Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
Inventors
Fu, Jiping • Lou, Yan • HE, Yigang
Assignees
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Publication Number
US-11420936-B2
Publication Date
2022-08-23
Expiration Date
Abstract
The present disclosure is directed certain Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and their use in the treatment of diseases mediated by HIF-2α such as cancer. Also provided is the use of HIF-2α inhibitors in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. In particular, the present disclosure is directed to methods for the treatment of cancers using a HIF-2α inhibitor in combination with a PARP inhibitor and pharmaceutical compositions comprising the same.
Core Innovation
The disclosure is directed to selected fluorinated benzonitrile compounds comprising a 3-fluoro-5-oxy substitution pattern connected to a stereochemically defined cyclopenta[cd]indene-derived group. The selected compounds are defined by named structural formulas that specify tetrahydro, hydroxy, and hexafluoro characteristics on the cyclopenta[cd]inden moiety.
One selected compound is 3-fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, and another selected compound is the corresponding 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile. The disclosure also includes pharmaceutically acceptable salt forms of these compounds.
A pharmaceutical composition is provided that comprises the selected compound(s) and/or pharmaceutically acceptable salt(s), formulated with pharmaceutically acceptable excipients. The disclosed compounds are further directed to a therapeutic use in which a therapeutically effective amount is administered to treat pulmonary arterial hypertension.
Claims Coverage
The independent claims cover three categories: a compound selection claim, a pharmaceutical composition claim, and a treatment method claim. The core inventive focus is the stereochemically defined hexafluoro cyclopenta[cd]indenyl-hydroxy substituted 3-fluoro-5-oxy benzonitrile scaffold, including the (1R,2R,2aS) and (1R,2S,2aS) variants and pharmaceutically acceptable salts.
Stereochemically defined hexafluoro cyclopenta[cd]indenyl-hydroxy benzonitrile compounds
A compound selected from 3-fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition comprising the stereochemically defined compounds
A pharmaceutical composition comprising a compound selected from 3-fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a pharmaceutically acceptable salt thereof.
Treating pulmonary arterial hypertension with the stereochemically defined compounds
A method of treating pulmonary arterial hypertension comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from 3-fluoro-5-(((1R,2R,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile and 3-fluoro-5-(((1R,2S,2aS)-1,2,3,3,4,4-hexafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.
Overall, the independent claims are directed to selection of two stereochemically defined hexafluoro cyclopenta[cd]indene-derived benzonitrile compounds, pharmaceutical compositions comprising those compounds and/or salts, and administering a therapeutically effective amount of those compounds or salts formulated with a pharmaceutically acceptable excipient to treat pulmonary arterial hypertension.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic targeting of HIF-2α, including cancer and non-oncology indications.
Treating pulmonary arterial hypertension by administering a therapeutically effective amount of the selected stereochemically defined compounds or pharmaceutically acceptable salts in a pharmaceutical composition with a pharmaceutically acceptable excipient.
Treatment of HIF-2α-mediated diseases, including cancer.
Combination therapy involving HIF-2α inhibition and PARP inhibition via effects on hypoxia-related pathways and DNA repair vulnerability.
Potential indications beyond cancer explicitly listed: VHL disease, PAH, reflux esophagitis, NASH, IBD, autoimmune disease, and iron disorders.
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