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-10815242-B2
Publication Date
2020-10-27
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 patent relates to compounds of formula II, including pharmaceutically acceptable salts, stereoisomers, Z (zusammen) isomers, E (entgegen) isomers, and combinations thereof. The structure is defined by an integer m selected from 0-4 and variable substituents R1, R2, R3, R4, R5, and R6, with broad substituent sets and optional stereochemical forms. The compound space includes substituted heterocyclic compounds and related scaffold drawings and embedded structure depictions.
Each R occurrence is independently selected from aliphatic, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl motifs, including ring-linked and heteroatom-containing variants, and may be substituted with 0-5 R' groups. Two R groups bound to the same atom may form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms, optionally substituted and optionally fused to aryl, heteroaryl, cycloalkyl, or heterocyclyl moieties. The R' substituent set includes halogen, oxo, carbonyl, nitro, cyano, CF3, OCF3, NCS, and related oxygen-, nitrogen-, sulfur-, alkyl-, and aryl-containing groups.
The disclosure also includes pharmaceutical compositions comprising a compound of formula II in a therapeutically effective amount together with an acceptable carrier, adjuvant, or vehicle. Dependent embodiments further include a second therapeutic agent selected from an antipsychotic, memantine, or an acetylcholine esterase inhibitor (AChE-I), including donepezil, galantamine, or rivastigmine and their pharmaceutically acceptable forms. The partial content also includes specific enumerated substituted heterocyclic compounds represented by chemical structures within the broader formula-based claim scope.
Claims Coverage
The provided material centers on one broad independent claim for a formula II compound and dependent claims that narrow the chemical scope and add pharmaceutical composition embodiments. In total, the consolidated claim coverage reflects four inventive features.
Formula II compound with variable substituents and stereochemistry
A compound of formula II, or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof, wherein m is an integer selected from 0-4 and R1, R2, R4, and R5 are each independently selected from the specified substituent groups, R3 is selected from the specified substituent groups, and R6 is independently H or (C1-C6)alkyl.
R groups forming substituted rings and optional fusion
Each R is independently substituted with 0-5 R' groups, and two R groups bound to the same atom may form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms, optionally substituted and optionally fused to aryl, heteroaryl, cycloalkyl, or heterocyclyl moieties.
Enumerated substituted heterocyclic compounds
The compound is selected from a listed set of substituted heterocyclic compounds represented by the provided chemical structures, including pharmaceutically acceptable salts and Z/E stereoisomers or combinations thereof.
Pharmaceutical composition with second therapeutic agent
A pharmaceutical composition comprising the compound in a therapeutically effective amount together with an acceptable carrier, adjuvant, or vehicle, and optionally a second therapeutic agent selected from an antipsychotic, memantine, or an acetylcholine esterase inhibitor (AChE-I), including donepezil, galantamine, or rivastigmine and their pharmaceutically acceptable forms.
The claim coverage is centered on a formula II compound defined by broad but constrained substituent sets, stereochemical variants, and optional ring formation/fusion, together with pharmaceutical compositions containing the compound in a therapeutically effective amount and optional combination with specified second therapeutic agents.
Stated Advantages
Enhances b15-containing GABA_A receptor function.
Increases GABA-gated Cl currents.
Treats, preserves, or improves cognitive function.
Supports treatment of cognitive impairment across multiple CNS disorders, including schizophrenia, bipolar disorder (mania), Alzheimer's disease, MCI, and age-related cognitive impairment/decline.
Addresses blood-brain barrier considerations via quaternization to form water/oil-soluble products.
Provides pharmaceutical dosage forms and routes of administration, including extended/controlled release and implants.
Enables combination therapy with antipsychotics, memantine, or acetylcholine esterase inhibitors, including donepezil, galantamine, and rivastigmine.
Documented Applications
Treating cognitive impairment associated with central nervous system (CNS) disorders, including age-related cognitive impairment, Mild Cognitive Impairment (MCI) and amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia including Alzheimer's disease (AD) and prodromal AD, PTSD, schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction.
Pharmaceutical compositions for use with a second therapeutic agent selected from an antipsychotic, memantine, or an AChE-I, including donepezil, galantamine, or rivastigmine.
Treatment of cognitive impairment in schizophrenia, bipolar disorder (mania), Alzheimer's disease, MCI, and age-related cognitive impairment/decline.
Use of the compounds in pharmaceutical compositions with defined dosage forms and administration routes, including extended/controlled release and implants.
Combination therapy with antipsychotics, memantine, and AChE-I agents such as donepezil, galantamine, and rivastigmine.
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