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-11312721-B2
Publication Date
2022-04-26
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 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, including pharmaceutically acceptable salts, tautomers, stereoisomers, Z (zusammen) isomers, E (entgegen) isomers, or combinations thereof. The formula IV compounds are defined by variable groups R1, R2, R3, R4, R5, R6, R8, and R10, with m and n independently selected from 0-4 and R2 independently substituted with 0-5 R′. The allowed substituent classes include halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, SiR3, nitrogen- and sulfur-containing groups, and related carbonyl-, phosphate-, and carbonate/carboxylate-related forms.
R3 is absent or selected from a defined substituent set, R6 is —H or —(C1-C6)alkyl, and R8 and R10 are selected from alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl classes with each occurrence independently substituted with 0-5 R′. Each R is independently selected from aliphatic, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl-based groups, with heterocyclyl and heteroaryl heteroatom counts specifically defined, and two R groups may form a 3- to 10-membered aromatic or non-aromatic ring with optional fusion and substitution.
The provided content also presents specific numbered compounds and illustrated structures within the formula IV space, including compounds sharing a common polycyclic heteroaromatic or fused heterocyclic scaffold with substituent variation such as methoxy, halogen, cyano, trifluoromethyl, and O-heterocycle motifs. In one portion, the disclosure characterizes benzodiazepine derivative compounds and states that they are ε-containing GABA_A receptor positive allosteric modulators and/or GABA_A receptor agonists associated with cognitive impairment in CNS disorders.
Claims Coverage
The consolidated claim coverage centers on one broad independent formula IV compound claim with multiple inventive feature groupings, plus dependent narrowing to specific numbered structures and, in some items, pharmaceutical compositions with a second therapeutic agent.
Formula IV compound with pharmaceutically acceptable forms
A compound of formula IV, or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof.
Variable substituent framework for R2 and integer constraints
R2 is independently substituted with 0-5 R′, m and n are independently integers selected from 0-4, and R2-related linkage options include —OR8, —SR8, —(CH2)nOR8, —(CH2)nO(CH2)nR8, and —(CH2)nN(R3)R10 where stated.
Defined substituent sets for R, R3, R6, R8, and R10
R1, R2, R4, and R5 are independently selected from enumerated substituent groups; R3 is absent or selected from an enumerated set; R6 is —H or —(C1-C6)alkyl; R8 is alkyl, cycloalkyl, aryl, or heteroaryl with 0-5 R′ substitution; and R10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl with 0-5 R′ substitution.
Heterocyclyl and heteroaryl ring constraints with optional fusion
Heterocyclyl has 1-4 heteroatoms selected from N, NH, O, S, SO, and SO2, heteroaryl has 1-4 heteroatoms selected from N, NH, O, and S, and rings may be optionally fused to aryl, heteroaryl, cycloalkyl, or heterocyclyl groups.
Specific numbered compounds within formula IV space
The compound of claim 1 is selected from a listed group of specific numbered compounds and illustrated structures, including salts, tautomers, stereoisomers, Z forms, and E forms.
Pharmaceutical composition with a second therapeutic agent
A pharmaceutical composition comprising the compound and a second therapeutic agent in addition to the therapeutic agent(s) already present.
Second therapeutic agent as an antipsychotic
The second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine, and ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph of it.
Second therapeutic agent as an AChE-I
The second therapeutic agent is an AChE-I selected from Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
Overall, the claim coverage is dominated by the formula IV scaffold with extensively enumerated substituent and ring-system constraints, optional stereochemical and tautomeric forms, and dependent narrowing to specific numbered compounds. Some items further extend coverage to pharmaceutical compositions containing the compound together with a named second therapeutic agent.
Stated Advantages
Blood-brain barrier penetration or direct CNS delivery.
The compounds are described as ε-containing GABA_A receptor positive allosteric modulators and/or GABA_A receptor agonists.
The disclosure states use in addressing cognitive impairment associated with CNS disorders.
Behavioral outcomes and receptor-binding or receptor-occupancy effects are described for exemplary compounds.
Documented Applications
Metabolic studies.
Imaging (PET/SPECT).
Radioactive treatment.
Drug/substrate tissue distribution assays.
Treatment of cognitive impairment and multiple CNS disorders including schizophrenia/bipolar, dementia/Alzheimer’s disease, PTSD, ALS, cancer-therapy cognitive impairment, Parkinson’s disease, autism, mental retardation, obsessive-compulsive disorder, and substance addiction.
Combination regimens with antipsychotics, memantine, and acetylcholinesterase inhibitors.
Use of cognitive testing approaches in animals/humans, including Radial Arm Maze, Morris water maze, CIBIC-plus, MMSE, NPI, CDR, CANTAB, MATRICS, R-fMRI, and FDG-PET.
Formulated as a pharmaceutical composition for an ε-containing GABAA receptor positive allosteric modulator/agonist context, with administration routes including topical, systemic, local, oral, parenteral, and inhalation.
Imaging/metabolic studies using unlabeled and isotopically labeled compounds, including isotopically labeled analogs such as 18F, 3H, and 14C.
Age-related cognitive impairment.
Mild cognitive impairment and related forms.
Dementia and Alzheimer’s disease, including prodromal AD.
Post traumatic stress disorder, schizophrenia, bipolar disorder and mania.
ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson’s disease, autism spectrum disorders including fragile X disorder and Rett syndrome, compulsive behavior, and substance addiction.
Therapeutic methods and medicament use involving administration of a therapeutically effective amount.
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