Oxygenated amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid 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-11453642-B2
Publication Date
2022-09-27
Expiration Date
Abstract
The present invention relates to oxygenated amino and ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives, in particular the compounds of formula 1, 2, 3, 4, 5 or 6, 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 compounds of formula 1, or pharmaceutically acceptable salts thereof, in a defined structural context including selections for R1, R2, R3, R4, R5, and X. The disclosure encompasses stereoisomers, including racemic forms and optical isomers, as well as resolution and prodrug concepts associated with formula 1 to formula 6 compounds.
The medical use is for treating, preventing, ameliorating, or treating or ameliorating inflammatory, autoimmune and/or allergic disorders, and also for treating proliferative, neoplastic, and/or dysplastic diseases. The compounds are proposed to act via inhibition of the PI3K/Akt pathway, including inhibition of Akt phosphorylation or activation, and the document further describes immunomodulatory effects including inhibition of mast cell degranulation and reduced release of TNF-α and IL-6.
The disclosure provides biological characterization for compound examples 1a to 1e, including mast cell degranulation inhibition measured by β-hexosaminidase release in an FcεRI context and effects on Akt phosphorylation (Ser473). Further in vivo efficacy examples are provided in mouse delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis models, together with pharmacokinetic comparison of polymorphic forms of compound 1a.
Claims Coverage
The independent claim coverage is centered on administration of a formula 1 compound, or a pharmaceutically acceptable salt, for treating or ameliorating inflammatory, autoimmune and/or allergic disorders. The combined claim set presents four inventive features, with dependent refinements directed to disorder selection, pharmaceutical composition context, and specific illustrated embodiments.
Treating or ameliorating inflammatory, autoimmune and/or allergic disorders with formula 1 compound administration
Administering a compound of formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the compound of formula 1 is defined with specific selections for R1, R2, R3, R4, R5, and X.
Selection of inflammatory, autoimmune and/or allergic disorder from listed conditions
Selecting the inflammatory, autoimmune and/or allergic disorder to be treated from atopic dermatitis, contact dermatitis, urticarias, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, alopecia areata, graft-versus-host disease, transplant rejection, COPD, allergic asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and lung fibrosis.
Using pharmaceutical composition context for administration
Administering the compound of formula 1 as part of a pharmaceutical composition.
Employing specific illustrated compound embodiments of formula 1
Limiting the compound to a specific illustrated chemical structure, including 1b, 1c, 1d, or 1e, or a pharmaceutically acceptable salt thereof.
Overall claim coverage is anchored in a method for administering a formula 1 compound, or pharmaceutically acceptable salts, to treat or ameliorate inflammatory, autoimmune and/or allergic disorders, with dependent refinements for disorder selection, pharmaceutical composition context, and specific illustrated formula 1 embodiments.
Stated Advantages
Improved safety or tolerability, supported by low cytotoxicity and reduced corticosteroid-like adverse effects.
Broad anti-inflammatory activity in Th1/Th2 animal models, including delayed type hypersensitivity and allergic contact dermatitis.
Comparison to corticosteroids including dexamethasone.
Inhibition of mast cell degranulation and reduction of release of TNF-α and IL-6.
Documented Applications
Treating, preventing, or ameliorating inflammatory, autoimmune and/or allergic disorders.
Treating proliferative, neoplastic, and/or dysplastic diseases.
In vivo mouse delayed-type hypersensitivity model efficacy.
In vivo mouse allergic contact dermatitis model efficacy.
In vivo collagen type II-induced arthritis efficacy.
Mast cell degranulation inhibition by β-hexosaminidase release.
Reduction of Akt phosphorylation (Ser473).
Pharmacokinetic comparison of polymorphic forms of compound 1a.
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