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-10815195-B2
Publication Date
2020-10-27
Expiration Date
Abstract
The present invention relates to oxygenated amino or ammonium-containing sulfonic acid, phosphoric 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 describes compounds of formulas 1, 1b, 1c, 1d, and 1e, as well as related formulae 2 to 36, including all stereoisomers, pharmaceutically acceptable prodrugs, ester derivatives, acyloxy derivatives, amide derivatives, salts, solvates, and crystal forms. The disclosed structures incorporate variable substituents such as R1 to R16 and X and include ring options such as pyrrolidine, piperidine, and azepane.
The invention positions the compounds as inhibitors of the PI3K/Akt pathway, including inhibition associated with Akt kinase activation and phosphorylation. The compounds are characterized as immunomodulatory and mast-cell-stabilizing agents that inhibit mast cell degranulation and reduce release of pro-inflammatory mediators, including TNF-α and IL-6.
The invention includes medical use for treatment, prevention, and amelioration of inflammatory, autoimmune, and allergic disorders, notably rheumatoid arthritis, and also proliferative, neoplastic, and dysplastic diseases including cancer. The disclosure further relates to cotherapy with immunomodulatory drugs and anti-inflammatory drugs, and reports representative experimental findings tied to mast cell degranulation, Akt phosphorylation, and in vivo immune-driven inflammation models and an arthritis model.
Claims Coverage
The independent claims cover 5 inventive features across multiple formula-defined compound scopes, with the main inventive coverage residing in structural definition through alternative formulae and explicit substituent limitations. All provided independent claims include coverage of pharmaceutically acceptable salts and solvates, and one claim variant expressly excludes compounds comprising formula 1a.
Formula 1 compound defined by substituent constraints and ionic headgroup selection
A compound of formula 1 with R1 as a C10-20 hydrocarbon group, R2 as a C1-4 alkyl group, R3 as H or absent, R4 as a C3-6 alkylene group substituted with one or more specified groups, R5 as specified sulfur, phosphate, phosphite, phosphonate, or related anionic or protonated groups, and X as N+ or N, together with a pharmaceutically acceptable salt or solvate thereof.
Formula 1b compound with salts and solvates
A compound of formula 1b, or a pharmaceutically acceptable salt or solvate thereof.
Formula 1 compound variant with enumerated R5 options and exclusion of formula 1a
A compound of formula 1 with R1 as a C10-20 hydrocarbon group, R2 as a C1-4 alkyl group, R3 as H or absent, R4 as a C3-6 alkylene group substituted with one or more specified groups, R5 as an enumerated set including sulfur and phosphate, phosphonate, and carboxylate options, and X as N+ or N, where the compound does not comprise formula 1a, and further covering a pharmaceutically acceptable salt or solvate thereof.
Formula 1c compound with salts and solvates
A compound of formula 1c, or a pharmaceutically acceptable salt or solvate thereof.
Formula 1d or 1e compound with salts and solvates
A compound of formula 1d or 1e, or a pharmaceutically acceptable salt or solvate thereof.
The claim set defines several structurally distinct compound scopes by formula alternatives, with the strongest structural definition appearing in formula 1 via explicit constraints on R1, R2, R3, R4, R5, and X. One independent claim additionally limits the scope by requiring that the compound does not comprise formula 1a.
Stated Advantages
Inhibition of mast-cell degranulation, including reduced β-hexosaminidase release.
Reduced cytotoxicity as reflected by increased MTC compared to miltefosine.
Inhibition of Akt phosphorylation (Ser473) at the PI3K/Akt axis.
Reduced ear swelling in mouse delayed-type hypersensitivity and allergic contact dermatitis models versus vehicle.
Fewer corticosteroid-like immune effects, with observations including no lymph node reaction impact.
Reduced arthritis score and paw thickness in collagen type II-induced arthritis versus comparison conditions described.
Lack of dexamethasone-like reductions in body weight and immune organ weights in collagen type II-induced arthritis.
Comparable oral pharmacokinetics and absorption behavior across polymorphs for compound 1a.
Low cytotoxicity.
Reduced corticosteroid-like adverse effects compared with dexamethasone and diflorasone.
Documented Applications
Treatment or use for inflammatory, autoimmune, and allergic disorders, notably rheumatoid arthritis, including cotherapy with immunomodulatory and anti-inflammatory drugs.
Use in mouse delayed-type hypersensitivity model for inhibiting antigen challenge responses as measured by reduced ear swelling.
Use in mouse allergic contact dermatitis model for reduced ear swelling versus vehicle.
Use in collagen type II-induced arthritis model for reduced arthritis score and paw thickness.
Treatment, prevention, and amelioration of proliferative, neoplastic, and dysplastic diseases including cancer.
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