N-sulphonylpyrroles and their use as histone deacetylase inhibitors
Inventors
Maier, Thomas • Bär, Thomas • Beckers, Thomas • Zimmermann, Astrid • Schneider, Siegfried • Gekeler, Volker
Assignees
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Publication Number
US-8815855-B2
Publication Date
2014-08-26
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, are novel effective HDAC inhibitors.
Core Innovation
The invention concerns novel N-sulphonylpyrrole derivatives defined by formula (I) and a ring-system definition Ia. The compounds have a substituent-variable system in which R1-R6 are extensively variable, including R6 being -T1-Q1, and Q1 being selected from Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, with further defined substitution options. R7 is defined as hydroxyl or 2-aminophenyl, and the compounds include pharmaceutically acceptable salts.
Within formula (I), the terminal ring substituent options are specified, including that Q1 may be unsubstituted or substituted by R61 and/or R62 on the terminal ring. The variable definitions describe cases where T2 is a bond, methylene, dimethylene or trimethylene, and R61 is selected from methyl, methoxy, hydroxyl, trifluoromethyl, hydroxymethyl, methylsulphonylamino, methylcarbonylamino, dimethylaminosulphonyl, and other listed substituent patterns. The substituent system also includes formation of heterocyclic ring Het1 and Het2 with Het1 and Het2 selected from morpholino, piperidino, pyrrolidino, piperazino and 4-methyl-piperazino.
The invention states that the N-sulphonylpyrrole derivatives of formula (I) are effective histone deacetylase (HDAC) inhibitors. The document frames histone deacetylation as part of the histone code involving histone proteins H2A/B, H3 and H4, and it positions the disclosed derivatives as agents that inhibit HDAC activity. The compounds are therefore presented as anti-cancer/anti-neoplasia agents by virtue of their HDAC inhibitory activity.
Claims Coverage
The independent claims cover treating cancer or benign neoplasia by administering a therapeutically effective and tolerable amount of a compound of formula I, with highly specific substituent constraints that define the main structural scope through R1-R6 and R7.
Treating cancer or benign neoplasia by administering formula I derivatives
A method for treating cancer or benign neoplasia comprising administering to a patient a therapeutically effective and tolerable amount of a compound of formula I, or a salt thereof, in which R1-R5 are hydrogen, R6 is -T1-Q1 with T1 a bond, and Q1 is selected from Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or Q1 is unsubstituted with further restrictions on Ha2/Ha3/Ha4. R7 is hydroxyl or 2-aminophenyl.
Defined R6 = -T1-Q1 substituent system with Het1/Het2 terminal-ring constraints
The formula I compound is limited such that R6 is -T1-Q1 where Q1 is substituted or unsubstituted, and where R61 is one of the listed options, including patterns that, together with inclusion of the nitrogen atom, form a heterocyclic ring Het1, and similarly R613/R614 can form a heterocyclic ring Het2. Het1 and Het2 are restricted to morpholino, piperidino, pyrrolidino, piperazino or 4-methyl-piperazino, and T2/T3/T4/T5 are each constrained to be bonds or specific carbon chain lengths.
HDAC inhibitor compound of formula I in specified cancer treatment scope
The method targets cancer types as enumerated in the independent claim, comprising treating selected cancers and benign neoplasia by administering the defined formula I compound that is characterized in the document as an effective histone deacetylase (HDAC) inhibitor, with the compound structure limited by the specified R1-R6 and R7 definitions.
The inventive scope centers on administering a therapeutically effective and tolerable amount of a defined N-sulphonylpyrrole compound of formula I, including pharmaceutically acceptable salts, to treat enumerated cancer and benign neoplasia categories. The core structural restrictions are the fixed hydrogen substituents at R1-R5, the constrained -T1-Q1 definition at R6 including the allowed Q1 radicals and terminal-ring substitution patterns that generate Het1/Het2, and R7 being hydroxyl or 2-aminophenyl.
Stated Advantages
Compounds of formula I are effective histone deacetylase (HDAC) inhibitors.
A therapeutically effective and tolerable amount is administered to treat cancer or benign neoplasia.
Documented Applications
Treating cancer or benign neoplasia by administering a therapeutically effective and tolerable amount of a compound of formula I, with cancer types enumerated in the claims.
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