Compounds and pharmaceutical composition associated with ubiquitination-proteasome system
Inventors
Yen, Yun • Liou, Jing-Ping • Pan, Shiow-Lin
Assignees
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Publication Number
US-10745350-B2
Publication Date
2020-08-18
Expiration Date
Abstract
The invention relates to new compounds with low cytotoxicity for blocking ubiquitination-proteasome system in diseases. Accordingly, these compounds can be used in treatment of treating disorders including, but not limited to, cancers, neurodegenerative diseases, inflammatory disorders and autoimmune disorders and metabolic disorders.
Core Innovation
The invention relates to compounds having Formula (I), with defined substituents R1-R6, a defined core linkage X, and parameters m and n. The substituent definitions include halogen, alkyl, alkenyl, alkynyl, amino, nitro, hydroxyl, cyano, alkoxy, alkylthio, alkylamino, aryl, and heterocyclic groups, with defined heteroatom-count limits, and the scope also includes fused bicyclic ring possibilities for R4 and alkylene-R6 forms for R5.
The compound scope further covers a tautomer or stereoisomer thereof, as well as a solvate, prodrug, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts include acid addition salts and basic salts, including inorganic and organic acid addition salts and pharmaceutically acceptable counterions or cations.
The disclosed compounds are described as designed to block the ubiquitination-proteasome system with low cytotoxicity and are particularly related to inhibition of ITCH E3 ligase. The examples describe 2-chloro naphthalene-1,4-dione derivatives, including amino-naphthalene-1,4-dione cores formed with indoles, heteroaryl amines, substituted indolinylamino groups, quinolinylamino substitution, isoindolinylamino substitution, benzamide products, and piperazinylbenzylamino substitutions.
Therapeutic applications are described for the compounds and compositions, including cancer, autoimmune/inflammatory disorders, neurodegenerative diseases, metabolic disorders, and other disease areas. The disclosure also provides pharmaceutical compositions containing the compounds.
Claims Coverage
The provided claim set centers on one independent claim for a broad Formula (I) compound and includes related forms and pharmaceutical compositions. A total of four inventive features are represented across the provided claims content.
Formula (I) compound definition
A compound having Formula (I) with R1-R5 defined by extensive substituent options, X defined as —C(O), —S(O)2—, or —NH—C(O)—, and m and n defined as integers within the stated ranges.
Tautomer, stereoisomer, solvate, prodrug or pharmaceutically acceptable salt coverage
The compound of Formula (I) is also defined to include a tautomer or stereoisomer thereof, or a solvate, prodrug, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
Combination pharmaceutical composition with a second therapeutic agent
The pharmaceutical composition further comprises a second therapeutic agent.
Coverage centers on a broad Formula (I) chemical space with extensive substituent and ring constraints, extends to tautomers, stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts, and includes pharmaceutical compositions with a pharmaceutically acceptable carrier and optionally a second therapeutic agent.
Stated Advantages
Low cytotoxicity.
Documented Applications
Therapeutic indications described for neoplastic diseases (cancer), neurodegenerative diseases such as ALS, Parkinson's disease, Alzheimer's disease, and Huntington's disease, inflammatory disorders, autoimmune disorders, and metabolic disorders including IDDM and multiple sclerosis.
Biological evaluation includes blocking ITCH self-ubiquitination and effects involving IL-6.
In vitro contexts described using cell lines including HL-60, HCT-116, MDA-MB-231, Hep3B, RAW264.7, and human RA-FLS cells.
In vivo evaluation is described using an adjuvant-induced arthritis model, including measurement approaches referenced by the patent including micro-CT.
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