Substituted xanthine derivatives
Inventors
Gerlach, Kai • Eickmeier, Christian • Sauer, Achim • JUST, Stefan • Chenard, Bertrand L.
Assignees
Boehringer Ingelheim International GmbH • Boehringer Ingelheim Pharma GmbH and Co KG
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Publication Number
US-10329292-B2
Publication Date
2019-06-25
Expiration Date
Abstract
The present invention relates to substituted xanthine derivatives, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels.
Core Innovation
The patent describes substituted xanthine derivatives and substituted heterocyclic compounds as TRPC5 antagonists. The compounds inhibit TRPC5-mediated ion flux and TRPC5-mediated inward and outward current, and the reported activity is characterized in vitro using a TRPC5 patch clamp framework with quantitative IC50 and percent block data.
A central theme is improved selectivity versus hERG. The document states that the substituted xanthine derivatives show TRPC5 inhibition while demonstrating reduced hERG interaction, and it relates this selectivity to structural changes versus WO2014/143799, including replacement of C8 phenyl with heteroaryl such as 3-pyridyl and 2-pyrazinyl and use of cyclopropylmethyl-O and difluorocyclopropylmethyl-O substitutions instead of a methoxy group.
The patent also describes compounds and pharmaceutically acceptable salts supported by chemical structures and associated identifiers, including substituted heteroaryl and fused bicyclic cores bearing halogen and cyclopropyl or fused substituents. It further presents preparation and analytical characterization of multiple intermediates and examples, with MS and HPLC data and structural depictions for the corresponding compounds.
Claims Coverage
The provided claim set includes independent claim coverage directed to a compound or pharmaceutically acceptable salt, with dependent claims refining compound identity through chemical structure images and files, and additional claims covering a pharmaceutical composition and a method of treating TRPC5-mediated disorders by administering an effective amount. Four inventive features are explicitly reflected in the combined claim text.
Compound or pharmaceutically acceptable salt
A compound as depicted in the claim text, or a pharmaceutically acceptable salt thereof.
Compound identity defined by chemical structure depictions
The compound is defined by the provided chemical structure images and files.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound together with a pharmaceutically acceptable excipient.
Treating a TRPC5-mediated disorder by administering an effective amount
A method for treating a TRPC5-mediated disorder in a subject by administering an effective amount of the compound, with the disorder selected from enumerated psychiatric, neurological or neurodegenerative, pain, seizure, non-neuronal, cancer, and other listed condition categories.
Across the provided claim text, coverage is anchored to a specified compound or pharmaceutically acceptable salt, defined by chemical structure depictions, and extends to a pharmaceutical composition and a TRPC5-mediated disorder treatment method using an effective amount in a subject for enumerated condition categories.
Stated Advantages
Improved selectivity versus hERG, with potent TRPC5 inhibition alongside reduced hERG interaction.
Potent inhibition of TRPC5-mediated ion flux and TRPC5-mediated inward and outward current, supported by IC50 and percent block data.
TRPC5 inhibition is beneficial for psychiatric conditions, neurological or neurodegenerative conditions, pain, seizures, non-neuronal conditions, and cancer.
Documented Applications
Treatment of a TRPC5-mediated disorder in a subject by administering an effective amount of the claimed compound, including enumerated psychiatric conditions, anxiety and fear-related disorders, memory disorders, disorders associated with impaired impulse control and addiction, and listed neurodegenerative and brain-related conditions.
Use in an in vitro TRPC5 patch clamp assay context for measuring TRPC5-mediated ion flux and current and for comparative evaluation of hERG inhibition.
Using a pharmaceutical composition that includes the compound and a pharmaceutically acceptable excipient.
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