Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Inventors

Mekonnen, Belew • Butera, John A. • Huang, Jianxing • Patel, Hemantbhai

Assignees

Hager Biosciences LLC • Agenebio Inc

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. It also 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 brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.

Core Innovation

The invention relates to compounds according to formula VII or formula IV, including pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. The compounds are defined by variable parameters including m and n, together with multiple substituent positions such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and related R′ groups, with explicit substitution-count limits and substituent classes including halogen, OMe, CF3, OCF3, CN, alkyl, aryl, heteroaryl, cycloalkyl, alkoxy, and oxygen-containing motifs.

A central aspect of the disclosure is the breadth of allowed functional-group variation under the formula definitions. R2 is defined as (CH2)nOR8 or (CH2)nO(CH2)nR8, with n from 0-4, and R8 selected from H, alkyl, cycloalkyl, aryl, and heteroaryl groups, subject to additional substitution limits. The disclosed structures comprise fused heteroaromatic or polycyclic nitrogen-containing scaffold variations, supported by representative numbered structures and chemical structure depictions.

The claims further tie the compound families to methods of treating brain cancer and cognitive impairment associated with brain cancer in a subject in need thereof, optionally wherein the brain cancer is medulloblastoma. The method claims require a compound or a pharmaceutical composition comprising the compound, selected from enumerated compound lists, and include the corresponding pharmaceutically acceptable forms. The disclosure also states that the compounds are GABA_A ε receptor positive allosteric modulators and are used in methods to treat cognitive impairment and/or brain cancer, including medulloblastoma, and to improve and/or preserve cognitive function.

Claims Coverage

The consolidated claim coverage includes two formula-based compound families and method-of-treatment claims. In total, the independent claims center on structurally defined formula VII and formula IV compounds with extensive substituent-variable constraints, plus treatment of brain cancer and cognitive impairment associated with brain cancer using selected numbered compounds or pharmaceutical compositions, optionally with medulloblastoma specified.

Overall, the claims cover formula VII and formula IV substituted heteroaromatic compounds with extensive but bounded substituent variability, together with selected numbered compounds and methods for treating brain cancer or cognitive impairment associated with brain cancer, optionally medulloblastoma, using the selected compounds or pharmaceutical compositions comprising them.

Stated Advantages

Documented Applications