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-11564895-B2
Publication Date
2023-01-31
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 proposed as compounds of formula 1 or formula 2, including exemplified compounds 1a-1d. The disclosure links their pharmacological activity to inhibition of the PI3K/Akt kinase pathway, with suppression of Akt phosphorylation and activation, including Akt phosphorylation at Ser473.
The derivatives are intended for treating and/or preventing inflammatory, autoimmune/allergic, and proliferative/neoplastic/dysplastic diseases. The problem addressed is inflammatory and immune-driven disease, including delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis, as well as inflammatory responses associated with mast cell degranulation.
Non-clinical support described includes in vitro inhibition of mast cell degranulation, including β-hexosaminidase release in IgE/antigen-stimulated RBL-2H3 cells, together with concentration-dependent suppression of Akt phosphorylation at Ser473. In vivo efficacy described includes anti-inflammatory effects in Th1 delayed-type hypersensitivity, Th2 allergic contact dermatitis, and collagen type II-induced arthritis.
The disclosure also states a favorable safety profile, including low cytotoxicity and a high therapeutic window versus degranulation IC50. The formula scope is defined by specific substituent classes for R1 through R5 and X, including R1 being a C10-20 hydrocarbon group, R5 being a C2-8 alkyl group with one or more hydrogen atoms replaced by —OH or a C5-7 cycloalkyl group with optional oxygen replacement and —OH/—CH2OH substitutions, and X being N+ or N when R3 is absent.
Claims Coverage
The cited independent claim covers a method of inhibiting mast cell degranulation and treating inflammatory disease responses by administering an effective amount of a specified compound of formula 1 or a pharmaceutically acceptable salt or solvate. The claim is supported by multiple inventive features, with dependent refinements to the biological target, disease indication, and administration route.
Formula 1 hydroxy-substituted amino/ammonium derivatives
Administering an effective amount of 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 R3 is absent; R4 is —H or a C1-4 alkyl group; R5 is a C2-8 alkyl group with one or more hydrogen atoms replaced by —OH or R5 is a C5-7 cycloalkyl group with optional oxygen replacement and one or more hydrogen atoms independently replaced by —OH or —CH2OH; X is N+ or, if R3 is absent, X is N; and p is 1, 2 or 3.
Inhibiting mast cell degranulation and treating inflammatory responses
Using the method to inhibit mast cell degranulation and an inflammatory response in delayed-type hypersensitivity, allergic contact dermatitis, or collagen type II-induced arthritis, by administering the compound to a subject in need of such a treatment.
Pharmaceutically acceptable salts and solvates
Administering the compound as a pharmaceutically acceptable salt or solvate thereof.
Akt kinase inhibition
In a refined scope, inhibiting Akt kinase as part of the method.
Disease-specific allergic contact dermatitis indication
In a refined scope, using the method for inhibiting the inflammatory response in allergic contact dermatitis.
Disease-specific collagen type II-induced arthritis indication
In a refined scope, inhibiting collagen type II-induced arthritis.
Administration routes of oral, topical, or transdermal
In a refined scope, administering the compound via an oral route, a topical route, or a transdermal route.
Overall, the claim coverage centers on administering a formula 1 hydroxy-substituted amino/ammonium derivative, or its pharmaceutically acceptable salt or solvate, to inhibit mast cell degranulation and treat inflammatory responses in delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis, with additional dependent refinements to Akt kinase inhibition and oral, topical, or transdermal administration.
Stated Advantages
Low cytotoxicity.
High therapeutic window versus degranulation IC50.
Anti-inflammatory efficacy in delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis, compared with dexamethasone in described models.
Documented Applications
Treating or preventing anti-inflammatory responses in delayed-type hypersensitivity (Th1), including mouse ear swelling.
Treating or preventing allergic contact dermatitis (Th2) using topical and oral effects, with described differential effects versus corticosteroid on local lymph nodes and body weight.
Treating or preventing collagen type II-induced arthritis (CIA), including reduced arthritis scores and immune organ effects compared with dexamethasone.
In vitro inhibition of mast cell degranulation, including β-hexosaminidase release in IgE/antigen-stimulated RBL-2H3 cells.
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