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-10143668-B2
Publication Date
2018-12-04
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
The invention relates to hydroxy-substituted amino and ammonium derivatives represented by compounds of formula 1 and formula 2, including compounds 1a-1d, for use as medicaments. The disclosed medicaments are intended for treating and/or preventing inflammatory, autoimmune, allergic, and proliferative or neoplastic or dysplastic diseases.
The invention addresses inflammation in subjects by providing a method in which inflammation inhibition is associated with at least one of Akt kinase activation and mast cell degranulation. The proposed mechanistic basis is targeting the PI3K/Akt pathway, including Akt kinase activation and Akt phosphorylation at Ser473, together with inhibiting mast-cell degranulation using mast-cell stabilizer type action.
The document contrasts the disclosed approach with corticosteroids and other biologics and emphasizes an advantage regarding safety. It states advantageously low cytotoxicity and a favorable safety profile versus dexamethasone, including comparative tolerability described as maximum tolerated concentration and safety index.
Claims Coverage
The provided claim set includes one independent claim. The independent claim covers a method of inhibiting inflammation via administering an effective amount of a compound of formula 1, where the inflammation inhibition is associated with at least one of Akt kinase activation or mast cell degranulation, with extensive structural definition constraints for R1–R5, X, and the index p, plus pharmaceutically acceptable salts or solvates.
Inhibiting inflammation via Akt kinase activation or mast cell degranulation
A method of inhibiting inflammation that comprises at least one of Akt kinase activation or mast cell degranulation, comprising administering to a subject in need of such inhibiting an effective amount of a compound of formula 1.
Formula 1 hydroxy-substituted amino/ammonium compound structure
The method includes administering a compound of formula 1 wherein R1 is a C10-20 hydrocarbon group; R2 is a C1-4 alkyl group and R3 is —H, a C1-4 alkyl group or absent; and R2 and R3 can be mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with nitrogen atom X with optional ring substitution; R4 is —H or a C1-4 alkyl group; R5 is a C2-8 alkyl group optionally hydroxyl-replaced or a C5-7 cycloalkyl group optionally oxygen-replaced with independent hydroxyl or —CH2OH replacements; X is N+ or, if R3 is absent, X is N; and p is 1, 2 or 3, or a pharmaceutically acceptable salt or solvate thereof.
The inventive scope is defined by inflammation inhibition linked to either Akt kinase activation and/or mast cell degranulation and administration of a formula 1 hydroxy-substituted amino/ammonium derivative meeting the specified structural constraints, optionally as pharmaceutically acceptable salts or solvates.
Stated Advantages
Advantageously low cytotoxicity.
Favorable safety profile versus dexamethasone, reflected in maximum tolerated concentration and safety index.
Reduced adverse effects reported for compound 1a compared with corticosteroid treatment in the described in vivo setting.
Documented Applications
Treating and/or preventing inflammatory, autoimmune/allergic disorders and proliferative/neoplastic/dysplastic diseases using compounds of formula 1 or formula 2.
Anti-inflammatory treatment in a Th1-driven delayed type hypersensitivity (DTH) model.
Anti-inflammatory treatment in a Th2-driven allergic contact dermatitis model.
Treatment of autoimmune hepatitis characterized by inflammation.
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