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-11142529-B2
Publication Date
2021-10-12
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 a a5-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, or pharmaceutically acceptable salts, isomers, combinations thereof, hydrates, solvates, polymorphs, and isotopically labeled compounds. The compounds are defined by extensive substituent framework constraints including R1, R2, R3, R4, R5, R6, R8, R10, R and R′, with formula-specific linkage options, integer range limits, and enumerated chemical groups. The disclosed scope also includes compound structures identified by reference numbers and representative example compounds with varied substituent patterns.
R2 is constrained to specific motifs including —OR8, —SR8, —(CH2)nOR8, —(CH2)nO(CH2)nR8, —(CH2)nR8, and —(CH2)nN(R3)R10 or —(CH2)nN(R″)R10, with n independently selected from defined integer ranges and R2 independently substituted with 0-5 R′. R8 and R10 are independently selected from alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl classes, each optionally substituted with 0-5 R′. R1, R3, R4, and R5 are independently selected from enumerated halogen and heteroatom-containing substituents, and two R groups may be taken together to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms.
The invention further includes compounds described as β-containing GABA-A receptor positive allosteric modulators, including benzodiazepine derivatives, triazole/oxa and related heterocycles, and compounds intended for imaging when isotopically labeled. The disclosed material also includes pharmaceutical compositions, therapeutic methods for cognitive impairment associated with central nervous system disorders, and combinations with antipsychotics, memantine, and acetylcholinesterase inhibitors. The compounds and methods are presented with multiple representative structures and schematic general synthetic routes.
Claims Coverage
The consolidated claim coverage includes multiple independent claim types: a formula IV structural Markush claim, a selection claim directed to specified compound structures by reference number, and claims covering pharmaceutically acceptable variants. Across the claims, the main inventive features are the constrained formula IV scaffold, the defined substituent selections and ring-forming options, and the selection-based coverage of listed compound structures.
Formula IV compound with constrained R2 linkage and substitution limits
A compound of formula IV, or a pharmaceutically acceptable salt, isomer, or combination thereof, wherein R2 is selected from —OR8, —SR8, —(CH2)nOR8, —(CH2)nO(CH2)nR8, —(CH2)nR8, or —(CH2)nN(R3)R10 or —(CH2)nN(R″)R10, and wherein R2 is independently substituted with 0-5 R′, with n independently selected from defined integer ranges.
Enumerated substituent classes and ring-forming options
Each occurrence of R1, R3, R4, and R5 is independently selected from enumerated substituents including halogen and multiple carbon-, oxygen-, nitrogen-, sulfur-, phosphorus-, carbonyl-, and thiocarbonyl-containing groups, and two R groups may be taken together with their carbon atom to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms.
Substituted R8 and R10 groups
Each R8 is independently selected from (C1-C6)alkyl, (C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, each occurrence optionally substituted with 0-5 R′; and each R10 is independently selected from (C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, each occurrence optionally substituted with 0-5 R′.
Selected compound from specified compound structures
A compound selected from a specified list of compound structures identified by reference numbers, including pharmaceutically acceptable salts, isomers, or combinations thereof.
The claim coverage centers on a formula IV compound class with tightly defined linkage patterns, substitution limits, and ring-forming/heteroatom constraints, together with separate selection-based claims to specific compound structures and pharmaceutically acceptable variants.
Stated Advantages
Not explicitly described in patent.
Documented Applications
β-containing GABA-A receptor positive allosteric modulator activity evaluation using binding assays, TEVC electrophysiology in Xenopus oocytes, and receptor selectivity assessments.
In vivo cognitive behavioral studies including Radial Arm Maze and Morris water maze tasks, together with receptor occupancy/exposure analysis and LC/MS/MS exposure analysis.
Treating cognitive impairment associated with central nervous system (CNS) disorders, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD), Alzheimer’s disease (AD), prodromal AD, 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.
Imaging uses for isotopically labeled compounds, including PET and SPECT.
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