Benzofurazan anti-amyloid compounds and methods
Inventors
Reed, Mark A • Wood, Thomas K • Banfield, Scott C • Barden, Christopher J
Assignees
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Publication Number
US-9328078-B2
Publication Date
2016-05-03
Expiration Date
Abstract
In general, among other things, compounds of Formula I are provided: in which R11 is selected from the group consisting of benzylamino, N-methylbenzylamino, morpholino, thiomorpholino, pyrrolidino, etc.; R13 is selected from the group consisting of 3-(1-ethanol-2-yl)phenyl, 3-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, 2-(1-ol-2,2,2-trifluoroethan-2-yl)phenyl, etc.; and R12 and R14 are each independently hydrogen or alkyl. Methods of treatment are also provided.
Core Innovation
The invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, with R11 selected from specified amino-containing substituents and related heterocyclic amines, R13 selected from specified aryl and acyl substituents, and R12 and R14 each independently hydrogen or alkyl. The disclosed compounds include benzo[c][1,2,5]oxadiazole-based TRV-series compounds and named examples such as TRV-1370, TRV-1375 through TRV-1399, TRV-1415 through TRV-1468, and TRV-1434 through TRV-1455.
The document also includes chemical synthesis and characterization of these compounds, with reported structures, yields, and 1H NMR. The examples describe preparation of substituted anilines and benzo[c][1,2,5]oxadiazole bromides or boronic acid derivatives, and further transformations install CF3-containing side chains and form pendant ring systems and functionalized analogs.
The invention also relates to Alzheimer’s β-amyloid oligomer inhibition and to a biotin-Aβ(1-42) oligomeric assay used to measure inhibition of Aβ oligomer formation by test compounds. The document connects the benzo[c][1,2,5]oxadiazole-based compounds with amyloid aggregation results and Aβ240 inhibition, and states therapeutic scope for amyloidosis and amyloid disease, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion disease, and systemic amyloidoses including senile systemic amyloidosis.
Claims Coverage
The consolidated claim coverage includes one independent Formula I compound claim, with dependent claim refinements for Aβ240 inhibition potency and therapeutic use in amyloid disease, including Alzheimer’s disease. The independent scope centers on explicit substituent selection sets for R11 and R13, with R12 and R14 each independently hydrogen or alkyl.
Formula I compounds with defined substituents
A compound of Formula I, or a pharmaceutically acceptable salt thereof, in which R11 is selected from a specified group of amine-containing substituents, R13 is selected from a specified group of phenyl and acyl substituents including alcohol- and trifluoroethan-1-yl variants, and R12 and R14 are each independently hydrogen or alkyl.
Aβ240 inhibition potency threshold at 20 μM
Compounds of the Formula I set that inhibit Aβ240 at 20 μM by 65% or more.
Therapeutically treating an amyloid disease by administering a Formula I compound
Treating an amyloid disease in a subject by administering a therapeutically effective amount of a compound defined by Formula I.
Applying treatment to Alzheimer’s disease as an amyloid disease embodiment
The method is applied to an amyloid disease that is Alzheimer’s disease.
Total daily dose range for administration
The method includes administering a total daily dose of about 0.0003 to about 50 mg/kg body weight.
Overall, the claim coverage is directed to Formula I compounds defined by explicit R11, R13, R12, and R14 selections. The dependent claim refinements add an Aβ240 potency threshold and therapeutic use for amyloid disease, including Alzheimer’s disease, with an explicit total daily dose range.
Stated Advantages
Provides inhibition of Aβ oligomer formation as measured by a biotin-Aβ(1-42) oligomeric assay.
Enables treatment of amyloid disease in a subject by administering a therapeutically effective amount.
Inhibits amyloid aggregation.
Documented Applications
Use of a biotin-Aβ(1-42) oligomeric assay to measure inhibition of Aβ oligomer formation by test compounds.
Treating an amyloid disease in a subject by administering a therapeutically effective amount of a compound of Formula I.
Treating Alzheimer’s disease as an amyloid disease embodiment.
Treating amyloidosis/amyloid disease by administering a benzofurazan anti-aggregation therapeutic compound.
Treatment scope described for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, prion disease, and systemic amyloidoses including senile systemic amyloidosis.
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