Substituted xanthines as inhibitors of transient receptor potential cation channel subfamily c, member 5 activity
Inventors
Assignees
Hydra Bioscienes LLC • Boehringer Ingelheim International GmbH
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Publication Number
US-11198696-B2
Publication Date
2021-12-14
Expiration Date
Abstract
The present invention relates to compounds of formula I a process for their manufacture, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels. R1, R2, R3, R4 and R5 have meanings given in the description.
Core Innovation
The invention is directed to compounds of formula I, or pharmaceutically acceptable salts thereof, defined by specific substituent selections for R1, R2, R3, R4, and R5. The substituent options include ethyl, isopropyl, isobutyl, or cyclobutyl for R1; multiple benzyl or substituted benzyl groups for R2; hydrogen, fluoro, or C1-C3 alkyl optionally substituted with one or more fluoro substituents for R3; hydrogen or fluoro for R4; and an oxygen-attached substituent pattern for R5, with * denoting the point of attachment to the oxygen atom.
The compounds are identified as TRPC5 inhibitors and are described as modulating TRPC5 by inhibiting TRPC5-mediated ion flux and/or inward current and/or outward current. The subject matter addresses the need for compounds that inhibit TRPC5 activity in a subject, including for TRPC5-mediated disorders, and the disclosed therapeutic use includes administration of a formula I compound or pharmaceutically acceptable salt thereof.
The disclosure also includes selected compounds from the claimed formula embodiments and provides synthetic preparation and characterization of intermediates and examples corresponding to the TRPC5-targeting scaffold designs. The partial content reports analytical characterization by MS and HPLC retention times, and notes that example compounds show potency/activity values in a low nanomolar range.
Claims Coverage
The independent claim coverage centers on one broad formula I compound definition and method-of-use coverage for inhibiting TRPC5 activity in a subject. Across the provided claims, the inventive features are the formula-defined compounds with enumerated substituent options, selected compounds from a recited group, and administration of an effective amount to inhibit TRPC5 activity, with some claim coverage limited to specified TRPC5-mediated disorder categories.
Formula I compound with defined R1-R5 substituent options
A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R1 represents ethyl, isopropyl, isobutyl, or cyclobutyl; R2 represents one of multiple specified benzyl or substituted benzyl groups; R3 represents hydrogen, fluoro, or C1-C3 alkyl optionally substituted with one or more fluoro substituents; R4 represents hydrogen or fluoro; and R5 is a substituent pattern with * as the point of attachment to an oxygen atom, optionally substituted with fluoro and C1-C3 alkyl, with each C1-C3 alkyl optionally fluoro-substituted.
Selected formula compound group
A compound selected from the group consisting of formula-based embodiments, or a pharmaceutically acceptable salt thereof.
TRPC5 activity inhibition by administration
A method of inhibiting TRPC5 activity in a subject by administering an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.
TRPC5-mediated disorder treatment selection
The TRPC5 inhibition method is applied to subjects having TRPC5-mediated disorders, including neurodegenerative, neurological, or psychiatric disorder categories, and narrower selections such as borderline personality disorder, major depression, major depressive disorder, and post-traumatic stress disorder.
The claim coverage is centered on formula-defined compounds of the TRPC5-targeting scaffold and their use in methods of inhibiting TRPC5 activity. The claims also recite selected compounds from a group and limit treatment to TRPC5-mediated disorder contexts, including specified psychiatric disorder selections.
Stated Advantages
Higher TRPC5 inhibition potency is stated relative to WO 2014/143799.
Compounds modulate TRPC5 by inhibiting TRPC5-mediated ion flux and/or TRPC5-mediated inward current and/or TRPC5-mediated outward current.
Some example compounds are associated with potency/activity values in a low nanomolar range.
Documented Applications
Treating or preventing TRPC5-associated conditions by administering a compound of formula I or a pharmaceutically acceptable salt thereof.
Treating a TRPC5-mediated disorder by administering a compound of formula I or a pharmaceutically acceptable salt thereof.
Inhibiting TRPC5 activity in a subject by administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
Treatment of a subject with a disorder mediated by TRPC5, including neurodegenerative, neurological, or psychiatric disorders.
Treatment of borderline personality disorder, major depression, major depressive disorder, or post-traumatic stress disorder.
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