Therapeutics for central nervous system disorders
Inventors
Li, Chiang J. • CHEN, Suzhen • Liu, Jifeng
Assignees
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Publication Number
US-11370748-B2
Publication Date
2022-06-28
Expiration Date
Abstract
The invention provides novel compounds, pharmaceutical compositions and methods of preparation and use thereof for treating disease affecting the central nervous system such as multiple sclerosis.
Core Innovation
The invention relates to therapeutics for central nervous system disorders, including multiple sclerosis and demyelinating disease, using compounds represented by Formula (I)–(III). The described compounds include variable substituents such as R1/R2/R3, Y, and X, and include allowable stereoisomers, diastereomers, tautomers, and pharmaceutically acceptable salts and solvates.
In the disclosed compound set, Y is alkyl or substituted alkyl, alkoxy or substituted alkoxy, or aryl or substituted aryl, while X is CR1′R3′, NR1′, O, or S, with R1′ and R3′ each independently selected from hydrogen and alkyl. The compounds can be provided as enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts, including hydrochlorides.
The invention also includes pharmaceutical compositions comprising one or more of the disclosed compounds, together with pharmaceutically acceptable excipients, carriers, or diluents, and methods of therapeutic or prophylactic treatment of central nervous system diseases. The document reports biological effects consistent with enhanced remyelination, promotion of oligodendrocyte maturation, inhibition of microglia activation, reduction of TNF-α release, and improved clinical outcomes in Experimental Autoimmune Encephalomyelitis models compared with dimethyl fumarate.
Claims Coverage
The independent claim set includes one independent compound claim directed to a compound of Formula (III). The inventive coverage is primarily defined by the structural definition of Y and X in Formula (III), including allowed stereochemical and salt/tautomer forms; additional dependent coverage narrows specific options for X and Y and includes pharmaceutical composition and central nervous system disease treatment use in mammals.
Formula (III) compound with defined Y and X substituents
A compound of formula (III) wherein Y is alkyl or substituted alkyl, alkoxy or substituted alkoxy, aryl or substituted aryl; and X is CR1′R3′, NR1′, O, or S, wherein each of R1′ and R3′ is independently selected from hydrogen and alkyl, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.
The claim coverage centers on the Formula (III) compound definition with Y as an alkyl/alkoxy/aryl group, optionally substituted, and X as CR1′R3′, NR1′, O, or S, together with permitted stereochemical, tautomeric, and pharmaceutically acceptable salt/solvate forms. The dependent claims further narrow X and Y selections and include pharmaceutical compositions for treating central nervous system diseases such as demyelinating disease and multiple sclerosis in mammals.
Stated Advantages
Enhanced remyelination as indicated by MBP and LFB measures.
Promotion of oligodendrocyte maturation and effects on oligodendrocyte precursor cells.
Inhibition of microglia activation and reduced TNF-α release.
Reduced activated microglia survival and induction of cell death.
Protection against axon damage.
Improved EAE clinical scores compared with dimethyl fumarate.
Documented Applications
Therapeutic and prophylactic treatment of central nervous system diseases and disorders in a mammal, including demyelinating disease and multiple sclerosis.
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