Fused thiophene derivatives and their uses
Inventors
MELDRUM, Eric • DE CHASSEY, BENOÎT • MACHIN, PETER • LANARO, Roberta • Macleod, Calum • Malagu, Karine Fabienne • Proisy, Nicolas • VESEY, DAVID ROBERT • WINSHIP, PAUL COLIN MICHAEL • Chambers, Mark
Assignees
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Publication Number
US-11492347-B2
Publication Date
2022-11-08
Expiration Date
Abstract
The present invention relates to a new class of fused thiophene derivatives and their uses for treating diseases such as infection, cancer, metabolic diseases, cardiovascular diseases, iron storage disorders and inflammatory disorders.
Core Innovation
The invention relates to compounds of formula (I) defined by a substituent framework for X and R3, with R2 fixed as —COOH and n being 0, 1, or 2. X represents —CR1bR1b′, and the R1 substituents independently include hydrogen, halogen, (C1-C6)alkyl, optionally halogen-substituted (C1-C6)alkyl, (C1-C6)alkyloxy, cyano, or an aryl group optionally substituted by halogen, (C1-C6)alkyl, hydroxy, and (C1-C6)alkyloxy. The structure also allows cycloalkyl formation or bridged carbocyclyl formation from pairs of R1 substituents, and includes stereoisomers and pharmaceutical salts.
R3 is defined as a 5-10 membered ring system, saturated or unsaturated, selected from an aryl optionally fused to a dioxole, heteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, and pyrazolyl, cycloalkyl, heterocycloalkyl, or a 5-10 membered bridged carbocyclyl or heterocyclyl. R3 is optionally substituted by halogen, (C1-C6)alkyl optionally halogen-substituted, (C1-C6)alkyloxy, —NH—(C1-C6)alkyl, —N—((C1-C6)alkyl)2, hydroxy, carbonyl-containing substituents such as —NHCOR7 and —NHCO2R7, and heterocycle, heterocycloalkyl/heterocycloalkyloxy/spiroheterocycloalkyl options. The proviso excludes 2-[(4-Chlorobenzoylamino]-6,6-dimethyl-5,7-dihydro-4H-benzothiophene-3-carboxylic acid.
The disclosure includes example compounds and medicinal chemistry schemes describing preparation of benzamido-thiophene-3-carboxylate scaffold intermediates and downstream acid/ester forms. The examples include benzothiophene/cyclopenta[b]thiophene-3-carboxylic acid derivatives with substituted phenyl and amine/heterocycle portions, and provide characterization information such as 1H NMR, LC/MS retention times and MS m/z, and yields for multiple specific compounds.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim defining formula (I) and one independent pharmaceutical composition claim. The main inventive features are the defined X substituent framework with n being 0, 1, or 2, the fixed R2 as —COOH, the constrained and extensively substitutable R3 ring system, inclusion of stereoisomers and pharmaceutical salts, and an explicit exclusion of a named compound.
Compound of formula (I) with defined X and n
X represents —CR1bR1b′, n is 0, 1, or 2, and the R1 substituents independently are hydrogen, halogen, (C1-C6)alkyl optionally substituted by at least one halogen, (C1-C6)alkyloxy, cyano, or an aryl optionally substituted by halogen, (C1-C6)alkyl, hydroxy, and (C1-C6)alkyloxy; selected R1 pairs can form a cycloalkyl or a bridged carbocyclyl, and at least two of the R1 substituents are not hydrogen.
Fixed carboxylic acid substituent R2
R2 represents —COOH.
Defined 5-10 membered ring system R3
R3 represents a 5-10 membered ring selected from an aryl optionally fused to a dioxole, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, cycloalkyl, heterocycloalkyl, or a 5-10 membered bridged carbocyclyl or heterocyclyl, optionally substituted by halogen, (C1-C6)alkyl, (C1-C6)alkyloxy, —NH—(C1-C6)alkyl, —N—((C1-C6)alkyl)2, hydroxy, carbonyl-containing substituents, heterocycle, heterocycloalkyl/heterocycloalkyloxy/spiroheterocycloalkyl options, and related allowed substituent classes.
Stereoisomers and pharmaceutical salts with a specific exclusion
The stereoisomers and pharmaceutical salts thereof are included, with the proviso that the compound of formula (I) is not 2-[(4-Chlorobenzoylamino]-6,6-dimethyl-5,7-dihydro-4H-benzothiophene-3-carboxylic acid.
Pharmaceutical composition with excipient
A pharmaceutical composition that includes a compound as defined in claim 1 together with an acceptable pharmaceutical excipient.
The claim coverage is dominated by the formula (I) compound class defined by X, R2 as —COOH, and the selected 5-10 membered ring system R3 with broad but specified substitution options, together with stereoisomers, pharmaceutical salts, and an explicit exclusion. A separate independent claim covers a pharmaceutical composition comprising the claimed compound and an acceptable pharmaceutical excipient.
Stated Advantages
Compounds can be formulated as pharmaceutical or veterinary compositions for treating infectious/viral and bacterial infections and cancers.
Compounds are described as modulators of NEET proteins (mitoNEET/NAF-1/MiNT; CISD1/2/3).
Stated potential roles include iron storage disorders, aging, neurodegenerative disease, cardiovascular disease, and inflammatory disease.
Documented Applications
Treatment of infectious/viral and bacterial infections.
Treatment of cancers.
Modulation of NEET proteins (mitoNEET/NAF-1/MiNT; CISD1/2/3) with stated potential roles in iron storage disorders, aging, neurodegenerative disease, cardiovascular disease, and inflammatory disease.
Medicinal chemistry schemes describing preparation of benzamido-thiophene-3-carboxylate scaffold intermediates and downstream acid/ester forms.
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