Compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
Inventors
NAMPALLY, Sreenivasachary • Gabellieri, Emanuele • Molette, Jerome
Assignees
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Publication Number
US-11684625-B2
Publication Date
2023-06-27
Expiration Date
Abstract
The present invention relates to novel compounds of formula (I) that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).
Core Innovation
The invention relates to compounds of formula (I), including stereoisomers, racemic mixtures, tautomers, and pharmaceutically acceptable salts. The compounds are defined by structural variables A, B, E, V, G, Y/Y1/Y2/Y3, Z, R, Ra, Rd, Re, Rf, Rg, R2, R3, R4, R5, and n, with A attached to the N atom at any available position and G selected from a benzene ring and a pyridine ring.
Within formula (I), B is NRa, E and V are independently selected from N, NR5, O and S, and Y, Y1, Y2 and Y3 are CZ, with Z independently selected from H, halogen, O-alkyl, alkyl and CN. R includes substituent options including —NR3R4, Ra is selected from H and alkyl, Rd, Re, Rf and Rg are H, and R2 is independently selected from alkyl and —O-alkyl, including the condition that geminal pairs of R2 can be joined to form a 3 to 6-membered ring.
The invention further includes pharmaceutical compositions comprising the compound of formula (I) and optionally a pharmaceutically acceptable carrier or excipient. It also includes pharmaceutical mixtures containing the compound of formula (I), at least one additional biologically active therapeutic agent different from the compound, and a pharmaceutically acceptable carrier with a diluent or excipient, with components present in therapeutically effective amounts.
The disclosed uses relate to Tau aggregation, including methods of decreasing Tau aggregation by administering a therapeutically effective amount of the compound of formula (I) to a subject in need. The content also describes use in treating, preventing, or alleviating Tau-protein aggregate-associated disorders and in inhibiting or preventing Tau aggregate formation.
Claims Coverage
Independent claims are directed to a compound of formula (I) and to therapeutic and formulation embodiments tied to Tau aggregation. The inventive features comprise the defined compound scaffold, pharmaceutical composition and mixture packaging, and methods for decreasing Tau aggregation, for a total of 4 main inventive features across the consolidated claim set.
Compound of formula (I) with defined substituent framework
A compound of formula (I), including stereoisomers, racemic mixtures, tautomers, and pharmaceutically acceptable salts, wherein A, B, E, V, G, Y/Y1/Y2/Y3, Z, R, Ra, Rd, Re, Rf, Rg, R2, R3, R4, R5, and n are defined by the stated selections and constraints.
Pharmaceutical composition with a carrier or excipient
A pharmaceutical composition comprising the compound defined by formula (I) and optionally a pharmaceutically acceptable carrier or excipient.
Method of decreasing Tau aggregation by administration
A method for decreasing Tau aggregation by administering a therapeutically effective amount of the compound defined by formula (I) to a subject in need.
Pharmaceutical mixture with an additional biologically active therapeutic agent
A pharmaceutical mixture containing the compound defined by formula (I), at least one additional biologically active therapeutic agent different from the compound, and a pharmaceutically acceptable carrier with a diluent or excipient.
The claim coverage centers on the structurally defined formula (I) compound family and extends to pharmaceutical compositions, mixture formulations with additional biologically active therapeutic agents, and Tau-aggregation-related therapeutic methods.
Stated Advantages
Decreases Tau aggregation.
Inhibits or prevents Tau aggregate formation.
Provides treatment, prevention, or alleviation of Tau-protein aggregate-associated disorders.
Provides use as an analytical reference and an in vitro screening tool.
Brain uptake.
Cell permeability.
Solubility.
Metabolic stability.
Documented Applications
Treating, preventing, or alleviating Tau-protein aggregate-associated disorders by decreasing Tau aggregation.
Inhibiting or preventing Tau aggregate formation, including intracellular interference with Tau aggregates.
Pharmaceutical compositions comprising the compound of formula (I) and optionally a pharmaceutically acceptable carrier or excipient.
Pharmaceutical mixtures containing the compound of formula (I), at least one additional biologically active therapeutic agent different from the compound, and a pharmaceutically acceptable carrier with a diluent or excipient.
Use as an analytical reference and as an in vitro screening tool.
Treating, alleviating, or preventing tau-aggregate disorders (tauopathies), including neurofibrillary tangles in Alzheimer’s disease.
Decreasing Tau aggregation by administering the disclosed compounds to a subject in need.
Tau disaggregation characterization using Thioflavin T assays for full-length Tau and Tau K18.
Full-length Tau aggregation inhibition characterization using Thioflavin T assays.
Cellular evaluation of intracellular Tau aggregation/misfolding using AlphaLISA and immunocytochemistry with MC1.
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