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 disclosure defines compound families of Formula IV and related formula embodiments by detailed ring and heteroatom constraints and extensive substituent definitions. The variable groups include R1 through R6, R8, R9, R′, and R″, with allowed motifs such as alkyl, cycloalkyl, aryl, heteroaryl, halogen, nitrile, nitro, alkoxy, aminoalkyl, CF3, and carbonyl-containing groups, together with ring-closure selections and structural constraints on aromatic and non-aromatic ring formations.

The document also presents multiple small-molecule compounds identified by example numbers and provides their chemical characterization, including structure depictions, MS [M+1] values, 1H NMR data, and isolated yields for named compounds. The examples report preparation of listed compounds through iterative chemical transformations that generate structurally related analogs, including boronic acid coupling to give biaryl and heteroaryl analogs, and include oxime, amide-oxime, and amino-oxime formation together with nitrile and other intermediate conversions.

Across the provided items, the selected compounds are connected to pharmaceutical compositions and therapeutic methods. The claim-directed uses include treating cognitive impairment associated with a central nervous system disorder and slowing the progression of, alleviating, or ameliorating a brain cancer, including cognitive impairment associated with brain cancer and medulloblastoma.

Claims Coverage

The consolidated independent claim coverage centers on selecting compounds from specified groups, including pharmaceutically acceptable forms. The claim sets also extend to pharmaceutical compositions and therapeutic methods for cognitive impairment associated with CNS disorders and for brain cancer, including medulloblastoma.

The claim coverage is anchored by compound selection from defined groups with pharmaceutically acceptable forms, and is extended to compositions and therapeutic methods directed to CNS-related cognitive impairment and brain cancer. The most specific indication repeated across the inputs is medulloblastoma.

Stated Advantages

Documented Applications