Compounds and their methods of use
Inventors
Reddy, Kiran • MARTINEZ BOTELLA, Gabriel • Griffin, Andrew Mark • Marron, Brian Edward
Assignees
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Publication Number
US-11918571-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
Core Innovation
The disclosure relates to administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to treat a neurological disorder that is epilepsy or an epilepsy syndrome. The compounds of Formula (I) are defined by constraints on X, Y, and Z as CR, and by a defined aromatic portion A that is phenyl or pyridyl substituted with one or more R3. R is specified as hydrogen or C1-6 alkyl, and R1 is restricted to hydrogen, deuterium, or C1-6 alkyl, with optional substitution patterns for the C1-6 alkyl group.
Further structural constraints define each R3 as independently selected from C1-6 alkyl, C3-8 carbocyclyl, fluoro, chloro, and ORc, with optional substitution by one or more R5 on the C1-6 alkyl and C3-8 carbocyclyl options. Each Rc is independently selected from hydrogen, deuterium, C1-6 alkyl, or C3-8 carbocyclyl, with optional substitution by one or more R6, and each R6 is independently selected from C1-6 alkyl, deuterium, C1-6 haloalkyl, C3-8 carbocyclyl, halogen, cyano, nitro, and OH. Each R5 is independently selected from C1-6 alkyl, deuterium, halogen, oxo, cyano, nitro, and ORc, and each R7 is independently selected from C1-6 alkyl, halogen, and oxo.
The disclosure also characterizes the compounds in pharmaceutical terms, including pharmaceutically acceptable salts, pharmaceutical compositions, and routes of administration such as parenteral injection and oral administration, together with controlled/quick/sustained release concepts. It further states that combination therapy may be employed with other agents, including anti-epilepsy agents and cardiovascular drug classes. The therapeutic coverage described includes specific neurological disorder categories such as epileptic encephalopathy and genetic epilepsy.
Claims Coverage
The independent claims include one treatment method for epilepsy or an epilepsy syndrome using compounds of Formula (I) with defined substituent-variable constraints. The claim scope is governed by multiple inventive structural features specifying the Formula (I) substitution variables and the allowed substituent sets.
Method of treating epilepsy or an epilepsy syndrome with a formula (I) compound
A method of treating a neurological disorder, wherein the neurological disorder is epilepsy or an epilepsy syndrome, comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Defined formula (I) scaffold
X, Y, and Z are each CR, and A is phenyl or pyridyl substituted with one or more R3.
Selected substituent sets
R is hydrogen or C1-6 alkyl; R1 is hydrogen, deuterium, or C1-6 alkyl optionally substituted with R4; R3, R4, R5, Rc, R6, and R7 are each selected from the explicitly recited groups.
Overall, the claim coverage centers on administering Formula (I) compounds, including deuterium-containing options, with defined substituent selection rules for X, Y, Z, A, and the R-group variables to treat epilepsy or an epilepsy syndrome.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a neurological disorder that is epilepsy or an epilepsy syndrome by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
Patch-clamp electrophysiology on HEK-293 cells expressing human NaV1.6 using an INaL assay with ATX-II, with qualitative inhibition categories A/B/C.
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