Amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use
Inventors
Schlechtingen, Georg • Knölker, Hans-Joachim • Friedrichson, Tim • Jennings, Gary • Braxmeier, Tobias
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9850265-B2
Publication Date
2017-12-26
Expiration Date
Abstract
The present invention relates to amino- or 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.
Core Innovation
A method is provided for treating or ameliorating an inflammatory, autoimmune and/or allergic disorder by administering a compound of formula 1, or compounds of the other formulae, to a subject in need. The administered compound includes defined substituent options and may be provided as a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer. The compounds are amino/ammonium-containing sulfonic/phosphonic/carboxylic acid derivative compounds designed to inhibit the PI3K/Akt kinase pathway, with Akt described as a key mediator in inflammatory, autoimmune and/or allergic signaling.
The treated disorder is selected from a specified list of inflammatory, autoimmune and/or allergic disorders, including psoriasis, atopic dermatitis, anaphylaxis, food allergy, inflammatory bowel disease, rheumatoid arthritis, SLE, scleroderma, dry eye disease, allergic conjunctivitis, allergic rhinitis, allergic asthma, autoimmune hepatitis, multiple sclerosis, and contact dermatitis. The document also reports selected compounds showing inflammatory/allergic activity, including inhibition of mast cell degranulation in RBL-2H3 cells, inhibition of Akt phosphorylation (pSer473), and suppression of TNF-α and IL-6 in LPS-stimulated PBMCs.
In animal models, the document describes inhibition of delayed-type hypersensitivity and allergic contact dermatitis, with activity comparable to dexamethasone in a DTH model. The patent further states low cytotoxicity and a more favorable corticosteroid side-effect profile, including avoidance of corticosteroid adverse effects such as reduced lymph node weight/cell number. General synthetic routes to prepare compounds of formulae 1–6 are also described, and formula 6 is introduced as a further structural variant.
Claims Coverage
Two independent claims are identified. Each centers on administering a defined compound to treat or ameliorate an inflammatory, autoimmune and/or allergic disorder, with broader coverage provided by compound-formula scope.
Administration of a compound of formula 1 to treat inflammatory, autoimmune and/or allergic disorders
A method of treating or ameliorating an inflammatory, autoimmune and/or allergic disorder by administering a compound of formula 1, wherein R1 is a C10-20 hydrocarbon group; R2 is a C1-4 alkyl group; R3 is —H, a C1-4 alkyl group or absent; R4 is a C1-6 alkylene group; R5 is —SO3−, —SO3H, —PO3H−, —PO3^2−, —PO3H2, —PO2(OC1-3alkyl)−, —PO2H(OC1-3alkyl), —PO(OC1-3alkyl)2, —CO2−, or —CO2(C1-3alkyl); and X is N+ or, if R3 is absent, X is N; and wherein said compound or a pharmaceutically acceptable salt, solvate, stereoisomer, polymorph, or prodrug thereof treats or ameliorates the disorder.
Administration of a compound of any of the following formulae to treat inflammatory, autoimmune and/or allergic disorders
A method of treating or ameliorating an inflammatory, autoimmune and/or allergic disorder by administering a compound of any of the following formulae to a subject in need of such a treatment, optionally using a pharmaceutically acceptable salt, solvate or prodrug thereof.
The independent claims define therapeutic methods based on administering compounds with specified structural elements to treat or ameliorate inflammatory, autoimmune and/or allergic disorders, with broader coverage for compounds of any of the listed formulae.
Stated Advantages
In vitro inhibition of mast cell degranulation in RBL-2H3 cells with quantified potency, maximum tolerated concentration, and safety index values.
Inhibition of Akt phosphorylation (pSer473) associated with the PI3K/Akt axis.
Suppression of TNF-α and IL-6 in LPS-stimulated PBMCs.
In vivo inhibition of delayed-type hypersensitivity and allergic contact dermatitis with quantified ear-swelling inhibition compared with vehicle and dexamethasone.
Broad anti-inflammatory effects in Th1/Th2 animal models.
Low cytotoxicity.
More favorable corticosteroid side-effect profile, including avoidance of corticosteroid adverse effects such as reduced lymph node weight/cell number.
Documented Applications
Treatment or amelioration of inflammatory, autoimmune and/or allergic disorders, including psoriasis, atopic dermatitis, contact dermatitis, dermatitis herpetiformis, anaphylaxis, food allergy, allergic reactions to venomous stings, urticarias, inflammatory bowel disease, autoimmune liver diseases, autoimmune and allergic eye conditions, allergic rhinitis, allergic conjunctivitis, allergic asthma, hypersensitivity pneumonitis, rheumatoid arthritis, SLE, scleroderma, dry eye disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, autoimmune hepatitis, multiple sclerosis, diabetic macular edema, COPD, and alopecia areata.
Topical/oral use in allergic contact dermatitis models.
Mast-cell-related settings through described mast-cell degranulation inhibition/stabilization and immune mediator release inhibition in an in vitro mast cell model.
Interested in licensing this patent?