Phenyl carbamate compounds for use in preventing or treating pediatric epilepsy and epilepsy-related syndromes
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Publication Number
US-9956197-B2
Publication Date
2018-05-01
Expiration Date
Abstract
The present invention provides a pharmaceutical composition for preventing and/or treating a pediatric epilepsy or epilepsy-related syndrome comprising the phenyl carbamate compound as an active ingredient, and a use of the phenyl carbamate compound for preventing and/or treating pediatric epilepsy or pediatric epilepsy-related syndromes.
Core Innovation
The document discloses substituted phenyl carbamate compounds in which a substituted phenyl group is carried by carbamate functionality to form hydroxyalkyl carbamates or carbonates. The examples include 2-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, and 2-iodophenyl variants, together with hydroxypropyl, hydroxybutyl, hydroxyhexyl, and hydroxy-3-methyl-butyl chain selections. Regioisomeric monocarbamates and stereoisomeric forms, including racemates and specific enantiomer or diastereomer forms, are described among the synthesized compounds.
The examples further describe synthesis of carbamates from substituted diols and related starting materials, with isolation, purification by silica gel column chromatography, and characterization data including 1H NMR data and yields. The compound set includes N-substituted carbamates such as N-methyl, N-propyl, N-isopropyl, N-cyclopropyl, N-cyclohexyl, and related benzyl or bicycloheptane-substituted variants. The described examples are presented as a structured chemical scope across the compound series.
The patent also links the phenyl carbamate compound series to pediatric epilepsy or pediatric epilepsy-related syndrome treatment. The stated problem is treatment of pediatric epilepsy in pediatric subjects, and the described compound selection covers specific chemical formula 1 embodiments, including stereochemical forms and named substituted phenyl carbamates, within this treatment framework.
Claims Coverage
The claims cover a pediatric treatment method using a therapeutically effective amount of a chemical formula 1 compound or a pharmaceutically acceptable salt. One independent claim is directed to the method, and dependent claims refine the compound definition, stereochemical form, substituent options, and named pediatric epilepsy or pediatric epilepsy-related syndrome selections. The inventive features include administering chemical formula 1 compounds to pediatric subjects in need of treatment and constraining the chemical-variable structure with a specific proviso for 2-chloro substitution.
Therapeutically effective administration of chemical formula 1 for pediatric epilepsy
A method of treating pediatric epilepsy or pediatric epilepsy-related syndrome in a pediatric subject by administering a therapeutically effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, where X is a halogen, n is an integer from 1 to 5, R1 is a linear or branched alkyl group of C1-C4, A is a carbamoyl group represented by the specified structure, and R2 is selected from hydrogen, a linear or branched alkyl group of C1-C4, a cycloalkyl group of C3-C8, and benzyl, with the proviso that R1 is methyl, propyl or butyl when at least one X is 2-chloro.
Stereochemical form selection of the phenyl carbamate compound
The method specifies that the phenyl carbamate compound is present in one of several stereochemical forms, including racemate, specific enantiomer(s), diastereomer(s), or mixtures thereof.
Constrained variable options for halogen and substituent selections
The method specifies X as one of chlorine, fluorine, iodine, or bromine, n as 1 or 2, and R2 and R3 each independently selected from hydrogen or various named hydrocarbon groups including methyl, propyl, isopropyl, cyclopropyl, cyclohexyl, bicycloheptane, and benzyl.
Selected substituted phenyl carbamate compounds for treatment
The method is carried out using a phenyl carbamate compound selected from a specified group of substituted phenyl carbamates, including explicitly named examples such as 1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate, 1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate, 1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate, 1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate, 1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamate, and related named 2,3-, 2,4-, and 2,6-dichloro phenyl carbamate variants.
Selection of stereoisomeric and N-substituted phenyl carbamate variants
The method selects the phenyl carbamate compound from a specified group of 2-chlorophenyl, 2-fluorophenyl, and 2-iodophenyl carbamate variants including different stereoisomers and racemates, including N-methyl, N-propyl, N-isopropyl, N-cyclopropyl, and N-cyclohexyl substituted forms and hydroxypropyl or hydroxybutyl groups.
Selection of named pediatric epilepsy or epilepsy-related syndromes
The method further selects pediatric epilepsy or a pediatric epilepsy-related syndrome from a specified group of named epilepsy types and syndromes, including Benign Myoclonic Epilepsy (BME), Severe Myoclonic Epilepsy of Infancy Borderland (SMEB), Severe Infantile Multifocal Epilepsy (SIMFE), Intractable Childhood Epilepsy with Generalized Tonic Clonic Seizures (ICE-GTC), Dravet syndrome (Ds), Severe Myoclonic Epilepsy of Infancy (SMEI), and other listed pediatric epilepsy conditions and syndromes.
The claims cover a pediatric treatment method by administering a therapeutically effective amount of a chemical formula 1 phenyl carbamate or pharmaceutically acceptable salt, with dependent claims narrowing the coverage by stereochemical form, constrained halogen and substituent options, selection of explicitly named substituted phenyl carbamates including N-substituted variants, and selection of named pediatric epilepsy or epilepsy-related syndromes.
Stated Advantages
“Remarkably excellent” anti-epilepsy activity
Low toxicity in epilepsy models
Documented Applications
Treatment of pediatric epilepsy or pediatric epilepsy-related syndromes using compounds of chemical formula 1 and pharmaceutically acceptable salts in pediatric subjects.
Use of epilepsy models including a multiple-hit rat model of infantile spasm (IS) and other seizure tests to evaluate anti-epilepsy activity.
Coverage of pediatric epilepsy syndromes by age onset, including Benign Myoclonic Epilepsy of Infancy (BME), Dravet syndrome/SMEI (Ds/SMEI), Lennox-Gastaut syndrome (LGS), West syndromes/infantile spasms, and other listed pediatric epilepsy syndromes.
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