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-11814378-B2
Publication Date
2023-11-14
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 invention relates to compounds of formula (I), including all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof. The compounds are defined by a scaffold in which variable groups and heteroatom selections are constrained through specific selection rules, including A, B, E, V, G, J, Q, Y, Z and substituent families such as R, R_a, R_b-R_g and R_j. The scaffold also permits defined bridges and ring formation options, with attachment and substitution rules governing the allowed structural space.
B is selected from O and NRa, E and V are independently selected from N, NR5, O and S, and G is selected from a benzene ring and a pyridine ring. J is selected from O and N-R1, Q is selected from N and C-R1, and Y is selected from CZ and N, with conditional requirements when Y is N. Z is independently selected from H, halogen, O-alkyl, alkyl and CN, and Rj is independently selected from halogen, O-alkyl, CF3, CN and NR3R4.
The disclosure links these compounds to disorders associated with Tau protein aggregates. It states therapeutic use for treating or alleviating such disorders, decreasing Tau aggregation, preventing Tau aggregate formation and/or inhibiting Tau aggregation, interfering intracellularly with Tau aggregates, and reducing Tau misfolding and hyperphosphorylation in vivo. The indicated disorder context includes Tau-associated neurological and related diseases, with Alzheimer's disease and progressive supranuclear palsy explicitly named.
Claims Coverage
The independent claims are directed to a formula-based compound class, with pharmaceutically acceptable forms, and to therapeutic method claims for Tau protein aggregate-associated disorders. Across the claim coverage, the core structural variables are governed by selection rules, and the method claims focus on treating or alleviating such disorders, decreasing Tau aggregation, preventing Tau aggregate formation and/or inhibiting Tau aggregation, reducing Tau misfolding and hyperphosphorylation, and intracellularly interfering with Tau aggregates.
Compounds of formula (I) with defined structural variables and allowed substitution and bridges
A compound of formula (I), including stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs, wherein A, B, E, V, G, J, Q, Y, Z, R, R_a, R_b-R_g and R_j are selected and constrained according to the defined groups and conditional rules, including permitted bridges and ring formation options.
Tau-aggregate-associated treatment using the formula (I) compound
A method for treating or alleviating a disorder or abnormality associated with Tau protein aggregates by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.
Decreasing Tau aggregation by administering the formula (I) compound
A method for decreasing Tau protein aggregation by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject with a Tau-aggregate-associated disorder.
Intracellular interference with Tau aggregates using the formula (I) compound
A method for intracellularly interfering with Tau aggregates by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject with a disorder associated with Tau protein aggregates.
Overall, claim coverage combines extensive structural selection rules for compounds of formula (I) with therapeutic method claims tied to Tau protein aggregate-associated disorders. The claim set centers on treating or alleviating such disorders and on functional outcomes including decreasing Tau aggregation and intracellularly interfering with Tau aggregates.
Stated Advantages
Treat or alleviate disorders or abnormalities associated with Tau protein aggregates.
Decrease Tau aggregation.
Prevent Tau aggregate formation and/or inhibit Tau aggregation.
Reduce Tau misfolding and hyperphosphorylation in vivo.
Reduce neuroinflammatory markers.
Interfere intracellularly with Tau aggregates.
Documented Applications
Treating or alleviating disorders associated with Tau protein aggregates by administering an effective amount of the claimed compound or pharmaceutically acceptable salt to a subject in need.
Decreasing Tau aggregation in a subject with a Tau-aggregate-associated disorder.
Intracellularly interfering with Tau aggregates in a subject with a disorder associated with Tau protein aggregates.
Treatment indication lists explicitly include Alzheimer's disease and progressive supranuclear palsy, along with other Tau-associated neurological and related diseases.
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