a reduction in the rate of plaque formation in the brain of the subject; and/or said administration produces an improvement in the cognitive abilities of the subject; and/or said administration produces an improvement in, a stabilization of, or a reduction in the rate of decline of the clinical dementia rating (CDR) of the subject. ### Claim 4 (depends on 1) The method of claim 1, wherein said hydantoin is a compound having a formula: or a pharmaceutically acceptable salt thereof. ### Claim 5 (depends on 4) The method of claim 4, wherein said method is a method of delaying the transition from a cognitively asymptomatic pre-Alzheimer's condition to a pre-Alzheimer's cognitive dysfunction. ### Claim 6 (depends on 4) The method of claim 4, wherein said method is a method of delaying the onset of a pre-Alzheimer's cognitive dysfunction. ### Claim 7 (depends on 4) The method of claim 4, wherein said method is a method of delaying the progression of a pre-Alzheimer's cognitive dysfunction to Alzheimer's disease. ### Claim 8 A method of ameliorating one or more symptoms of Alzheimer's disease, and/or reversing Alzheimer's disease, and/or reducing the rate of progression of Alzheimer's disease, said method comprising: administering to a subject in need thereof a hydantoin in an amount sufficient to ameliorate one or more symptoms of Alzheimer's disease, and/or to reverse Alzheimer's disease, and/or to reduce the rate of progression of Alzheimer's disease, wherein said hydantoin is a compound having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof. ### Claim 9 (depends on 8) The method of claim 8, wherein: said subject is diagnosed with early stage Alzheimer's disease; or said subject is diagnosed with mid-stage Alzheimer's disease; or said subject is diagnosed with late-stage Alzheimer's disease. ### Claim 10 (depends on 8) The method of claim 8, wherein: said administering ameliorates one or more symptoms of Alzheimer's disease; and/or said administering reduces the rate of progression of Alzheimer's disease; and/or said administering results in a reduction in the CSF of levels of one or more components selected from the group consisting of Aβ42, sAPPβ, total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and/or an increase in the CSF of levels of one or more components selected from the group consisting of Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPα/sAPPβ ratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio; and/or said administration produces a reduction of the plaque load in the brain of the subject; and/or said administration produces a reduction in the rate of plaque formation in the brain of the subject; and/or said administration produces an improvement in the cognitive abilities of the subject; and/or said administration produces an improvement in, a stabilization of, or a reduction in the rate of decline of the clinical dementia rating (CDR) of the subject; and/or said administration produces a perceived improvement in quality of life by the subject; and/or said administering results in reduced cerebral amyloidosis and/or downstream neurodegeneration. ### Claim 11 (depends on 8) The method of claim 8, wherein: said subject shows a clinical dementia rating indicative of Alzheimer's disease; and/or said subject has a familial risk for having Alzheimer's disease; and/or said subject has a familial Alzheimer's disease (FAD) mutation. ### Claim 12 (depends on 8) The method of claim 8, wherein said hydantoin is a compound having a formula: or a pharmaceutically acceptable salt thereof. ### Claim 13 A method of slowing the progression, stopping, or reversing age-related macular degeneration (AMD) in a mammal, said method comprising administering to said mammal a hydantoin in an amount sufficient to slow the progression, stop, or reverse age-related macular degeneration in said mammal, wherein said hydantoin is a compound having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof. ### Claim 14 (depends on 13) The method of claim 13, wherein said hydantoin is a compound having a formula: or a pharmaceutically acceptable salt thereof. ### Claim 15 A method for delaying the onset of a disease or a disorder, or reversing or retarding the progress of the disease or the disorder, or reducing the severity of the disease or the disorder, or alleviating one or more symptoms of the disease or the disorder, wherein the disease or the disorder is associated with BACE activity and characterized by the production of amyloid deposits and/or neurofibrillary tangles in a subject, wherein said method comprises providing to said subject a therapeutically effective amount of a hydantoin, wherein said hydantoin is a compound having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof. ### Claim 16 (depends on 15) The method of claim 15, wherein said hydantoin is a compound having a formula: or a pharmaceutically acceptable salt thereof.