Benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use
Inventors
Davidowitz, Eliot J. • Moe, James G. • Reitz, Allen B. • Bian, Haiyan • Gluchowski, Charles • Hendrix, James • Yehaskel, Albert S. • McDonnell, Mark E. • Loughran, H. Marie
Assignees
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Publication Number
US-12331043-B2
Publication Date
2025-06-17
Expiration Date
Abstract
Novel benzofurans, benzothiophenes and indoles useful as inhibitors of tau oligomer formation, useful for the treatment of neurodegenerative diseases and related conditions are disclosed. The invention also relates to the pharmaceutically acceptable salts of said compounds, processes for the preparation of said compounds, intermediates used in the preparation of said compounds, and pharmaceutical compositions containing said compounds. The invention further relates to methods of use of said compounds, salts of said compounds, and said compositions in treating neurodegenerative diseases and related conditions.
Core Innovation
The invention relates to compounds selected from the group consisting of compounds of formula (I) and compounds having formula (II) through formula (XVIII), including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. The compounds are defined by extensive substituent selections for R1a, R1b, R1c, R1d, R2, X, Y, R5, R6, R7a, R7b, R7c, and additional ring-forming and atom-forming variables so that specific structural relationships are maintained across the formulas.
The invention addresses tau oligomer formation and presents the described compounds as tau oligomer formation inhibitors. The document describes substituted 4-(benzofuran-2-yl)butan-2-one compounds bearing varied heteroaryl substituents, and some examples are converted to HCl salts including di HCl salt.
The document further describes pharmaceutical formulations comprising tau oligomer formation inhibitors together with pharmaceutically acceptable carriers and/or excipients. The formulations are described with multiple routes of administration, including oral, parenteral, transdermal, inhalation, ocular/aural, rectal/vaginal.
Claims Coverage
The independent claim defines a large genus of compounds across formulas (I) through (XVIII) with extensive substituent and ring-formation constraints, including stereochemical and salt/solvate forms, and requires that the compound is in a pharmaceutically acceptable carrier. Dependent claims further narrow coverage to particular listed embodiments.
Genus of formula I through XVIII compounds
A compound selected from the group consisting of compounds of formula (I) and compounds having formula (II) through formula (XVIII), including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
Substituent framework for R1a, R1b, R1c, R1d, R2, X, R5, Y, R6, and R7a through R7c
The claim defines substituent selections and ring-formation constraints for R1a, R1b, R1c, R1d, R2, X, R5, Y, R6, R7a, R7b, and R7c, including X selected from oxygen, sulfur, NH, and NR5, R5 as C1-6 alkyl, and Y including optionally substituted 2-benzimidazole.
Three to six membered saturated ring formation
R3a and R3b are taken together with the atom to which they are bound to form a three to six membered saturated ring.
Additional formula variants with A-group and R10/R11 constraints
Additional formula variants include constraints on A1 through A10 being selected from nitrogen and CR10 with limits on nitrogen positions, and R10 selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11, with R11 independently selected from hydrogen and C1-6 alkyl.
Pharmaceutically acceptable carrier requirement
Wherein the compound is in a pharmaceutically acceptable carrier.
The claim coverage centers on a broad, formula-defined genus of substituted compounds spanning formulas (I) through (XVIII), with key limitations on substituent selection, ring formation, additional A-group variants, and inclusion of enantiomers, diastereomers, hydrates, solvates, salts, and complexes, together with a pharmaceutically acceptable carrier.
Stated Advantages
Inhibits tau oligomer formation.
Designed for treating neurodegenerative diseases including Alzheimer’s disease.
Documented Applications
Treatment of neurodegenerative diseases, including Alzheimer’s disease, by inhibiting tau oligomer formation.
Formulations comprising tau oligomer formation inhibitors for use with pharmaceutically acceptable carriers/excipients are described for multiple routes of administration including oral, parenteral, transdermal, inhalation, ocular/aural, rectal/vaginal.
Example syntheses and analytical characterization are provided for substituted 4-(benzofuran-2-yl)butan-2-one compounds bearing varied heteroaryl substituents, including conversion to HCl salts for some examples.
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