Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
Inventors
Mekonnen, Belew • Butera, John A. • Huang, Jianxing • Patel, Hemantbhai • Jiang, Qin • Herr, Robert Jason • FREEMAN, Emily Elizabeth • Mayhew, Nicholas James
Assignees
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Publication Number
US-12291535-B2
Publication Date
2025-05-06
Expiration Date
Abstract
This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. It also relates to the use of an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) in treating cognitive impairment associated with CNS disorders in a subject in need or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. It also relates to the use of an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) in treating brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.
Core Innovation
The invention relates to a compound of formula X, or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, defined by an integer m selected from 0 to 4 and multiple substituent variables including R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, and R′. The compound class is described as a substituted heterocyclic, fused polycyclic, fused heteroaromatic, polycyclic nitrogen-rich heteroaromatic, or pentaazatetracyclo scaffold, with extensive constraints on allowed group types and substitution-count limits.
R1 is independently selected from halogen, (C6-C10) aryl, OMe, CN, C≡C-R8, CHF2, CF3, OCF3, OCHF2, (C1-C6) alkyl, (C1-C6) alkyl-(C6-C10) aryl, 5- to 10-membered heteroaryl, (C1-C6) alkyl-5-10 membered heteroaryl, or (C3-C6) cycloalkyl. R2 is selected from H, CH2R8, CH3, or CH2-OR8, and each occurrence of R8 is independently selected from H and alkyl, aryl, heteroaryl, cycloalkyl, heteroaryl-alkyl, alkyl-aryl, and alkyl-cycloalkyl groups, with additional limits that each R8 excluding H and (C1-C6) alkyl is independently substituted with 0 to 5 halogen, (C1-C6) alkyl, CF3, OCF3, or O-(C1-C6) alkyl.
R3 is selected from C≡CR9 or (C1-C6) alkyl-C≡C-R10, where R9 is selected from 5- to 10-membered heteroaryl, (C1-C6) alkyl-5-10 membered heteroaryl, or 5-10 membered heterocycle and is independently substituted with 0 to 5 R11. Each R11 is independently selected from halogen, CF3, OCF3, OMe, (C6-C10) aryl, (C1-C6) alkyl, or 5-10 membered heteroaryl, while R10 is selected from H, halogen, (C1-C6) alkyl, (C6-C10) aryl, 5-10 membered heteroaryl, (C3-C6) cycloalkyl, CH2-(C3-C6) cycloalkyl, CH2-(C6-C10) aryl, or CH2-5-10-membered heteroaryl and is independently substituted with 0 to 5 R′. The disclosure also includes example structures with chlorinated, fluorinated, brominated, methoxy, trifluoromethyl, and ether-linked substituents, together with pharmaceutical compositions and treatment uses for cognitive impairment associated with a central nervous system disorder.
Claims Coverage
The consolidated claims coverage centers on a compound of formula X with extensive substituent restrictions and substitution-count limits. Across the provided material, there are 6 core inventive features: the formula X compound framework, the R1 and R2 substitution framework, the R8 substitution limits, the R3/R9/R10/R11/R′ substitution system, terminal substituent constraints on R4/R5/R6, and the pharmaceutical composition and treatment-use layers.
Compound of formula X with constrained substituent framework
A compound of formula X, or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein m is an integer selected from 0 to 4 and R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, and R′ are defined by enumerated substituent options and substitution-count limits.
R1 and R2 substitution framework
R1 is independently selected from halogen, (C6-C10) aryl, OMe, CN, C≡C-R8, CHF2, CF3, OCF3, OCHF2, (C1-C6) alkyl, (C1-C6) alkyl-(C6-C10) aryl, 5-10 membered heteroaryl, (C1-C6) alkyl-5-10 membered heteroaryl, or (C3-C6) cycloalkyl; and R2 is selected from H, CH2R8, CH3, or CH2-OR8.
R8 group definition with substitution limits
Each occurrence of R8 is independently H, (C1-C6) alkyl, (C6-C10) aryl, 5- to 10-membered heteroaryl, 5-10 membered heteroaryl-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-(C6-C10) aryl, or (C1-C6) alkyl-(C3-C6) cycloalkyl, and each R8 excluding H and (C1-C6) alkyl is independently substituted with 0 to 5 halogen, (C1-C6) alkyl, CF3, OCF3, or O-(C1-C6) alkyl.
R3, R9, R10, R11, and R′ substitution system
R3 is selected from C≡CR9 or (C1-C6) alkyl-C≡C-R10; R9 is selected from 5-10 membered heteroaryl, (C1-C6) alkyl-5-10 membered heteroaryl, or 5-10 membered heterocycle and is independently substituted with 0 to 5 R11; R11 is selected from halogen, CF3, OCF3, OMe, (C6-C10) aryl, (C1-C6) alkyl, or 5-10 membered heteroaryl; R10 is selected from H, halogen, (C1-C6) alkyl, (C6-C10) aryl, 5-10 membered heteroaryl, (C3-C6) cycloalkyl, CH2-(C3-C6) cycloalkyl, CH2-(C6-C10) aryl, or CH2-5-10-membered heteroaryl and is independently substituted with 0 to 5 R′; and R′ is selected from Cl, F, (C1-C6) alkyl, OMe, or (C6-C10) aryl.
Terminal substituent constraints on R4, R5, and R6
Each of R4, R5, and R6 is independently H or (C1-C6) alkyl.
Pharmaceutical composition and treatment of cognitive impairment associated with a CNS disorder
A pharmaceutical composition comprising a compound of formula X, or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, in a therapeutically effective amount together with an acceptable carrier, adjuvant, or vehicle, and a method of treating cognitive impairment associated with a central nervous system disorder by administering the compound.
Overall, claim coverage is concentrated in the independent definition of a formula X compound with tightly specified substituent sets and substitution-count limits for R8, R9/R11, and R10/R′, together with constrained R4/R5/R6 options. The provided material also includes pharmaceutical composition and treatment-use language for cognitive impairment associated with a central nervous system disorder.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of cognitive impairment associated with a central nervous system disorder.
Pharmaceutical compositions comprising a compound of formula X in a therapeutically effective amount together with an acceptable carrier, adjuvant, or vehicle.
Treatment of age-related cognitive impairment, including Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment (AAMI), and Age Related Cognitive Decline (ARCD).
Treatment of dementia and listed CNS conditions including Alzheimer’s Disease (AD) and prodromal AD, PTSD, schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), autism spectrum disorders, fragile X disorder, and Rett syndrome.
Treatment of cognitive impairment associated with cancer-therapy-related cognitive impairment and brain cancers, including brain tumors and medulloblastomas.
Treatment of Parkinson’s disease psychosis.
Combination therapy for cognitive impairment, including combinations involving antipsychotics, memantine, and acetylcholinesterase inhibitors.
Pharmaceutical compositions for administration by topical, systemic, or local routes, including oral, parenteral, intranasal, and implant/device formats, with slow/controlled release.
Animal-model-based assessment of cognitive impairment, including Radial Arm Maze (RAM).
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