Oxygenated 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

GRI Bio Inc

Abstract

The present invention relates to oxygenated 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, or a proliferative, neoplastic or dysplastic disease or disorder.

Core Innovation

The disclosure encompasses compounds of formulas 16, including compounds represented by formula 1a, and includes pharmaceutically acceptable salts, solvates, prodrugs, and all stereoisomers, including racemates and isolated optical isomers. It further defines diastereomeric derivatives and presents resolution and isolation approaches for obtaining isolated optical isomers.

The compounds are described as Akt inhibitors capable of inhibiting Akt activation and Akt phosphorylation (Ser473), including inhibition of the PI3K/Akt signaling pathway and membrane domain enrichment that results in allosteric inhibition with reference to the pleckstrin homology (PH) domain. The reported biological effects include suppression of cellular inflammatory responses involving mast cells and inhibition of mast cell degranulation measured by -hexosaminidase release.

The therapeutic framing covers inflammatory, autoimmune, and allergic disorders, including rheumatoid arthritis, delayed type hypersensitivity, allergic contact dermatitis, and proliferative, neoplastic, and dysplastic diseases. The disclosure also reports in vivo efficacy in mouse delayed-type hypersensitivity, allergic contact dermatitis, and collagen type II-induced arthritis models, together with polymorphism-related characterization and in vivo pharmacokinetic comparison across polymorphic forms.

Claims Coverage

The consolidated claim coverage centers on 1 inventive feature: a compound defined by formula 1a, including pharmaceutically acceptable salts and solvates. A dependent claim further covers a pharmaceutical composition comprising the compound with a pharmaceutically acceptable excipient.

The claims are directed to the compound of formula 1a, including pharmaceutically acceptable salts or solvates, and to a pharmaceutical composition that includes that compound together with a pharmaceutically acceptable excipient.

Stated Advantages

Documented Applications