Oxygenated and amino- or ammonium-containing phosphonic 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-12528775-B2
Publication Date
2026-01-20
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 a compound of formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R1 is a C10-20 hydrocarbon group, R2 and R3 are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, and the ring is optionally substituted with one or more groups selected from hydroxyl, O(C1-3 alkyl), O—C(O)—(C1-3 alkyl), C1-3 alkyl, —NH2, —NH(C1-3 alkyl) or —N(C1-3 alkyl)(C1-3 alkyl). The compound further defines R4 as a C3-6 alkylene group substituted with one or more groups selected from hydroxyl, O(C1-3 alkyl), O—C(O)—(C1-3 alkyl), O—C(O)—O(C1-3 alkyl), O—C(O)—NH2, O—C(O)—NH(C1-3 alkyl), O—C(O)—N(C1-3 alkyl)(C1-3 alkyl), O(CH2)2OH or O(CH2)3OH, and R5 as —PO3H−, —PO3^2−, —PO3H2, —PO2(OC1-3 alkyl), —PO2H(OC1-3 alkyl), or —PO(OC1-3 alkyl)2. X is N+, and the scope further covers pharmaceutical prodrug forms intended to provide regenerated active compounds in vivo.
The document relates to the medical use of these compounds for treating, preventing, or ameliorating inflammatory, autoimmune/allergic, and proliferative/neoplastic/dysplastic diseases, including a broad range of disorders. The compounds are positioned as mast-cell stabilizers by inhibiting mast cell degranulation and immune mediator release, and this is linked to inhibition of the PI3K/Akt signaling axis and Akt phosphorylation/activation, including Akt phosphorylation (Ser473).
The disclosed pharmacology and pharmacokinetics support efficacy concepts associated with inhibition of signaling pathways and inhibition of mast cell degranulation, including in models referenced in the document. The document reports anti-inflammatory efficacy in Th1/DTH and allergic contact dermatitis models, inhibition of TNF-α and IL-6 from LPS-stimulated PBMCs, low cytotoxicity, and pharmacokinetic behavior across polymorphic forms of compound 1a.
Claims Coverage
The independent claim covers a class of compounds of formula 1, including pharmaceutically acceptable salts, solvates, and prodrugs, with specified structural constraints. The main inventive features are the formula-1 scaffold defined by R1, the ring-forming relationship of R2/R3 with X+, and the substitution patterns for R4 and R5.
Formula 1 compound with defined ring-forming substituents
A compound of formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2 and R3 are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, wherein said ring is optionally substituted with one or more groups independently selected from —OH, —O(C1-3 alkyl), —O—C(O)—(C1-3 alkyl), C1-3 alkyl, —NH2, —NH(C1-3 alkyl) or —N(C1-3 alkyl)(C1-3 alkyl), and wherein X is N+.
C10-20 hydrocarbon substituent and R4 substitution pattern
The compound of formula 1 is defined such that R1 is a C10-20 hydrocarbon group; and R4 is a C3-6 alkylene group substituted with one or more groups independently selected from —OH, —O(C1-3 alkyl), —O—C(O)—(C1-3 alkyl), —O—C(O)—O(C1-3 alkyl), —O—C(O)—NH2, —O—C(O)—NH(C1-3 alkyl), —O—C(O)—N(C1-3 alkyl)(C1-3 alkyl), —O(CH2)2OH or —O(CH2)3OH.
R5 phosphate-related substituent options
The compound of formula 1 is defined such that R5 is selected from —PO3H−, —PO3^2−, —PO3H2, —PO2(OC1-3 alkyl), —PO2H(OC1-3 alkyl), or —PO(OC1-3 alkyl)2.
Across the independent claim, the inventive subject matter is a formula-1 compound family characterized by a C10-20 hydrocarbon R1, a pyrrolidine/piperidine/azepane ring formed by linked R2 and R3 together with X+ and optionally substituted with selected groups, a C3-6 alkylene R4 bearing selected substituents, and an R5 chosen from defined phosphate-related options.
Stated Advantages
Low cytotoxicity.
Anti-inflammatory efficacy comparable to dexamethasone in Th1/DTH and allergic contact dermatitis models.
Inhibition of TNF-α and IL-6 from LPS-stimulated PBMCs.
Mast-cell stabilizing activity through inhibition of mast cell degranulation and immune mediator release.
Documented Applications
Treating, preventing, or ameliorating dermatologic disorders including psoriasis, atopic dermatitis, and contact dermatitis.
Treating, preventing, or ameliorating inflammatory bowel disease including Crohn’s disease and ulcerative colitis.
Treating, preventing, or ameliorating respiratory diseases including asthma, allergic asthma, and lung fibrosis.
Treating, preventing, or ameliorating autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and autoimmune hepatitis.
Treating, preventing, or ameliorating neoplastic/dysplastic disorders including cancer and neoplasia.
Treating, preventing, or ameliorating ocular conditions including dry eye disease and diabetic macular edema.
Treating, preventing, or ameliorating allergic and hypersensitivity disorders including anaphylaxis, food allergy, urticarias (including acute urticarias and chronic urticarias), and allergic conjunctivitis.
Treating, preventing, or ameliorating immune-mediated conditions including graft-versus-host disease, host-versus-graft disease, and transplant rejection.
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