Hydroxy-substituted amino and ammonium derivatives and their medical use
Inventors
Schlechtingen, Georg • Knolker, Hans-Joachim • Friedrichson, Tim • Jennings, Gary • Braxmeier, Tobias
Assignees
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Publication Number
US-10952977-B2
Publication Date
2021-03-23
Expiration Date
Abstract
The present invention relates to hydroxy-substituted amino and ammonium derivatives, in particular the compounds of formula (1) or (2), and their medical use, including their use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder, or a proliferative, neoplastic or dysplastic disease or disorder.
Core Innovation
Hydroxy-substituted amino/ammonium derivatives are claimed as compounds according to Formula 1 and Formula 2, including pharmaceutically acceptable salts, solvates, and prodrugs. The disclosure describes these compounds for treating or preventing inflammatory, autoimmune/allergic, and proliferative/neoplastic/dysplastic diseases, and proposes inhibition of the PI3K/Akt kinase pathway, including reduced Akt Ser473 phosphorylation.
In the disclosed mechanism, the compounds act as mast cell stabilizers. Inhibition of mast cell degranulation is described, including inhibition of IgE/DNP-induced mast cell degranulation and suppression of β-hexosaminidase release in the reported context. The disclosure further links the mast cell-related effects with inflammatory mediators such as TNF-α and interleukin-6.
The disclosure emphasizes therapeutic potential in animal models and compares with dexamethasone. Documented efficacy is described for Th1-driven delayed-type hypersensitivity and Th2-driven allergic contact dermatitis, including topical and oral administration, and for collagen type II-induced arthritis. The disclosure also highlights advantageously low cytotoxicity and provides representative compounds (1a–1d) together with key results such as IC50, maximum tolerated concentration (MTC), and safety index (SI) for degranulation inhibition.
Claims Coverage
The provided claim content covers one independent claim centered on administering Formula 1 compounds, or pharmaceutically acceptable salts/solvates, to inhibit mast cell degranulation and related inflammatory conditions.
Administering Formula 1 hydroxy-substituted amino/ammonium derivatives to inhibit mast cell degranulation and Akt kinase in inflammatory diseases
A method of inhibiting mast cell degranulation, Akt kinase, delayed-type hypersensitivity, allergic contact dermatitis inflammatory response, or collagen type II-induced arthritis, comprising administering an effective amount to a subject in need, using a compound of Formula 1 with defined R1–R5, X, and p constraints, or a pharmaceutically acceptable salt or solvate thereof.
The inventive coverage centers on administration of Formula 1 hydroxy-substituted amino/ammonium derivatives, or pharmaceutically acceptable salts/solvates, to inhibit mast cell degranulation and related Akt/PI3K-associated inflammatory responses in delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis.
Stated Advantages
Advantageously low cytotoxicity.
Broader efficacy relative to dexamethasone in animal models.
Documented Applications
Th1-driven delayed-type hypersensitivity in animal models.
Th2-driven allergic contact dermatitis, including topical and oral administration.
Collagen type II-induced arthritis in animal models.
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