Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
Inventors
Mekonnen, Belew • Butera, John A. • Huang, Jianxing
Assignees
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Publication Number
US-12024525-B2
Publication Date
2024-07-02
Expiration Date
Abstract
This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of α5-containing GABAA receptor agonist (e.g., a α5-containing GABAA receptor positive allosteric modulator) as described herein in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction.
Core Innovation
The invention relates to compounds of Formula IV and their pharmaceutically acceptable forms, including salts, tautomers, stereoisomers, Z (zusammen) and E (entgegen) isomers, or combinations thereof, for use in treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof. Formula IV defines a broad chemical space through variable substituents and ring constraints, including R2, R3, R4, R5, R6, R7, R8, R10, R, and R′, with independently selected substitution limits and defined heteroatom-containing options.
The disclosed scaffold includes substituted fused heteroaromatic, bicyclic, tetracyclic, and heterocyclic embodiments, with permitted substituents such as halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CN, CF3, OCF3, NO2, NCS, and other functional-group-containing fragments. The structural scope also includes ring-forming and fused ring arrangements, optional fusion to aryl or heteroaryl systems, and specific linker motifs such as OR8, SR8, and (CH2)n-based linkers.
The document further describes multiple enumerated Formula IV compound embodiments shown as chemical drawings and associated MOL/CDX/TIF files. These examples include varied aryl and heteroaryl substituents, methoxy, fluoro, chloro, bromo, cyano, and oxo substitutions, and are presented as concrete embodiments within the same Formula IV chemical space for therapeutic use.
Claims Coverage
The consolidated claim coverage includes one independent method claim and a corresponding pharmaceutical composition claim. The claims collectively recite 3 inventive features centered on treating cognitive impairment associated with a CNS disorder by administering Formula IV compounds, defining the Formula IV structural scope, and providing a pharmaceutical composition containing the same compounds in a therapeutically effective amount.
Treating cognitive impairment associated with a CNS disorder using Formula IV compounds
A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising administering a compound of Formula IV or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer thereof, or combinations thereof.
Formula IV structural scope with defined substituent constraints
The Formula IV compound is defined by variable substituent rules for R2, R3, R4, R5, R6, R7, R8, R10, R, and R′, including independently substituted 0-5 R′ positions, integer ranges for n and p, and selection sets that include halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and multiple heteroatom-containing functional groups.
Pharmaceutical composition with therapeutically effective amount and acceptable carrier
A pharmaceutical composition comprising a compound according to Formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combinations thereof in a therapeutically effective amount, and an acceptable carrier, adjuvant or vehicle.
Overall, the claim coverage is centered on administering Formula IV compounds, as defined by extensive substituent and ring-system constraints, to treat cognitive impairment associated with a CNS disorder, and on corresponding pharmaceutical compositions containing the same compounds in a therapeutically effective amount.
Stated Advantages
Reported cognitive improvement in aged-impaired rat models is linked to ε-containing GABA-A receptor positive allosteric modulator activity.
Reported receptor binding selectivity categories and functional potentiation categories relative to ε-containing versus other α-containing GABA-A receptor subtypes are described.
Treating cognitive impairment associated with a central nervous system (CNS) disorder.
Documented Applications
Treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof.
Treating age-related cognitive impairment.
Treating mild cognitive impairment (MCI).
Treating amnestic MCI.
Treating dementia including Alzheimer’s disease.
Treating schizophrenia and bipolar disorder.
Treating amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson’s disease (PD), autism, compulsive behavior, substance addiction, cancer-therapy-related cognitive impairment, and RDoC.
Positive allosteric modulation activity directed to ε-containing GABA-A receptors (ε1β2γ3β2) with binding and functional assay contexts including [3H]Ro15-1788 and TEVC GABA-gated Cl− current measurements.
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