Aminonapthoquinone compounds and pharmaceutical composition for blocking ubiquitination-proteasome system in diseases
Inventors
Yen, Yun • Liou, Jing-Ping • Pan, Shiow-Lin
Assignees
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Publication Number
US-11919858-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The invention relates to compounds of formula (I) with low cytotoxicity for blocking the ubiquitination-proteasome system in diseases. Accordingly, these compounds can be used in treatment of disorders including, but not limited to, cancers.
Core Innovation
The invention relates to therapeutically treating multiple myeloma, colorectal adenocarcinoma, breast cancer or ovarian cancer by administering an effective amount of a compound of Formula (I) to a cell or a subject. Formula (I) includes variable substituents R1, R2, R3, R4 and R5, together with X, Y, m and n, and includes a tautomer, enantiomer, stereoisomer, solvate, or a pharmaceutically acceptable salt thereof.
The compounds are described as aminonapthoquinone compounds of Formula (I), including associated compound exemplars within Formula (I) type scaffolds and related ring fragments such as indole, quinoline, indazole and indazolyl. The disclosure includes broad definitional forms for the compounds, including prodrugs, pharmaceutically acceptable salts, solvates, hydrates, tautomers, isomers, stereoisomers and enantiomers.
The compounds are described as inhibiting the ubiquitination-proteasome system, with inhibition associated with ITCH E3 ligase inhibition and blocking ITCH self-ubiquitination. Biological evaluation in the document includes kinase panel activity, in vitro growth inhibition measurements, in vivo xenograft anti-tumor efficacy studies in nude mice, IL-6 suppression in macrophage cells and RA fibroblast-like synoviocyte cells, and an adjuvant-induced arthritis rat model showing reduced arthritis and preserved bone mineral density.
Claims Coverage
The independent claim set covers 1 method claim for therapeutically treating multiple myeloma, colorectal adenocarcinoma, breast cancer or ovarian cancer by administering an effective amount of a compound of Formula (I), and the claims further define the compound by R1 to R5, X, Y, m and n. Dependent claims narrow the Formula (I) parameter ranges and, in one case, restrict the compound to a specific exemplified substituted benzamide.
Therapeutically treating specified cancers using Formula (I) compounds
A method for therapeutically treating multiple myeloma, colorectal adenocarcinoma, breast cancer or ovarian cancer, comprising administrating an effective amount of the compound of Formula (I) to a cell or a subject, wherein R1 is a halogen; each R2 is defined among specified groups; R3 and R4 are defined among specified groups; R5 is defined among specified hydroxy, cycloalkyl, phenyl, alkylpiperazinyl, alkylpyridinyl, alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazapurinyl, indanyl, morpholinoyl or alkylmorpholinoyl options with optional substituents; X is —C(O)—; Y is —N—; m is an integer of 0-3; and n is an integer of 1-7, or a tautomer, enantiomer, stereoisomer, or a solvate or a pharmaceutically acceptable salt thereof.
Restricting Formula (I) variable values for therapeutic administration
The method uses the Formula (I) compound with particular substituent and parameter values including m=0, X=C(O), R3=H and R4=H, with n being an integer and R1 being a halogen, and R5 restricted to defined groups selected from OH, cycloalkyl and enumerated optionally substituted ring systems, together with tautomers, enantiomers, stereoisomers, solvates and pharmaceutically acceptable salts.
Narrowing Formula (I) by constraining n and enumerating R5 options
The method further specifies selected substituent and parameter values, including a constrained n value range and R5 selected from defined optionally substituted ring/amine-containing options, together with tautomers, enantiomers, stereoisomers, solvates and pharmaceutically acceptable salts.
Using a Formula (I) compound selected from an explicit substituted benzamide list
The method defines the Formula (I) compound as one selected from specified substituted benzamide structures, including any tautomer, stereoisomer, solvate or pharmaceutically acceptable salt of the selected structure.
Using a specific exemplified pyridinyl benzamide derivative
The method uses the Formula (I) compound identified as 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-4-yl)benzamide, or a tautomer, solvate, or pharmaceutically acceptable salt thereof.
Overall, the claims cover therapeutic treating of specified cancers using administration of Formula (I) compounds with defined substituent constraints, further narrowed by fixed parameter values, constrained n ranges, enumerated R5 options, selection from an explicit list of substituted benzamides, and a specific exemplified pyridinyl benzamide derivative.
Stated Advantages
Significant antitumor activity in vivo, including complete regression in mice.
No significant body weight loss in the in vivo studies.
Low cytotoxic inhibition of the ubiquitination-proteasome system.
Inhibition associated with ITCH E3 ligase inhibition, including blocking ITCH self-ubiquitination.
Documented Applications
Therapeutically treating multiple myeloma, colorectal adenocarcinoma, breast cancer or ovarian cancer by administering an effective amount of a Formula (I) compound to a cell or a subject.
Multiple myeloma xenograft anti-tumor efficacy studies in nude mice using an RPMI-8226 multiple myeloma model.
Breast cancer xenograft anti-tumor efficacy studies in nude mice using an MDA-MB-231 breast cancer model.
Therapeutic use for cancer and for autoimmune disorders and inflammatory disorders.
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