Compositions for treating neurodegenerative diseases
Inventors
Rishton, Gilbert M. • Look, Gary C. • Catalano, Susan M.
Assignees
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Publication Number
US-11981636-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present disclosure relates to novel compounds of Formula I wherein each of Ra, Rb, Rd and Re is independently H; Rc is selected from the group consisting of H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino, R1 is selected from the group consisting of hydrogen, alkyl, phenyl, or —CH═C(CH3)2; and R2 is specific substituted cyclic amino groups. The invention also discloses pharmaceutical compositions containing the compounds and methods of using the compounds and pharmaceutical compositions for treating neurogenerative diseases, including Alzheimer's disease and cognitive decline.
Core Innovation
The invention relates to compounds of Formula I or pharmaceutically acceptable salts thereof, defined by independently selected substituents for Ra, Rb, Rd and Re, with Rc selected from H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino, and R1 selected from hydrogen, alkyl, phenyl, or —CH2C(CH3)2 or —CH=C(CH3)2. R2 is a substituted cyclic amino group selected from defined alternatives, including embodiments in which R3a is hydrogen or C1-C8 alkyl and n is an integer selected from 0, 1 and 2, or where R9 is independently selected from hydrogen, hydroxyl, sulfonyl, optionally substituted C1-C10 alkyl, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C10 cycloalkyl, and optionally substituted C3-C10 heterocycloalkyl.
The compounds are presented for pharmaceutical use in neurodegenerative diseases, particularly Alzheimer’s disease, cognitive decline, and mild cognitive impairment, and are associated with sigma-2 receptor binding. The described therapeutic concept includes inhibiting Abeta-related synapse loss and membrane trafficking deficits in neuronal cells, including Abeta oligomer binding and effects, and restoring synaptic plasticity processes associated with neuronal function, including LTP/LTD.
The invention also discloses pharmaceutical compositions comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, together with routes of administration. Methods of use are described for inhibiting amyloid beta effects on neuronal cells and for treating Alzheimer’s disease and mild cognitive impairment in a subject with Alzheimer’s disease.
Claims Coverage
The claim coverage centers on one core inventive feature for compounds of Formula I or pharmaceutically acceptable salts thereof, with dependent claims to a pharmaceutical composition and methods directed to Alzheimer’s disease, mild cognitive impairment, and inhibiting amyloid beta effects on neuronal cells.
Formula I compound with defined substituent framework
A compound of Formula I or pharmaceutically acceptable salt thereof wherein Ra, Rb, Rd and Re are independently H; Rc is selected from H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino; R1 is selected from hydrogen, alkyl, phenyl, —CH2C(CH3)2, or —CH=C(CH3)2; and R2 is a substituted cyclic amino group selected from defined classes, including embodiments with R3a hydrogen or C1-C8 alkyl and n selected from 0, 1 and 2, or with R9 independently selected from hydrogen, hydroxyl, sulfonyl, optionally substituted C1-C10 alkyl, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C10 cycloalkyl, and optionally substituted C3-C10 heterocycloalkyl.
Pharmaceutical composition with therapeutically effective amount
A pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Method for treating Alzheimer’s disease
A method for treating Alzheimer’s disease by administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the defined compound.
Inhibiting amyloid beta effect on neuronal cells
A method of inhibiting the effect of amyloid beta on a neuronal cell by administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the defined compound.
Method for treating mild cognitive impairment in Alzheimer’s disease
A method for treating mild cognitive impairment in a subject with Alzheimer’s disease by administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the defined compound.
The claims are anchored by the Formula I structural definition, including the specified substituent sets for Rc, R1, and substituted cyclic amino group R2 with n values, and extend to pharmaceutical compositions and administration methods for Alzheimer’s disease, mild cognitive impairment, and inhibiting amyloid beta effects on neuronal cells.
Stated Advantages
Inhibiting Abeta-related synapse loss and membrane trafficking deficits in neuronal cells.
Blocking Abeta oligomer binding and effects.
Therapeutic use for neurodegenerative diseases, especially Alzheimer’s disease and cognitive decline.
Inhibiting amyloid aggregation and amyloid deposition.
Inhibiting Abeta-induced neurotoxicity.
Documented Applications
Treatment of Alzheimer’s disease.
Treatment of mild cognitive impairment (MCI), including in subjects with Alzheimer’s disease.
Inhibiting the effect of amyloid beta on a neuronal cell.
Inhibiting synapse number decline associated with exposure to amyloid beta species, including Abeta oligomers.
Inhibiting membrane trafficking abnormalities associated with exposure to amyloid beta species.
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