Xanomeline derivatives and methods for treating neurological disorders

Inventors

Monn, James A. • Schlecht, Clifford Adam • Bennett, Dennis A. • Attardo, Giorgio

Assignees

Karuna Therapeutics Inc

Abstract

Provided herein are compounds comprising compounds of formula I and/or salts thereof; wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is fluorine, and the remainder are independently chosen from hydrogen and fluorine; and R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 are independently chosen from hydrogen and deuterium; with the proviso that when R1, R2, and R3 are fluorine, then at least one of R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is fluorine or at least one of R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 is deuterium. Also provided are medicaments comprising these compounds and methods for treating central nervous system disorders with the compounds and medicaments described herein.

Core Innovation

The disclosure relates to fluorinated and deuterated xanomeline derivatives and related variants, including compounds of Formula I and medicaments containing the compounds and methods for treatment using the medicaments. The disclosure also relates to substituted 1,2,5-thiadiazole derivatives that include alkoxy substituents, substituted tetrahydropyridinyl groups, and deuterated analogs, with salt forms including hydrochloride, dihydroxysuccinate, and tartrate salts.

The core concept includes fluorinated 1,2,5-thiadiazole derivatives and deuterated xanomeline-related compound structures and/or a salt thereof, including difluorohexyl oxy-substituted, perfluoroalkyl oxy-substituted, tetrahydropyridine-related, and fluoroalkyl/fluorinated ether substituents. The disclosure includes deuterium-enriched embodiments at stated enrichment levels and medicaments comprising the compound and/or a salt thereof formulated with a pharmaceutically acceptable carrier.

The disclosure describes combination medicaments comprising a deuterium-enriched compound of Formula I and trospium chloride, including a lead-in period approach in which trospium chloride is administered alone prior to administration of the compound. It also includes biological performance and evaluation in human liver microsome metabolic stability, muscarinic receptor functional agonism across mAChR subtypes M1–M5, in vivo rat oral pharmacokinetics, and analytical confirmation using LCMS and NMR.

Therapeutic contexts include treating pain and treating a central nervous system disorder such as schizophrenia, with broader disorder scope including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Lewy Body dementia, psychosis, cognition deficit, movement disorders, mood disorders, cognitive disorders, attention disorders, and addictive disorders. The disclosure also indicates exemplary compounds or structures in Table 1 and deuterated thiadiazole analogs in Examples 61-63.

Claims Coverage

The provided claim coverage combines independent coverage of selected compounds and/or salts thereof with dependent limitations including deuterium enrichment, medicament formulation with a pharmaceutically acceptable carrier, trospium chloride dose range, and therapeutic use. Across the items, the claims cover 6 core inventive features.

Overall, the claim coverage centers on selection of fluorinated/deuterated xanomeline derivatives and substituted 1,2,5-thiadiazole derivatives, optionally as salts, with deuterium enrichment and medicament formulations, and using them in methods for treating pain or schizophrenia with therapeutically effective amounts, including medicament embodiments containing trospium chloride within a stated dose range.

Stated Advantages

Documented Applications