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-10577328-B2
Publication Date
2020-03-03
Expiration Date
Abstract
The invention relates to a compound 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, multiple myeloma, cancers, neurodegenerative diseases, inflammatory disorders, autoimmune disorders and metabolic disorders.
Core Innovation
The invention relates to a compound of Formula (I) defined by Markush variables R1 to R5, X, Y, m and n, with R1 as halogen and X as C(O) and Y as N. The disclosed scope includes broad substituent options for R2, R3, R4 and R5, including alkyl, alkenyl, alkynyl, NH2, NO2, OH, CN, aryl, heterocyclic, cycloalkyl, phenyl, piperazinyl, pyridinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, indolyl, indazolyl, quinolinyl, azaindolyl, azaindazolyl, deazapurinyl, indanyl, and morpholinoyl groups. The compounds include tautomers, enantiomers, stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts, and the disclosure also describes prodrugs and related derivative forms, including esters and succinic anhydride.
The invention also describes aminonaphthoquinone and benzamide-type embodiments within the Formula (I) framework, including specific compound examples and internal code identifiers such as MPT0L016, MPT0L018, MPT0L056, and examples 11 to 37. These examples show variation of the disclosed scaffold by changing substituents and heteroaryl amine components such as aminothiazole, aminobenzimidazole, aminophenol/aniline derivatives, aminoindoles, aminoquinolines, aminoindazoles, aminoquinazolines/azaindoles, aminopyrazoles, and cycloalkylamine substituents. The disclosure states that these examples are consistent with the broad Formula (I) substituent scope.
For the specific compound MPT0L056, the disclosure reports blocking of ITCH self-ubiquitination in a lysine-dependent manner, protein kinase binding to multiple listed kinases, growth inhibition across multiple cancer cell lines, and in vivo antitumor activity in xenograft tumor models including RPMI8226 multiple myeloma, MDA-MB-231 breast cancer, and A2780 ovarian cancer. The disclosure further reports additional efficacy in colorectal cancer using HCT116, including MPT0L056 alone and in combination with the HDAC inhibitor MPT0E028, as well as anti-inflammatory and immune effects including IL-6 suppression in RAW264.7 and RA-FLS cells and anti-arthritis efficacy in an adjuvant-induced arthritis rat model.
Claims Coverage
The independent claims cover a Formula (I) compound class with defined substituent and linkage options, together with therapeutic methods and combination pharmaceutical compositions. The claim set includes one broad compound claim and dependent claims that narrow the Formula (I) scope, recite specific substituted embodiments, and specify use in multiple myeloma or colorectal adenocarcinoma, plus combination therapy with defined second therapeutic agent categories.
Formula (I) compound class with variable substituents
A compound of Formula (I) wherein R1 is halogen; R2 is selected from H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, NO2, C1-10 alkyloxy, C1-10 alkylthio, C1-10 alkylamino, C1-10 alkyloxyC1-10 alkyl, OH or CN, and C6-10 aryl or C5-7 heterocyclic having 1 to 3 heteroatoms selected from N, O and S; R3 is selected from H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, NO2, OH or CN; and R4 is selected from H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, NH2, NO2, OH and CN.
Defined R5 substituent options
R5 is OH, C3-8 cycloalkyl, or phenyl unsubstituted or substituted with one to three groups selected from OH, CN, halogen, NH2 or C1-4 alkylpiperazinyl, with additional options including C1-6 alkylpiperazinyl, C1-6 alkylpyridinyl, C1-6 alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazapurinyl, indanyl, morpholinoyl or C1-4 alkylmorpholinoyl, each optionally further substituted by OH, CN, halogen, NO2, C1-4 alkyl, or NH2.
Defined linkage and integer parameters
X is C(O), Y is N, m is an integer of 0-3, and n is an integer of 1-7.
Included stereochemical and salt forms
The compound is covered as a tautomer, enantiomer, stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.
Therapeutic treatment of multiple myeloma or colorectal adenocarcinoma
A method of therapeutically treating multiple myeloma or colorectal adenocarcinoma by administering an effective amount of the compound of claim 1 to a cell or a subject.
Combination pharmaceutical compositions with defined second therapeutic agents
A pharmaceutical composition wherein the second therapeutic agent is selected from mitotic inhibitors including vinca alkaloids and vepesid, anthracycline antibiotics, nucleoside analogs, EGFR inhibitors, folate antimetabolites, cisplatin/carboplatin, or HDAC inhibitors, and another composition wherein the second therapeutic agent is selected from corticosteroid, keratolytic agent, vitamin D3 derivative, PUVA, anthralin, alpha2-agonist, immunosuppressant, NSAID, COX-2 inhibitor, non-steroidal calcineurin inhibitor, steroidal anti-inflammatory agent, 5-amino salicylic acid, DMARD, hydroxychloroquine sulfate, inflammatory modulator, agent that interferes with B cell action, or penicillamine.
The claims center on a broad Formula (I) compound class with halogenated R1, variable R2 to R5 substituents, fixed linkage features X = C(O) and Y = N, integer parameters m and n, and coverage of tautomers, stereoisomers, solvates, and salts. The claim set also covers therapeutic use for multiple myeloma and colorectal adenocarcinoma and combination pharmaceutical compositions with defined cancer and anti-inflammatory or immune-modulating second therapeutic agents.
Stated Advantages
Efficiently blocks ITCH self-ubiquitination (Lys-dependent).
Significant tumor growth inhibition in an RPMI8226 multiple myeloma xenograft model.
Complete regression in mice.
No significant body-weight loss.
Significant antitumor activity in xenograft tumor models, with some complete regressions.
Growth inhibition across multiple cancer cell lines.
IL-6 suppression in RAW264.7 and RA-FLS cells.
Reduced paw swelling and prevention of bone mineral density/content loss in the adjuvant-induced arthritis rat model.
Low cytotoxicity is stated.
Documented Applications
Therapeutically treating multiple myeloma.
Therapeutically treating colorectal adenocarcinoma.
Combination pharmaceutical compositions using the compound of Formula (I) together with a specified second therapeutic agent category (including named categories such as mitotic inhibitors, anthracycline antibiotics, nucleoside analogs, EGFR inhibitors, folate antimetabolites, cisplatin/carboplatin, or HDAC inhibitors).
Combination pharmaceutical compositions using the compound of Formula (I) together with a specified second therapeutic agent category focused on anti-inflammatory and immune-modulating therapies (including corticosteroid, PUVA, NSAID, COX-2 inhibitor, DMARD, hydroxychloroquine sulfate, inflammatory modulator, and others listed).
Use in in vivo xenograft antitumor activity in RPMI8226 multiple myeloma, including significant tumor growth inhibition and complete regression in mice.
Therapeutic treatment of multiple myeloma by administering an effective amount of the compound of claim 1 to a cell or a subject.
Therapeutic treatment of colorectal adenocarcinoma by administering an effective amount of the compound of claim 1 to a cell or a subject.
Combination use with an HDAC inhibitor (MPT0E028) in colorectal cancer efficacy involving HCT116.
Anti-inflammatory and immune effects via IL-6 suppression in RAW264.7 and RA-FLS cells.
Anti-arthritis efficacy in an adjuvant-induced arthritis rat model, including reduced paw swelling and prevention of bone mineral density/content loss.
Antitumor activity in xenograft tumor models including RPMI8226 multiple myeloma, MDA-MB-231 breast cancer, and A2780 ovarian cancer.
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