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
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Publication Number
US-10829506-B2
Publication Date
2020-11-10
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 treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder.
Core Innovation
The invention relates to amino-/ammonium-containing sulfonic, phosphonic, and carboxylic acid derivatives defined by Formula 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The compounds are characterized by defined substituent variables R1 to R5 and X, where R1 is a C10-20 hydrocarbon group, R2 is a C1-4 alkyl group with R3 being H, R4 is a C1-6 hydrocarbon group, R5 is selected from sulfonyl, phosphorous-containing, phosphate-type, or carboxylic acid/carboxylate-type groups, and X is N+.
The disclosure further defines an alternative formula 6 as a quaternary ammonium N+ scaffold with substituents R1, R4, R5, and additional R6, n, and m parameters, and states that formula 5 compounds may correspond to formula 6 with shared definitions of R1, R4, R5, and R6/n/m. The scope extends to solid forms, polymorphs, stereoisomers, and pharmaceutical compositions that include the compound together with a pharmaceutically acceptable excipient.
The invention addresses treatment or prevention of inflammatory, autoimmune, and/or allergic disorders and reports biological evaluation of mast cell degranulation inhibition. The compounds are described as inhibiting the PI3K/Akt pathway, including Akt phosphorylation/activation and pSer473 reduction, with mast-cell stabilizing effects and in vivo efficacy in delayed-type hypersensitivity and allergic contact dermatitis models.
Claims Coverage
The independent claim coverage centers on a Formula 1 compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, with X = N+ and constrained substituents R1, R2/R3, R4, and R5. The inventive features are refined through dependent claims selecting specific R5 groups, fixing R4 to a (CH2)3 substituent, specifying R1 chain lengths, and extending coverage to a pharmaceutical composition with an excipient.
Quaternary ammonium compound defined by formula 1
A compound of Formula 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X is N+ and substituents are defined with R1 as a C10-20 hydrocarbon group, R2 as a C1-4 alkyl group with R3 being H, R4 as a C1-6 hydrocarbon group, and R5 selected from -SO3-, -SO3H, -PO3^2-, -PO3H2, -PO2(OC1-3 alkyl), -PO2H(OC1-3 alkyl), -PO(OC1-3 alkyl)2, -CO2-, -CO2H, or -CO2(C1-3 alkyl).
Specific sulfonyl R5 options
The Formula 1 compound wherein R5 is either -SO3 or -SO3H.
Specific phosphorous-containing R5 options
The Formula 1 compound wherein R5 is either -PO3^2-, -PO3H2-, or -PO3H2.
Fixed R4 substituent length
The Formula 1 compound wherein R4 is specified as a (CH2)3- substituent.
Specific straight-chain R1 alkyl chain lengths
The Formula 1 compound wherein R1 is a straight-chain alkyl group of the form -(CH2)n-CH3 with n equal to 11, 13, or 15.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the Formula 1 compound together with a pharmaceutically acceptable excipient.
The claim set defines a quaternary ammonium (X = N+) Formula 1 compound with constrained hydrocarbon substituents R1 and R4, fixed R2/R3 relationship, and selected R5 functional groups. Dependent claims narrow R5 to specific sulfonyl or phosphorous-containing variants, fix R4 to a (CH2)3 substituent, specify R1 chain lengths, and extend coverage to a pharmaceutical composition including a pharmaceutically acceptable excipient.
Stated Advantages
Treating or preventing inflammatory, autoimmune, and/or allergic disorders.
Inhibition of the PI3K/Akt pathway, including Akt phosphorylation/activation and reduction in Akt phosphorylation (pSer473).
Mast-cell stabilizing effects, including inhibition of mast cell degranulation and cytokine release such as TNF-α and IL-6.
Low cytotoxicity.
Reduced steroid-like adverse effects compared with corticosteroids such as dexamethasone.
In vivo efficacy in delayed-type hypersensitivity and allergic contact dermatitis models.
Documented Applications
Treatment or prevention of inflammatory, autoimmune, and/or allergic disorders, including psoriasis, atopic dermatitis, and urticaria variants.
Treatment or prevention of inflammatory bowel disease including Crohn's disease and ulcerative colitis.
Treatment or prevention of rheumatoid arthritis and systemic lupus erythematosus (SLE).
Treatment or prevention of COPD.
Treatment or prevention of dry eye disease (DED).
Treatment of diabetic macular edema.
Mast cell degranulation inhibition evaluation in cell-based context described with RBL-2H3 cells, FcεRI, IgE, and β-hexosaminidase.
Biological evaluation showing reductions in Akt phosphorylation (pSer473) along the PI3K/Akt axis.
In vivo application for delayed-type hypersensitivity (mouse ear swelling) model with reported inhibition versus dexamethasone.
In vivo application for allergic contact dermatitis (TDI) model with reported inhibition versus dexamethasone.
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