Pyridine derivatives and their use as sodium channel activators
Inventors
Lofstrand, Verner Alexander • Kim, Jung Yun • Clement, Helen • Burford, Kristen Nicole • Charifson, Paul • Johnstone, Shawn • SABBATANI, Juliette • Scholtes, Jan Felix • Zhang, Wei • Sun, Shaoyi
Assignees
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Publication Number
US-12054486-B2
Publication Date
2024-08-06
Expiration Date
Abstract
The present disclosure is directed to compounds of formula (1):wherein X, Y, R1, R2 and R3 are as described herein, as stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, and pharmaceutical compositions comprising the compounds of formula (I), as described herein, which are useful as voltage-gated sodium channel modulators and are therefore are useful in treating seizure disorders such as epilepsy.
Core Innovation
The invention relates to compounds of formula (I), including stereoisomers, enantiomers, tautomers, mixtures thereof, and pharmaceutically acceptable salts or solvates of the compounds. The compounds are defined by the relationships of X and Y, where X is C(R9) or N and Y is C(R9) or N, with the proviso that X is not N when Y is N and Y is not N when X is N. The scope further depends on selected substituent variables R1 through R12, with constraints on allowed group types and on conditions for ring formation by adjacent substituents.
The structural definition includes a substituted scaffold featuring variable linker and substituent groups, in which R1 and R2 are selected from defined classes and each n is independently 1, 2 or 3 and each m is independently 1 or 2. R3 is selected from a group of structures defined by whether a double or single bond is present and by the value of p, independently 1, 2, 3, or 4. The definition specifies allowed forms of substituents R6 and R7, including optionally substituted aryl and aralkyl, O-heterocyclyl, and cycloalkyl options, and includes a condition that when a particular selection is made for R3, then at least one of R6 and R7 is not hydrogen.
The disclosed compound class is further associated with pharmaceutical use, because methods for treating a disease or condition in a mammal are claimed in which a therapeutically effective amount of a compound of formula (I) modulates a voltage-gated sodium channel. The treatment scope is defined by selecting diseases or conditions from a listed group that includes epilepsy, seizure disorders, Dravet syndrome, and additional neurological and psychiatric disorders. In addition, a pharmaceutical composition is claimed that comprises a pharmaceutically acceptable excipient and the compound of formula (I), including the stereochemical and salt or solvate variants.
Claims Coverage
The independent claims cover compounds of formula (I) with extensive structural constraints, a pharmaceutical composition comprising an excipient and the formula (I) compound, and a treatment method based on administering a therapeutically effective amount to modulate a voltage-gated sodium channel. Across the claims, the core inventive features are organized into three inventive aspects.
Compound of formula (I) with defined X and Y relationship
A compound of formula (I), including stereoisomers, enantiomers, tautomers, mixtures thereof, and pharmaceutically acceptable salts or solvates, wherein X is C(R9) or N and Y is C(R9) or N, with the proviso that X is not N when Y is N and Y is not N when X is N.
Substituent-defined R1–R12 framework
The compound of formula (I) with R1 and R2 selected from defined classes, each n independently 1, 2 or 3 and each m independently 1 or 2, and R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 defined by the enumerated substituent options and integer ranges, including optional ring-forming relationships.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I), including stereoisomers, enantiomers, tautomers, mixtures thereof, and pharmaceutically acceptable salts or solvates, with the stated X/Y relationship and substituent constraints.
Treatment method by administering a therapeutically effective amount
A method for treating a disease or condition in a mammal by administering a therapeutically effective amount of a compound of formula (I) to modulate a voltage-gated sodium channel.
The claim coverage centers on formula (I) compounds defined by detailed X/Y linkage rules and substituent constraints for R1–R12, together with a pharmaceutical composition containing such a compound and a treatment method in which administration to a mammal modulates a voltage-gated sodium channel.
Stated Advantages
Provides pharmaceutical compositions comprising a compound of formula (I) formulated with pharmaceutically acceptable excipients.
Covers multiple dosage forms and multiple administration routes.
Includes combination therapy with sodium-channel–acting agents.
Includes kit-of-parts packaging and instructions.
Includes prodrugs or protected derivatives and isotopically labeled compounds.
Includes bioavailability and therapeutically effective amount language, with example dose ranges.
Not explicitly described in patent.
Documented Applications
Use of compound(s) of formula (I) for treating diseases or conditions by administering a therapeutically effective amount to modulate a voltage-gated sodium channel.
Treatment of diseases or conditions including epilepsy, seizure disorders, partial seizures, generalized seizures, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, Dravet syndrome, Lennox-Gastaut syndrome, multiple sclerosis, schizophrenia, autism, Alzheimer’s disease, tauopathies, Parkinsonism, and posttraumatic stress disorders.
Combination therapy use with sodium-channel–acting agents.
Treating a disease or condition in a mammal by administering a therapeutically effective amount of a compound of formula (I) to modulate a voltage-gated sodium channel.
Treating epilepsy, seizure disorders, Dravet syndrome, and other listed neurological and psychiatric disorders.
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