Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Inventors

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

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.

Core Innovation

The invention relates to compounds of formula II and pharmaceutically acceptable salts, hydrates, isomers, solvates, polymorphs, or combinations thereof, including isotopically labeled and unlabeled embodiments. The compounds are defined by a Markush structure in which m is 0-3 and R1, R2, R3, R4, R5, and R6 are selected from defined structural classes with optional R′ and R″ substitution limits. The disclosed scope includes halogen, alkyl, hydroxy, alkoxy, nitro, cyano, trifluoromethyl, OCF3, aryl, heteroaryl, heterocyclyl, and related aliphatic-linked options.

The disclosure further includes compounds of formulae I-IV and selected compound/structure entries within the same chemical family, together with pharmaceutical compositions comprising the disclosed compounds and a pharmaceutically acceptable carrier, adjuvant, or vehicle. It describes quaternized ionic derivatives formed by quaternization and covers injectable and oral dosage forms, extended or controlled release options, and patch or pump formats. The document also presents specific compound structures indexed in the compound/structure set, including compounds with methoxy, fluoro, bromo, cyano, phenoxy/phenyl-oxy, ester, carbonyl, and sulfonyl/sulfone substituent patterns on a shared fused heteroaromatic/piperidine-like core.

The patent states that the compounds are used for treating cognitive impairment associated with a central nervous system disorder, including dementia and Alzheimer’s disease, and also refers to age-related cognitive impairment and conditions identified as MCI/aMCI/AAMI/ARCD. It further identifies treatment of cognitive impairment associated with PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, Parkinson’s disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. Isotopically labeled compounds are also described for metabolic studies and PET/SPECT imaging, as well as drug tissue distribution assays and radioactive treatment of patients.

Claims Coverage

The consolidated claim coverage includes independent claims to a broad genus of formula II compounds with defined Markush substituent classes and substitution limits, a further genus of formula II compounds with additional structural constraints, and a selected enumerated compound set. Related coverage also includes pharmaceutical compositions comprising a therapeutically effective amount of a compound according to the compound formula with a pharmaceutically acceptable carrier, adjuvant, or vehicle, and treatment of cognitive impairment associated with CNS disorders.

Overall, the claims are centered on formula II Markush compounds with defined substituent classes and substitution limits, plus an enumerated set of specific compounds within the disclosed chemical family. The independent claim set also includes pharmaceutical compositions and treatment of cognitive impairment associated with CNS disorders.

Stated Advantages

Documented Applications