Compounds for the treatment or alleviation of disorders associated with Tau aggregates
Inventors
NAMPALLY, Sreenivasachary • Gabellieri, Emanuele • Molette, Jerome • Kroth, Heiko • Boudou, Cedric
Assignees
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Publication Number
US-12202840-B2
Publication Date
2025-01-21
Expiration Date
Abstract
The present invention relates to novel compounds 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 disclosed subject matter provides compounds of formula (I) and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. The compounds include structural variables selected according to specified options, including B selected from O and NR_a, defined relationships among E and V, X selected from N—R6 and HC—N(Me)2, and substituent selections for R and R6, where R is independently selected from H and alkyl, Ra is selected from H and alkyl, and R6 is alkyl.
The invention addresses Tau protein aggregate disorders and tauopathies associated with Tau protein aggregates. The disclosed compounds are expected to decrease Tau aggregates by recognizing and disaggregating aggregated Tau, prevent aggregation of Tau, and interfere with intracellular Tau aggregates, including Tau seeding and spread. The disclosure further states reducing Tau misfolding and hyperphosphorylation in vivo and reducing neuroinflammatory markers.
The document also states that pharmaceutical compositions contain the compounds and that the compounds are for medical use in treating Tau-aggregate disorders. Mixtures with other biologically active compounds are described, including combinations with agents used in amyloidosis and with cholinesterase inhibitors, as well as antibody and vaccine related mixtures.
Claims Coverage
The claim coverage centers on a formula (I) compound genus with specified stereochemical and solid-form variants, and on therapeutic and mixture claims tied to Tau protein aggregate disorders. The inventive features are the constrained scaffold selections in B, E/V, X, and the substitution constraints on R and R6, together with claims for treatment and mixtures.
Formula (I) compound genus
A compound of formula (I), including all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.
Constrained heteroatom selections and pairings
B is selected from O and NR_a, and E and V are limited to the specified pairings: E is N and V is S, E is S and V is N, E is N and V is O, or E is O and V is N.
Selected group X and substitution constraints
X is selected from N—R6 and HC—N(Me)2; R is independently selected from H and alkyl; Ra is selected from H and alkyl; and R6 is alkyl.
Tau protein aggregate disorder treatment
A method for treating or alleviating a disorder caused by Tau protein aggregates by administering an effective amount of a compound defined in formula (I) to a patient in need thereof.
Mixture including specified therapeutic members
A claimed mixture that further comprises specified members including pirenzepine or certain metabolites, pyroglutamated amyloid beta 3-42, and a cholinesterase inhibitor selected from tacrine, rivastigmine, donepezil, or galantamine.
Mixture permitting additional biologically active compounds
A claimed mixture that further comprises a biologically active compound selected from specified categories including agents for oxidative stress, apoptosis inhibition, metal chelation, inhibitors of DNA repair, secretase modulation categories, Tau proteins, neurotransmitters, beta-sheet disruption agents, amyloid beta clearing or depletion attractants, anti-inflammatory molecules, cholinesterase inhibitors, M1 agonists, an antibody, or a vaccine.
Treatment method limited to specific tauopathy disorders
The method where the disorder being treated is chosen from Alzheimer's disease, corticobasal degeneration, Pick's disease, or progressive supranuclear palsy.
The claim coverage is anchored by a formula (I) compound definition with explicit variable selections for B, E/V, X, R, Ra, and R6, and it extends to treatment methods for Tau protein aggregate disorders and to mixture compositions including specified therapeutic members and broader classes of biologically active compounds.
Stated Advantages
Decrease Tau aggregates by recognizing and disaggregating aggregated Tau.
Prevent aggregation of Tau.
Interfere with intracellular Tau aggregates, including Tau seeding and spread.
Reduce Tau misfolding and hyperphosphorylation in vivo.
Reduce neuroinflammatory markers.
Documented Applications
Treating or alleviating a disorder caused by Tau protein aggregates by administering an effective amount of a compound of formula (I) to a patient in need.
Treating tauopathy disorders chosen from Alzheimer's disease, corticobasal degeneration, Pick's disease, or progressive supranuclear palsy.
Use of a pharmaceutical composition containing a formula (I) compound for Tau-aggregate disorders.
Mixture formulations that include additional therapeutic categories and specified named agents, including combinations involving amyloidosis drugs and cholinesterase inhibitors, and antibody and vaccine related components.
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