Sulphonylpyrroles as inhibitors of HDACs novel sulphonylpyrroles
Inventors
Maier, Thomas • Beckers, Thomas • Hummel, Rolf-Peter • Feth, Martin • MUELLER MATTHIAS, null • Müller, Matthias • BAER THOMAS, null • Bär, Thomas • VOLZ JUERGEN, null • Volz, Jürgen
Assignees
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Publication Number
US-8232297-B2
Publication Date
2012-07-31
Expiration Date
Abstract
Compounds of a certain formula I, in which R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in the description, as well as salts thereof are novel effective HDAC inhibitors.
Core Innovation
The document describes specific (E)-configured N-hydroxy acrylamide compounds and related pyrrolosulfonamide compounds, together with salt forms. The core chemical structures are exemplified by (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, (E)-N-hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzene sulfonyl]-1H-pyrrol-3-yl)-acrylamide, (E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, and (E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide.
The salt concept is implemented by forming the compounds with an acid selected from a long list of inorganic and organic acids, or with a base selected from a list of salts including sodium salt, guanidinium salt, lithium salt, magnesium salt, calcium salt, potassium salt, ferric salt, ammonium salt, and triethylammonium salt. The document further provides salts and pharmaceutical forms that are used as described in the therapeutic claims and dependents.
The disclosed compounds are described as histone deacetylase inhibitors (HDAC inhibitors), inducing hyperacetylation and thereby altering gene expression, leading to cell cycle arrest, differentiation and/or apoptosis. The document links these biological effects to therapeutic use in neoplasia/cancer and other HDAC-sensitive diseases, supported by assay readouts including histone H3 acetylation and cytotoxicity/apoptosis measurements.
Claims Coverage
The independent claim coverage is centered on salt forms of particular (E)-configured N-hydroxy acrylamide/pyrrolosulfonamide compounds, with the salt being defined by either an explicitly listed acid or an explicitly listed base. The provided dependent-claim summaries further indicate refinements to particular salt pairings and expanded therapeutic use in cancer treatment, including combination therapy with anti-cancer agents and enumeration of target-specific anti-cancer therapeutic classes.
Salt of specified (E)-configured N-hydroxy acrylamide/pyrrolosulfonamide compound
A salt of a compound selected from the group consisting of (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, (E)-N-hydroxy-3-(1-[4-(([2-(1H-indol-2-yl)-ethyl]-methyl-amino)-methyl)-benzene sulfonyl]-1H-pyrrol-3-yl)-acrylamide, (E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, and (E)-N-hydroxy-3-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide, with an acid selected from a specified group or with a base selected from a specified group.
The independent claim coverage is centered on salt forms of particular (E)-configured N-hydroxy acrylamide/pyrrolosulfonamide compounds, with the salt being defined by either an explicitly listed acid or an explicitly listed base. The provided dependent-claim summaries further indicate refinements to particular salt pairings and expanded therapeutic use in cancer treatment, including combination therapy with anti-cancer agents.
Stated Advantages
The patent states that the specified salts of specific E-configured N-hydroxyacrylamide sulphonylpyrroles have advantageous properties.
Inhibits histone deacetylase (HDAC) activity.
Induces hyperacetylation.
Alters gene expression.
Leads to cell cycle arrest.
Induces differentiation and/or apoptosis.
Supports therapeutic use in neoplasia/cancer and other HDAC-sensitive diseases.
Provides combination therapy with standard anti-cancer agents and other anti-cancer agents.
Documented Applications
Methods for treating cancer by administering a therapeutically effective and tolerable amount of a salt to a patient.
A method for treating lung cancer by administering a therapeutically effective amount of a mesilate salt to a patient in need thereof.
Therapeutic combinations in which the first active ingredient comprises at least one salt as defined, combined with a second active ingredient comprising at least one anti-cancer agent selected from chemotherapeutic and target-specific anti-cancer agents for use in therapy.
Therapeutic use in neoplasia/cancer and other HDAC-sensitive diseases, as HDAC inhibitors that induce hyperacetylation and alter gene expression leading to cell cycle arrest, differentiation and/or apoptosis.
Combination therapy using the disclosed salt as a first active ingredient together with a second active ingredient that is at least one anti-cancer agent, using separate, sequential, simultaneous, concurrent, or chronologically staggered use in therapy.
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