WO2021231933A1 - Anti-epileptic pharmaceutical compositions and use thereof - Google Patents

Abstract

Compositions and methods for treating epilepsy in its various forms, which reduce the frequency, severity, or duration of seizure, are disclosed. Dosages, formulations, and routes of administration are also provided.

Description

ANTI-EPILEPTIC PHARMACEUTICAL COMPOSITIONS AND USE

THEREOF

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/025,813, filed May 15, 2020, which is incorporated herein by reference in its entirety.

FIELD

[0002] The herein disclosed embodiments relate to novel anti-epileptic pharmaceutical compositions for treatment of epilepsy.

BACKGROUND

[0003] Epilepsy is one of the most prevalent neurological disorders, affecting approximately 3 million people in the United States of America and about 50 million worldwide. Despite the availability of many anti-epileptic drugs (AEDs) in clinical practice, one third of the patients still suffer from recurrent and unprovoked seizures and are categorized as pharmaco-resistant. Significant amount of effort and resources have been put forward in the past three decades, seeking next generation drugs. Around 20 AEDs have been approved during this period, but the considerable unmet medical need remains to be addressed.

SUMMARY

[0004] Disclosed herein are novel compositions for treatment of epilepsy and use thereof. The herein disclosed compounds can be referred to as anti-epilepsy drugs (AEDs), or means for reducing seizure, and have a structure represented by Formula

_as further described herein below. In various embodiments, the AED is Compound 001, Compound 002, Compound 003, Compound 004, or Compound 005, as presented in Table 1 disclosed herein below, or any set of two or more of these compounds. Formula (I) contains several variable positions defined by alternative substituents. Various embodiments specifically include one or more of these alternative substituents, independently for each variable position. Various embodiments specifically exclude one or more of these alternative substituents, independently for each variable position. Various embodiments specifically include one of more of the individual species encompassed by Formula (I) or disclosed in Table 1. Various embodiments specifically exclude one of more of the individual species encompassed by Formula (I) or disclosed in Table 1. The herein disclosed compounds may be referred to as means for treating epilepsy, means for inhibiting seizure, and the like as described herein below. Such means may be further limited to include or exclude particular compounds or sets of compound as herein disclosed.

[0005] The human efficacious dose of the composition comprises of the claimed compound. In some embodiments the efficacious dose is from 15 mg/day to 700 mg/day. In other embodiments, the compounds are administered at from about 0.01 mg/kg/day to about 30 mg/kg/day, from about 0.1 mg/kg/day to about 15 mg/kg/day, or from about 0.2 to about 10 mg/kg/day.

[0006] Some embodiments disclosed herein comprise pharmaceutical compositions or formulations comprising the herein disclosed compounds. In some embodiments, the pharmaceutical composition or formulation has a content of a compound of Formula I that is from 0.01% to 50% by weight. In other embodiments the pharmaceutical composition or formulation has a content of a compound of Formula I that is from 1% to 25% by weight. In various embodiments, the pharmaceutical composition or formulation further comprises one or more of triglyceride lipids, surfactants, co-surfactants, saline, or water. In some embodiments, the pharmaceutical composition or formulation is 0.01% to 70% by weight of one or more triglyceride lipids. In some embodiments, the pharmaceutical composition or formulation is 20% to 60% by weight of one or more triglyceride lipids. In some embodiments, the pharmaceutical composition or is 0.01% to 25% by weight of one or more surfactants. In some embodiments, the pharmaceutical composition or formulation is 5% to 15% by weight of one or more surfactants. In some embodiments, the pharmaceutical composition or is 0.01% to 95% by weight of one or more hydrophilic co-surfactants. In some embodiments, the pharmaceutical composition or formulation is 20% to 70% by weight of one or more hydrophilic co-surfactants. In some embodiments, the pharmaceutical composition or formulation is 0.01% to 50% by weight saline or water.

[0007] Some embodiments disclosed herein are drawn to methods of treating epilepsy comprising administering a herein disclosed compound or pharmaceutical composition or formulation thereof. In various embodiments, the treated epilepsy is a focal epilepsy, for example, focal aware epilepsy, focal impaired awareness epilepsy, focal motor epilepsy, focal non-motor seizure epilepsy.

[0008] In some embodiments, the compound or pharmaceutical composition or thereof is administered acutely, for example to prevent the onset, or diminish the severity or duration, of a seizure. In one aspect of these embodiments, the compound may be administered intravenously. [0009] In some embodiments, the compound or formulation thereof is administered chronically, for example, to diminish the frequency, severity, or duration of seizure. In various aspects of these embodiments, the compound or pharmaceutical composition may be administered by oral administration, nasal administration, intramuscular injection, or subcutaneous injection.

[0010] In one aspect of the foregoing embodiments, the compound is Compound 003.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the herein disclosed embodiments are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present compositions, formulations, and treatments will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which their principles of operation are demonstrated, and to the accompanying drawings of which:

[0012] Figure 1 depicts an electrophysiological recording scheme for compound testing.

[0013] Figure 2 depicts the correlation between AED human plasma concentrations and EC50S of 18 FDA- approved anti-seizure medications as determined using the picrotoxin (PTX) seizure model.

[0014] Figure 3 depicts the plate layout for compound testing.

[0015] Figure 4 depicts atypical microelectrode array (MEA) assay results using licarbazepine as the AED. [0016] Figure 5 depicts parameter settings on NeuralMetricTool.

[0017] Figure 6 depicts Compound 003 EC50 values for various measures of seizure activity in a table as well as the data plots from which the EC50 were derived.

[0018] Figure 7 depicts Compound 003 monkey pharmacokinetics data in the correlation plot of AED assessments.

[0019] Figure 8 depicts the MEA recording data of licarbazepine.

DETAILED DESCRIPTION

[0020] In general, the presentation provides novel compositions for treatment of epilepsy and use thereof. I. Definitions

[0021] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0022] Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in “Nomenclature of Organic chemistry” (Pergamon Press, 1979), Sections A, B, C, D, E, F, and H. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0023] The term "C_m-C_n" or "C_m-C_n group" used alone or as a prefix, refers to any group having m to n carbon atoms, wherein m and n are 0 or positive integers, and n>m. For example, "Ci XV would refer to a chemical group having 1 to 6 carbon atoms.

[0024] The term “group” and “radical” are used interchangeably herein.

[0025] The term “hydrocarbon” used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.

[0026] The term “hydrocarbon radical” or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

[0027] The term “alkyl” used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. The term “lower alkyl” as used herein refers to an alkyl group having 1 to 6 carbon atoms.

[0028] The term “alkylene” used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.

[0029] The term “alkenyl” used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.

[0030] The term “alkynyl” used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.

[0031] The term “cycloalkyl,” used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. [0032] The term “cycloalkenyl” used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.

[0033] The term “cycloalkynyl” used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.

[0034] The term “aryl” used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.

[0035] The term “arylene” used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to links two structures together.

[0036] The term “heterocycle,” used alone or as a suffix or prefix, refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.

[0037] The term "heteroalkyl," used alone or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O and S.

[0038] The term "heteroaromatic," used alone or as a suffix or prefix, refers to a ring -containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring- containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).

[0039] The term “heterocyclic group,” “heterocyclic moiety,” “heterocyclic,” or “heterocyclo” used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.

[0040] The term “heterocyclyl” used alone or as a suffix or prefix, refers to a monovalent radical derived from a heterocycle by removing one hydrogen therefrom. [0041] The term “heterocyclylene” used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.

[0042] The term “heteroaryl” used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.

[0043] The term “heterocylcoalkyl” used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.

[0044] The term “heteroarylene” used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.

[0045] The term “heterocycloalkylene” used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.

[0046] The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.

[0047] The term "five-membered" used as prefix refers to a group having a ring that contains five ring atoms.

[0048] A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms, where 1, 2 or 3 ring atoms are independently selected from N, O and S.

[0049] Exemplary five-membered ring heteroaryls are thienyl, fiiryl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.

[0050] A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

[0051] Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0052] As a prefix, “substituted” refers to a structure, molecule or group in which one or more hydrogens are replaced with one or more Ci-i₂hydrocarbon groups or with one or more chemical groups that contain one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -NO2, -OR, -R’OR, -Cl, -Br, -I, -F, -CF3, -C(=0)R, -C(=0)OH, -NH₂, -SH, -NHR, -NR₂, -SR, -SO3H, -S0₂R, -S(=0)R, -CN, -OH, -C(=0)OR, -C(=0)NR_2. - NRC(=0)R, -NRC(=0)OR, -R’NR₂, oxo (=0), imino (=NR), thio (=S), and oximino (=N-OR), wherein each “R” is hydrogen or a Ci-i₂hydrocarbyl and “R”’ is a Ci-i₂hydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.

[0053] As a suffix, “substituted” used in relation to a first structure, molecule or group, followed by one or more names of chemical groups, refers to a second structure, molecule or group that results from replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. Thus, a “phenyl substituted by nitro” refers to nitrophenyl.

[0054] The term "optionally substituted" refers to groups, structures, or molecules that can be either substituted or not substituted.

[0055] It is understood that substituents and substitution patterns on the compounds of the application may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.

[0056] Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro- pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2.3.4.7-tetrahydro- l//-azepine homopiperazine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethylene oxide.

[0057] In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, fiiran, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4- oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazole, and 1,3,4- oxadiazole.

[0058] Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. [0059] In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.

[0060] Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3- dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2.3.4.7-tetrahydro- l//-azepinyl. homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3- dioxepinyl, and hexamethylene oxidyl.

[0061] In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.

[0062] Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrobzidinyl, and quinobzidinyl.

[0063] In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.

[0064] The term “alkoxy,” used alone or as a suffix or prefix, refers to radicals of the general formula -O- R, wherein R is selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. [0065] The term “amine” or “amino,” used alone or as a suffix or prefix, refers to radicals of the general formula -NRR’, wherein R and R’ are independently selected from hydrogen or a hydrocarbon radical.

[0066] Used alone or as a prefix or suffix, "acyl" means the group -C(=0)-R, wherein R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.

[0067] The term “Ci-C₆-lower alkyl-ester” as used herein means the group Ci-C₆alkylene-C(=0)-OR, wherein R is an optionally substituted hydrocarbyl.

[0068] The term “Ci-C₆-lower alkyl-amide” as used herein means the group Ci-C₆alkylene-C(=0)-NRR’, wherein R and R’ are independently, H or an optionally substituted hydrocarbyl.

[0069] The term “Ci-C₆-lower alkyl-acid” as used herein means the group Ci-C₆alkylene-C(=0)-OH.

[0070] “Halogen” includes fluorine, chlorine, bromine and iodine.

[0071] "Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.

[0072] A first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms there between.

[0073] "Link," "linked," or "linking," unless otherwise specified, means covalently linked or bonded.

[0074] The term “compound(s) of the application” or “compound(s) of the present application” as used herein means a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.

[0075] The term “composition(s) of the application” or “composition(s) of the present application” as used herein means a composition comprising at least one compound of the application and at least one an additional component, such as a carrier.

[0076] The term “pharmaceutically acceptable salt” means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.

[0077] A “pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula (I) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, or such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula (I) for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0078] A “pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula (I) or any of its intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0079] “Solvate” means a compound of Formula (I) or the pharmaceutically acceptable salt of a compound of Formula (I) wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.

[0080] The term “stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0081] "Patient" for the purposes of the present application includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In an embodiment the patient is a mammal, and in another embodiment the patient is human.

[0082] "Therapeutically effective amount" is an amount of a compound, that when administered to a patient, ameliorates a symptom of the disease, such as muscle contractions, odd sensations, abnormal head or eye movements, automatisms, repetitive movements, vision changes, and seizure events. The amount of a compound which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure. Thus, the term “therapeutically effective amount” means an amount of a herein disclosed compound, such as a compound of Formula (I), which is effective in treating epilepsy by, for example reducing the frequency, duration, severity and/or risk of a seizure. In some embodiments, the therapeutically effective amount is for reducing one or a subset of the forgoing seizure aspects.

[0083] The term “treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. In some embodiments, “treating” is limited to reducing the frequency, duration, severity and/or risk of a seizure, or any subset thereof.

[0084] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.

[0085] When introducing elements disclosed herein, the articles “a”, “an”, “the”, and “said” are intended to mean that there are one or more of the elements.

[0086] In embodiments comprising an “additional” or “second” component or element, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different. Some embodiments specifically exclude a 2nd, 3rd, or other additional element.

[0087] The term “and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable salts, solvates and/or radiolabeled versions thereof means that the compounds of the application exist as individual salts, hydrates or radiolabeled versions, as well as a combination of, for example, a salt of a solvate of a compound of the application or a salt of a radiolabeled version of a compound of the application.

[0088] In understanding the scope of the present application, the term “comprising” (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements, or process steps. [0089] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps.

[0090] The term “consisting essentially of’ as used herein is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0091] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art.

[0092] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0093] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by another atom or substituent.

[0094] Seizures may be preceded by sleep disruption, nausea, headache, irritability, depression, numbness on one side of body, or changes in ability to interact with things happening and surroundings, etc. Seizures may manifest as temporary confusion; a staring spell; uncontrollable jerking movements particularly of the arms and legs; loss of consciousness or awareness; psychic symptoms, such as fear, anxiety, of deja vu. In epilepsy a patient will typically experience the same type of seizure symptoms each time a seizure occurs. Seizures may be focal or generalized. Focal seizures (sometimes called simple partial seizures) do not cause loss of consciousness but can alter emotions or change the way things look, smell, feel, taste or sound, and may also cause involuntary jerking of a body part, such as an arm or leg. Such focal seizures can even result in sensory symptoms such as tingling, dizziness, or flashing lights. Other focal seizures (sometimes called complex partial seizures) do involve a change or loss of consciousness or awareness. A person having a complex partial seizure may stare into space and not respond appropriately to the environment, and may perform repetitive movements, such as hand-rubbing, chewing, swallowing, or walking in circles.

[0095] Generalized seizures, involving all areas of the brain, are generally classified as one of six types: absence seizures, atonic seizures, tonic seizures, clonic seizures, myoclonic seizures, and tonic-clonic seizures. Absence seizures, sometimes called petit mal seizures, commonly occur in children and are characterized by staring into space and subtle body movements such as eye blinking or lip smacking. These seizures cause brief loss of consciousness and may occur in clusters. Atonic seizures, sometimes call drop seizures, cause a loss of muscle control which can cause the person to suddenly collapse or fall down. Tonic seizures cause stiffening of the muscles, usually of the back arms and legs, and may also cause the person to fall. Clonic seizures are typified by repeated or rhythmic jerking muscle movements, typically of the neck face and arms. Myoclonic seizures usually manifest as sudden brief jerks or twitches of the arms and legs. Tonic-clonic seizures, sometime call grand mal seizures can cause an abrupt loss of consciousness, body stiffening and shakings, and sometimes loss of bladder control or biting of the tongue.

[0096] Seizures may be triggered by a variety of factors including lack of sleep; heavy use of alcohol; use of drugs such as cocaine, ecstasy, and the like; withdrawal of alcohol or drug use; fever; hormonal fluctuations, such as due to pregnancy or menstruation; visual stimuli, such as flickering or flashing lights; low blood sugar; high blood sugar; vitamin deficiencies; certain foods, perhaps linked to a food allergy; extreme emotional stress; general stress; and heatstroke.

[0097] Epilepsy often has no identifiable cause, but several factors that can contribute to its causation are recognized. These include genetic influence; head trauma; brain tumors or stroke; infectious disease, such as meningitis, AIDS, and viral encephalitis, prenatal injury, such as infection in the mother, poor nutrition, or oxygen deprivation; and developmental disorders, such as autism or neurofibromatosis. The nomenclature of epilepsy has changed overtime. A currently favored classification scheme divides epilepsy into generalized and focal epilepsy. Generalized epilepsy is further divided by seizure type between generalized motor ( grand mal) seizures and generalized non-motor or absence (petit mal) seizures. These can be further divided into typical, atypical, and myoclonic. Focal epilepsy is further divided into four types: focal aware (simple partial), focal impaired awareness (complex partial), focal motor (including atonic, tonic, clonic, myoclonic, and epileptic spasm) and focal non-motor seizures (involving perceptual changes including altered thinking, intense emotions, waves of heat or cold, racing heart, etc.). Epilepsy can also be further divided into syndromes, including West syndrome, Doose syndrome, Rasmussen’s syndrome, Dravet syndrome, and Lennox-Gastaut syndrome.

IL _ Compound

[0098] One embodiment of the application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or optical isomer, or combination thereof:

Formula (I) wherein:

R¹ is selected from the group consisting of C i -G, alkyl, C i -G, alkoxy, C i -G alkyl-ester, C i -G, alkyl-amide, C₁-C₆ alkyl-acid, C ₁ -G, haloalkyl, C ₁ -G, haloalkoxy, C ₁ -G, haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl, alkynyl, aryl- alkynyl, cycloalkenyl, heterocycloalkenyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O- heterocycloalkyl, and alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, each Ri group being optionally substituted with one or more independently-selected groups R₅;

R² and R³ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or

R² and R³ connect to form, together with the carbon atom to which they are attached, a three to seven- membered carbocyclic or heterocyclic ring; and

R⁴ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

X and Q are independently selected from CH₂, O, NR₇, S, SO and SO₂;

R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO₂R₅, CONHR₅, CON(R_f,)₂. SO₂NHR₅, S0₂N(R_f,)₂. C₁-C₆ alkyl, C ₁ -G, alkoxy, C ₁ -G, lower alkyl-ester, C ₁ -G, alkyl-amide, C ₁ -G, lower alkyl-acid, C₁-C₆ lower haloalkyl, C₁-C₆ lower haloalkoxy, C₁-C₆ haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O- alkylene -cycloalkyl and alkylene-O-alkylene-heterocycloalkyl; and

Rg and R7 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, provided that at least one of R¹, R² and R³ comprises a fluorine atom.

[0099] With respect to each of the preceding definitions of R¹- R⁴, R5-R7, X, and Q, some embodiments specifically and independently include a subset of the alternative substituents and some embodiments specifically and independently exclude a subset of the alternative substituents.

[00100] In some embodiments, the present application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer or optical isomer, or combination thereof:

Formula (I) wherein:

R¹ is selected from the group consisting of Ci-Cgalkyl, Ci-Cgcycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cgalkylene-aryl, Ci-Cgalkylene-heteroaryl, C2-Cgalkenyl, C2-Cgalkenylenearyl, C2- Cgalkenyleneheteroaryl, C2-Cgalkynyl, C2-Cgalkynylene-aryl, C3-Ci2Cyeloalkenyl, heterocycloalkenyl, Ci- Cgalkylene-O-Ci-Cgalkyl, Ci-Cgalkylene-0-C₃-Ci_2Cyeloalkyl , Ci-Cgalkylene-O-heterocycloalkyl, Ci- Cgalkylene-0-Ci-Cgalkylene-C₃-Ci₂cycloalkyl and Ci-Cgalkylene-O-Ci-Cgalkylene-heterocycloalkyl, each Ri group being optionally substituted with one or more independently-selected groups R5;

R²and R³ are each independently selected from the group consisting of hydrogen, halogen, Ci-Cgalkyl, C2- Cgalkenyl, C2-Cgalkynyl, Ci-Cghaloalkyl, C3-Ci2cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or

R² and R³ connect to form, together with the carbon atom to which they are attached, a three to seven- membered carbocyclic or heterocyclic ring; and R⁴ is selected from the group consisting of hydrogen, Ci-Cgalkyl, C₂-Cgalkenyl, C₂-Cgalkynyl, Ci- Cghaloalkyl, C₃-Ci_2Cyeloalkyl, heterocycloalkyl, aryl and heteroaryl;

X and Q are independently selected from CH2, O, NR7, S, SO and SO2;

R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO₂R₅, CONHRg, CON(Rg)₂, SO₂NHR₅, S0₂N(Rg)₂, Ci-Cgalkyl, Ci-Cgalkoxy, Ci-Cgalkyl-ester, Ci-Cgalkyl-amide, Ci-Cgalky 1-acid, Ci- Cghaloalkyl, Ci-Cghaloalkoxy, Ci-Cghaloalkyl-ester, C₃-Ci_2Cyeloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cghydroxyalkyl, C₃-Ci₂hydroxycycloalkyl, hydroxy-heterocycloalkyl, Ci-Cgcyanoalkyl, C₂-Cgalkenyl, C₂-Cgalkynyl, C₃-Ci_2Cyeloalkenyl, heterocycloalkenyl, Ci-Cgalkylenearyl, Ci-Cgalkyleneheteroaryl, Ci- Cgalkylene-O-Ci-Cgalkyl, Ci-Cgalkylene-0-C₃-Ci_2Cyeloalkyl, Ci-Cgalkylene-O-heterocycloalkyl, Ci- Cgalkylene-0-Ci-Cgalkylene-C₃-Ci_2Cyeloalkyl and Ci-Cgalkylene-O-Ci-Cgalkylene-heterocycloalkyl; and

Rg and R₇ are independently selected from the group consisting of hydrogen, Ci-Cgalkyl, C₂-Cgalkenyl, C₂- Cgalkynyl, Ci-Cghaloalkyl, C₃-Ci_2Cyeloalkyl, heterocycloalkyl, aryl and heteroaryl, provided that at least one of R¹, R² and R³ comprises a fluorine atom.

[0100] In some embodiments, Ri is selected from the group consisting of Ci-Cg alkyl, Ci-Cgcycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cg alkylene-aryl, Ci-Cg alkylene-heteroaryl, C₃-Ci₂cycloalkenyl, heterocycloalkenyl, Ci-Cgalkylene-0-C₃-Ci₂cycloalkyl, Ci-Cgalkylene-O-heterocycloalkyl, Ci- Cgalkylene-0-Ci-Cgalkylene-C₃-Ci_2Cyeloalkyl and Ci-Cgalkylene-O-Ci-Cgalkylene-heterocycloalkyl, each Ri group being optionally substituted with one or more independently-selected groups R₅, wherein R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO₂R₅, CONHRg, CON(Rg)₂, SO₂NHR₅, S0₂N(Rg)₂,Ci-Cgalkyl, Ci-Cgalkoxy, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, Ci-Cghydroxy alkyl, Ci- Cgcyanoalkyl, C₂-Cgalkenyl, C₂-Cgalkynyl and Ci-Cgalkylene-O-Ci-Cgalkyl.

[0101] In some embodiments, R¹ is selected from the group consisting of Ci-Cgcycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cgalkylene-aryl, Ci-Cgalkylene-heteroaryl, each Ri group being optionally substituted with one or more independently-selected groups R₅, wherein R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, Ci-Cgalkyl, Ci-Cgalkoxy, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, Ci- Cghydroxyalkyl, Ci-Cgcyanoalkyl, and Ci-Cgalkylene-O-Ci-Cgalkyl.

[0102] In some embodiments, R¹ is selected from the group consisting of aryl, heteroaryl, Ci-Cgalkylene- aryl and Ci-Cgalkylene-heteroaryl, each Ri group being optionally substituted with one or three independently-selected groups R₅, wherein R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, Ci-Cgalkyl, Ci-Cgalkoxy, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, Ci-Cghydroxyalkyl, Ci- Cgcyanoalkyl, and Ci-Cgalkylene-O-Ci-Cgalkyl. [0103] In some embodiments, R¹ is selected from the group consisting of Ci-Cgalkylene-aryl and Ci- C_galkylcnc-hctcroaryl. each R¹ group being optionally substituted with one or three independently-selected groups R5, wherein R5 is selected from the group consisting of hydroxy, halogen, cyano, nitro, Ci-C₄alkyl, Ci-C₄alkoxy, Ci-C₄haloalkyl, Ci-C₄haloalkoxy, Ci-C₄hydroxyalkyl, Ci-C_4Cyanoalkyl, and Ci-C₄alkylene- 0-Ci-C₄alkyl.

[0104] In some embodiments, R¹ is selected from the group consisting of Ci-C₄alkylene-aryl and Ci- Cralkylene-heteroaryl, each R¹ group being optionally substituted with one or three independently-selected groups R5, wherein R5 is selected from the group consisting of hydroxy, Cl, F, cyano, nitro, Ci-C₄alkyl, Ci- Cralkoxy, Ci-C₄fluoroalkyl, Ci-C₄fluoroalkoxy, Ci-C₄hydroxyalkyl, Ci-C_4Cyanoalkyl, and Ci-C₄alkylene- O-Ci-Cralkyl.

[0105] In some embodiments, R¹ is Ci-C₄alkylene-aryl optionally substituted with one R5 group, wherein R5 is selected from the group consisting of Cl, F, Ci-C₄alkyl, Ci-C₄alkoxy, Ci-C₄fluoroalkyl and Ci- C₄fluoroalkoxy.

[0106] In some embodiments, R¹ is Ci-C₂alkylene -phenyl substituted with one R5 group, wherein R5 is selected from the group consisting of Cl, F, CH₃, CH₃O, CF₃, CF₂H, CF₃O and CHF₂O. In some embodiments, the R₅ group is located at the para position.

[0107] In some embodiments, R¹ comprises a difluoromethoxy or a trifluoromethoxy substituent. In some embodiments, R¹ is p-trifluoromethoxybenzyl. In some embodiments, R¹ is p-difluoromethoxybenzyl. In some embodiments, at least one of R² and R³ is F and the other of R² and R³ is H. In some embodiments, R² and R³ are both F. In some embodiments, R¹ is p-trifluoromethoxybenzyl or p-difluoromethoxybenzyl and at least one of R² and R³ is F and the other of R² and R³ is H or R² and R³ are both F.

[0108] In some embodiments, R² and R³ are each independently selected from the group consisting of hydrogen, halogen, Ci-Cgalkyl and Ci-Cghaloalkyl. In some embodiments, R2 and R3 are each independently selected from the group consisting of hydrogen, Cl, F, Ci-C₄alkyl and Ci-C₄haloalkyl. In some embodiments, R2 and R3 are each independently selected from the group consisting of hydrogen, F, CH3, CF3 and CF2H. In some embodiments, R2 and R3 are both H or are both F, or one of R² and R³ is H and the other is F.

[0109] In some embodiments, R⁴ is selected from the group consisting of hydrogen Ci-C₄alkyl and Ci- Crhaloalkyl. In some embodiments, R⁴ is selected from the group consisting of hydrogen, Ci-C₄alkyl and Ci-C₄haloalkyl. In some embodiments, R⁴ is selected from the group consisting of hydrogen and CH₃. In some embodiments, R⁴ is H. [0110] In some embodiments, X and Q are independently selected from O and NR7, wherein R7 is selected from the group consisting of hydrogen, Ci-C4alkyl and Ci-C_thaloalkyl. In some embodiments, X and Q are independently selected from O and NR7, wherein R7 is selected from the group consisting of hydrogen and CH₃. In some embodiments, X is O.

[0111] In some embodiments Q is selected from O and NR7. In some embodiments Q is O.

[0112] In some embodiments, Re is selected from the group consisting of hydrogen and Ci-C4alkyl.

[0113] With respect to each of the preceding definitions of R¹- R⁴, R5-R7, X, and Q, some embodiments specifically and independently include a subset of the alternative substituents and some embodiments specifically and independently exclude a subset of the alternative substituents.

[0114] Compounds of Formula I, by its various definitions above, may be referred to as means for accomplishing a function, such as, means for inhibiting seizure or anti-epileptic means. Various embodiments specifically exclude compounds of Formula I according to one or another of the above definitions, or exclude one or more alternatives for one or more substituent groups.

[0115] Representative compounds according to the current application include, but not limited to the following examples:

7 -Benzy loxy-4H benzo [1,4] oxazin-3 -one ;

7-(4-Fluoro-benzyloxy)-4H-benzo[l,4]oxazin-3-one;

7-(4-Difluoromethoxy-benzyloxy)-4H-benzo[l,4]oxazin-3-one;

7 -(4-Trifluoromethoxy-benzyloxy) -4H-benzo [1,4] oxazin-3 -one ; and 7 -Benzy loxy-2,2-difluoro-4H-benzo [ 1 ,4]oxazin-3 -one ; or a pharmaceutically -acceptable salt, solvate, tautomer, optical isomer, or combination thereof.

[0116] In some embodiments, the present application includes a compound having the formula shown in Table 1, or a pharmaceutically-acceptable salt, solvate or tautomer, or combination thereof.

Table 1

[0117] It will be understood by those of skill in the art that when compounds of the present application contain one or more chiral centers, the compounds of the application may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present application includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula (I). The optically active forms of the compound of the application may be prepared, for example, by chiral chromatographic separation of a racemate or chemical or enzymatic resolution methodology, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described hereinafter. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994), incorporated by reference with regard to stereochemistry.

[0118] It will also be understood by those of skill in the art that certain compounds of the present application may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present application encompasses all such solvated forms of the compounds of Formula (I).

[0119] Within the scope of the application are also salts of the compounds of Formula (I). Generally, pharmaceutically acceptable salts of compounds of the present application are obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HC1 or acetic acid, to afford a salt with a physiologically acceptable anion. It is also possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present application having a suitably acidic proton, such as a carboxylic acid or a phenol or a quinolinone, with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. Additionally, quaternary ammonium salts can be prepared by the addition of alkylating agents, for example, to neutral amines.

[0120] The compounds of Formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of Formula (I). Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present application includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the application are the individual isomers of the compounds represented by Formula (I), as well as any wholly or partially equilibrated mixtures thereof. The present application also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

[0121] The compounds of the application may be used in their labelled or unlabelled form. In the context of this application the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound.

[0122] In another embodiment of the compounds of the present application may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging. The labelled isomer of the application preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this application the radionuclide is preferably selected from ²H (deuterium), ³H (tritium), ^UC, ¹³C, ¹⁴C, ¹⁴N, ¹⁵N, ¹⁸0, and ¹⁸F. The physical method for detecting the labelled isomer of the present application may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.

[0123] In yet another one embodiment of the present application, the compound of Formula (I) may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or /Moluenesulphonate.

[0124] In yet another aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) and at least one pharmaceutically acceptable carrier and/or excipient. In a further aspect, the carrier is a pharmaceutically-acceptable carrier.

[0125] In another aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I) to treat medical conditions such as epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety, Parkinson's disease, depression, Alzheimer’s disease and other related central nervous system (CNS) disorders; such compositions can comprise a compound of Formula (I) in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

[0126] For pharmaceutical use, the compounds of the present application are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraperitoneally, intra-arterially, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery. The compounds of the application are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice. For the oral mode of administration, the compounds of the application are used in the form of tablets, capsules, lozenges, chewing gum, sustained release formulations, emulsions, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose, high molecular weight polyethylene glycols, and lipids.

[0127] If desired, certain sweetening and/or flavoring agents may be added. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pHs of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes are controlled to render the preparation isotonic. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as ascorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers. For pulmonary administration, diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0128] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that are solid at room temperature but melt at body temperature. The substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, and mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. For example, see Remington's Pharmaceutical Sciences, 16th Ed. (Mack Publishing, Easton, PA, 1980, pp. 1530-1533) for further discussion of suppository dosage forms. Analogous gels or creams can be used for vaginal, urethral and rectal administrations.

[0129] Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.

[0130] Examples of pharmaceutically acceptable acid addition salts for use in the present application include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example. Examples of pharmaceutically acceptable base addition salts for use in the present application include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill. II. Formulation

[0131] One approach for preliminary preclinical evaluation of drug candidates is preparing a simple aqueous solution formulation, which allows for easy administration and low manufacturing cost. However, poor aqueous solubility of NCEs usually results in poor mass transfer across the gut wall and consequently low oral bioavailability and leads to variable pharmacokinetics among species. In order to achieve high drug exposure levels in animal toxicity studies, it is required to develop a suitable formulation using alternate solubilization techniques, such as formulating in cosolvent-based systems, suspensions, emulsions, solid dispersions and solutions, cyclodextrin inclusion complexes, salt formation, amorphous solid, etc.

[0132] Due to extremely low aqueous solubility of the certain compounds (e.g., less than 0.001 mg/mL), simple formulation approaches (solution in water-PEG mixture or powder in capsule) are not enough to address low exposure issue. Bioavailability enhancement technologies (lipid-based drug delivery system, solid amorphous dispersions, drug salt and cocrystal formation) have been utilized to improve the apparent solubility of these molecules.

[0133] In one aspect, the present embodiments provide a formulation using a Lipid-based Drug Delivery System (LBDDS). Such formulations comprise the active pharmaceutical ingredient (API), triglycerides, surfactants, co-surfactants and/or co-solvents, in single form or combination.

[0134] Of the bioavailability enhancing technologies, LBDDS is the most well-studied and well-established formulation approach for addressing solubility and/or permeability issues of molecules with poor permeability (formally characterized as Biopharmaceutics Classification System, class III and IV). Ronak Savla, Jeff Browne, Vincent Plassat, Kishor M. Wasan & Ellen K. Wasan; Review and analysis of FDA approved drugs using lipid-based formulations, Drug Development and Industrial Pharmacy 2017, 43, 1743. The methods include emulsions, oily solutions and dispersions. The least complex Lipid-based Formulations (LBF) comprise simple encapsulated solution of drugs in oils, which are exemplified by the many fat-soluble vitamin preparations.

[0135] In some embodiments, the LBDDS excipients are selected from lipids, water insoluble surfactants (HLB<12; HLB: Hydrophile-Lipophile Balance), water soluble surfactants (HLB>12), and hydrophilic cosolvents. The choice and relative percentage of excipients in LBDDS influence drug solubility, LBDDS dispersibility, and formulation properties.

[0136] In some embodiments, the oil phase consists of long-chain triglycerides like soybean oil, sesame oil, com oil, groundnut oil, polyethoxylated castor oil like Cremopher EL; medium-chain mono-, di- and triglycerides like Capmul MCM, Miglyol 812, Miglyol 810, Capryol 90, Captex200P, Vitamin E-TPGS and Imwitors. Surfactants commonly used are from the class of polysorbates like Tween 80, poloxamers like Lutrol F68, Myq, and Solutol HS 15 along with co-surfactants like polyethylene glycols like PEG 100, PEG 200, PEG 400, PEG 600, propylene glycols, glycerol, pyrrolidones, glycofiirol, Soluphor P, Pharmasolve, Labrasol, Gelucires, alcohol and lecithin. Aqueous phase can be plain water or buffered water.

[0137] In one embodiment, the API (Compound 003) was formulated in two types of vehicles for animal tests. The first formulation consisted of the recipients in the category of surfactants described above and water was developed for intravenous injection in animal pharmacokinetics study. An oral formulation was also developed after evaluating API salt formation, amorphous solid, and LBDDS. At least two lipid-based formulations were developed to enhance Compound 003 exposure level in animals to the extent that suitable for toxicity assessment. The formulations consisted of one to three excipients selected from triglycerides, surfactants, and co-surfactants described above.

[0138] The amount of API of the present composition can vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art. In general, the final composition can comprise, for example, from 0.01% by weight (% weight/weight (w/w) to 50% w/w of Compound 003, preferably 1% w/w to 25% w/w, with 0.01% w/w to 70% w/w of lipids, 0.01% w/w to 25% w/w of surfactants, 0.01% w/w to 95% w/w of water soluble cosurfactants, 0.01% w/w to 50% w/w of saline or water as excipients depending on the administered routes of formulations applied.

III. Dose

[0139] Choosing safe and effective drug dosing is a necessary step to conduct any animal or human studies, especially in the situation that the initial dose of a new drug candidate has not been determined in a specific species. It should be emphasized that the common approach of scaling of dose based on the body weight alone may lead to inappropriate dosing which could result in toxic and side effects or less therapeutic effects.

[0140] Since biochemical processes and functional systems vary significantly in different species, usually disparate pharmacokinetic profiles are observed among experimental animals. Therefore, extrapolation of dose from animals to humans needs consideration of body surface area, pharmacokinetics, and metabolite profiles to increase clinical trial safety and efficacy.

[0141] Four different methods namely dose by factor, similar drug, pharmacokinetically guided, and comparative approaches are described in literature to assess the initial dose (Reigner BG, Blesch KS. Estimating the starting dose for entry into humans: Principles and practice. Eur J Clin Pharmacol 2002, 57, 835). The “dose by factor” method is an empirical approach and uses the no observed adverse effect levels (NOAEL) of drug from preclinical toxicological studies to estimate a human equivalent dose (HED). However, it is questionable that dose selection be based solely on the minimum risk of toxicity, instead of choosing one with minimum pharmacologic activity in humans. For the sake of human safety, this approach is still the most acceptable and practical method to determine the initial dose for human study. In similar drug approach, the existing pharmacokinetics data for another drug of the same pharmacological category (similar drug) may be used. On the other hand, pharmacokinetically guided approach utilizes the drug activity instead of scaling of dose among species (Sharma V, McNeill JH. To scale or not to scale: The principles of dose extrapolation. Br J Pharmacol 2009, 157, 907). In case of comparative approach, different methods are utilized to determine initial dose, and the data are compared and optimize to get an initial dose.

[0142] The US Food and Drug Administration’s current guidance is based on “dose by factor” approach where the NOAEL of drug is scaled by making use of allometry to derive the maximum recommended starting dose (MRSD) for clinical studies (USFDA. USFDA. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Adult Healthy Volunteer. Rockville, MD, US Food and Drug Administration, 2005. This simple empirical approach considers the sizes of individual species based on body surface area which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size.

[0143] The compounds of present disclosure can be effectively administered, for example, at an oral or parenteral dose of from about 0.01 mg/kg/day to about 30 mg/kg/day. In some embodiments, administration will be from about 0.1 mg/kg/day to about 15 mg/kg/day, more preferably from about 0.2 to about 10 mg/kg/day. Therefore, the therapeutically effective amount of the active ingredient contained per dosage unit as described herein can be, for example, from about 1 mg/day to about 2100 mg/day for a subject having, for example, an average weight of 70 kg, assuming one dose/day. In some embodiments, the pharmaceutical compositions herein can contain, per dosage unit, from about 7.0 mg to about 1000 mg of the active ingredient. In other embodiments, the range is from about 15 mg to about 700 mg, preferably from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, to 500 mg, per day, of the active ingredient.

[0144] Effective administration of the herein disclosed compounds can be, for example, an oral or parenteral dose to achieve a blood concentration of from 0.1 - 50 mM, preferably from 1.0 -25 mM.

[0145] Effective administration of the herein disclosed compounds can be, for example, an oral or parenteral dose to achieve a brain concentration of from 0.5 - 250mM, preferably from 5- 125 mM. [0146] Effective administration of the herein disclosed compounds can comprise administration preferably once daily, or twice daily, or every other day.

IV Indications

[0147] The herein disclosed compounds, such as Compound 003, can be used to treat (that is, prevent or reduce the risk or occurrence of) seizures, particularly seizures due to epilepsy in it various forms, such as focal onset epilepsy, Dravet syndrome, and subclinical epilepsy in mild cognitive impairment (MCI) or Alzheimer’s disease. Other classifications of epilepsy include refractory epilepsy, photosensitive epilepsy, benign Rolandic epilepsy, Lennos-Gastaut syndrome, juvenile myoclonic epilepsy, and temporal lobe epilepsy. In some embodiments, treatment is limited to a specific form of epilepsy and is not used to treat epilepsy generally. In some embodiments, treatment with the herein disclosed compounds, such as Compound 003, results in reduced adverse CNS effects, such as sedation, somnolence, dizziness, and psychiatric effects including aggressive behavior, anxiety, change in personality, worsening depression or suicidal thoughts, rapidly changing moods and emotions. In still further embodiments, the herein disclosed compounds can be used to treat neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety, Parkinson's disease, depression, Alzheimer’s disease or other related central nervous system (CNS) disorders. Some embodiments specifically include or specifically exclude treatment of one or more of these conditions, diseases or disorders.

V _ Method of Treatment

[0148] The herein disclosed compounds, such as Compound 003, are designed to treat seizures, for example in various forms of epilepsy, or in other conditions, such as disclosed in the Indications section above. Thus, some embodiments are methods of treatment of seizure, of epilepsy, of particular forms of epilepsy, and of other conditions. Parallel embodiments include compositions for use in treating these various conditions and methods for making a medicament for treating these conditions.

[0149] Treatment of these conditions entails preventing or mitigating the frequency, severity, duration, onset, or risk of seizure, including, in some embodiments, eliminating them entirely. Reducing the severity of a seizure in an acute treatment setting can comprise comparison to the severity of the seizure immediately prior to administration. Reducing the frequency, severity, duration, onset, or risk of seizure, in a chronic treatment setting can comprise comparison to prior patient experience before initiation of treatment. Mitigating the risk of seizure can comprise raising a threshold for triggering a seizure or narrowing what can constitute a triggering influence or event. By virtue of preventing or mitigating seizure, related symptoms or side-effects may be reduced or eliminated. In this sense, the herein disclosed compounds also treat the symptoms or side-effects. In some embodiments the herein disclosed compounds may additionally have a direct effect on the symptom or side-effect. However, treating a symptom or side-effect without preventing or mitigating seizure is not treating seizure or epilepsy, etc. For example, wearing a helmet may reduce head injury due to seizure (a symptom of side-effect) but it is not a treatment of seizure or epilepsy. Prevention or mitigation of seizure and reduction of symptoms or side-effects are all benefits of treatment. Some embodiments specifically include or exclude one or more types of epilepsy, syndrome, indication, seizure, symptom or side-effect, trigger, contributing factor of causation, or subsets or combinations thereof.

[0150] Treatment comprises administration of the herein disclosed compounds by any route of administration. Various embodiments entail oral administration, nasal administration, or administration by injection, such as intramuscular injection, intravenous injection, or subcutaneous injection. In various embodiments, administration occurs twice a day, once a day, or every other day. The administration schedule should be adapted to provide a daily dosage, or to maintain a concentration of the drug in blood or brain, as described in the Dose section above.

[0151] In some embodiments, the patient is treated chronically, and the compound or pharmaceutical composition is administered according to a regular schedule. In some such embodiments administration is oral, nasal, or by injections such as intramuscular injection or subcutaneous injection. In some embodiments, the patient is treated acutely, that is, when the patient senses a seizure coming on, or after a seizure has begun. In some such embodiments administration is by intravenous injection or nasal (directly to the CNS).

[0152] As used herein, the term “treating” or “treatment” broadly includes, both collectively and as individual embodiments, any kind of treatment activity in man or other animals. Treatment activity includes the administration of the medicaments, dosage forms, and pharmaceutical compositions described herein to a patient, especially according to the various methods of treatment disclosed herein, whether by a healthcare professional, the patient his/herself, or any other person. Treatment activities include the orders, instructions, and advice of healthcare professionals such as physicians, physician’s assistants, nurse practitioners, and the like that are then acted upon by any other person including other healthcare professionals or the patient his/herself. In some embodiments, treatment activity can also include encouraging, inducing, or mandating that a particular medicament, or combination thereof, be chosen for treatment of a condition - and the medicament is actually used - by approving insurance coverage for the medicament, denying coverage for an alternative medicament, including the medicament on, or excluding an alternative medicament, from a drug formulary, or offering a financial incentive to use the medicament, as might be done by an insurance company or a pharmacy benefits management company, and the like. In some embodiments, treatment activity can also include encouraging, inducing, or mandating that a particular medicament be chosen for treatment of a condition - and the medicament is actually used - by a policy or practice standard as might be established by a hospital, clinic, health maintenance organization, medical practice or physicians group, and the like.

EXAMPLES

[0153] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments described in the present.

Example 1

Human Neurons and Cell Culture

[0154] Subtype-specific induced-neurons (iN) were derived from human induced pluripotent stem cells (hiPSC), and co-cultured with established primary human astrocyte via proprietary protocols (Zhang et al., Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells, Neuron 78:785- 798, (2013); Yang et al., Generation of pure GABAergic neurons by transcription factor programming, Nature Methods 14:621-628 (2017); WO2011/091048A1, WO2017/223052A1, each incorporated by reference in its entirety).

[0155] In brief, iPSCs were grown in mTeSRl medium (StemCell Technologies) on 6-well plates coated with MATRIGEL® (Coming, cat#354277) following a daily media change routine. For the generation of iN cells, iPSCs were harvested using TrypLE Select (Gibco) for enzymatic dissociation into single cells. Dissociated iPSCs were resuspended in mTeSRl medium containing 10 mM ROCK inhibitor Y-27632 (StemCell Technologies). For the generation of excitatory glutamatergic iN cells, iPSCs were infected with lentivirus for constitutive expression of reverse tetracycline transactivator (rtTA) and lentivirus for doxycycline inducible expression Ngn2 and a puromycin selection marker.

[0156] For the generation of inhibitory GABAergic iN cells, iPSCs were infected with lentivirus for constitutive expression of rtTA and lentivirus for doxycycline inducible expression of Ascii and a puromycin selection marker as well as Dlx2 and a hygromycin selection marker. Infected iPSCs for excitatory and inhibitory iN generation were separately seeded into MATRIGEF-coated 6-well plates and further expanded in mTeSRl medium until reaching approximately 70% confluency. At the day of differentiation induction (day 0), media was changed to mTeSRl medium supplemented with 2 pg/ml doxycycline to activate transgene expression. The next day (day 1), iPSCs were dissociated again into single cells using TrypFE and reseeded in N3 medium (DMEM/F12, N2 supplement, B27 supplement, insulin [10 pg/ml], non-essential amino acids) containing doxycycline and 5 pg/ml puromycin (excitatory iN cells) or doxycycline, 5 pg/ml puromycin and 140 pg/ml hygromycin (inhibitory iN cells) on MATRIGEF-coated plates. At day 2 and 3, complete media changes were performed. At day 4, iN cells were ready for co seeding with human primary astrocytes on multielectrode array (MEA) plates.

[0157] Primary human astrocytes (ScienCell) were grown in Astrocyte Basal Medium (ScienCell) containing 10% fetal bovine serum (Gibco) and Astrocyte Growth Supplement (ScienCell) on 15-cm dishes coated with poly-L-lysine. After expanding for two passages, primary astrocytes were used for neural co cultures on MEA plates.

[0158] Multielectrode Array

[0159] Multielectrode array plates (Axion, classic-48 MEA plates) were coated with polyethyleneimine and laminin sequentially. Immature but committed excitatory and inhibitory induced neurons (NeuCyte, SynFire Co-Culture Kit (MEA)) were seeded on coated plates at 70/30 ratio together with astroglial cells in neural medium on coated MEA plates. Neural medium was composed of Neurobasal-A medium, B27 supplement, glutamine, NT3, doxycycline and mouse laminin supplemented with 5% FBS and ROCK inhibitor Y -27632. Cell densities were 140K, 60K, and 70K per well for excitatory iNs, inhibitory iNs, and astrocytes respectively. A half-medium change with neural medium supplemented with 1% FBS and AraC was performed every other day for the first three weeks. After 1 week, half-media changes with neural medium supplemented with 1% FBS were perormed once every 3 days, and a full-media change was performed on day 21. All compound testing was scheduled on day 23 after seeding to avoid perturbation caused by media-change.

[0160] Multielectrode Array (MEA) Recording

[0161] Electrophysiological recordings were performed on Axion Maestro 768 channel amplifier systems with specialized 48-well MEA-plates (Axion, classic-48). Each well has an array of 16 electrodes (4x4) that record simultaneously. Acquisition rate was 12.5kHz, and analog filter was 0.2-5kHz band-pass. No digital filter was applied online during recording or offline during analysis. Concurrent with raw-data acquisition, local neuronal events were detected inline using adaptive threshold-search spike detection using AxIS adaptive threshold crossing method with a threshold of 8 standard deviations from system baseline noise for each channel and a pre- and post-spike duration of 0.84 ms and 2.16 ms, respectively. Spike lists were stored in separate files for later analysis (see below). The threshold for event detection was 8 standard- deviations from system baseline.

[0162] Before every recording session, MEA plates were acclimated for 20 minutes in the recording chamber of Maestro system. Environmental variables were controlled at 37°C and 5% CO2. To monitor the maturation of induced neuron culture, 15-minute recording was performed weekly at 7-, 14- and 21- days after seeding. These ontogeny data were used for quality control purposes.

[0163] For compound testing, an in-house established 15-30-90 recording scheme (Figure 1) was used. In brief, basal activity was recorded for 15 minutes, followed by the addition of picrotoxin (PTX) challenge to induce seizure-like activities. These elevated activities were monitored and allowed to stabilize for 30 minutes. At which point, test compounds were applied at various concentrations, and their effects were recorded for 90 minutes. Upon the completion of recording, cellular health of dosed neural cultures was quantitatively assessed by measuring of lactate dehydrogenase (LDH) release-dependent conversion of tetrazolium salt to red formazan. After MEA recording in the presence of compound/solvent, 50 pi of culture media was removed from each well and transferred to a 96-well plate to determine LDH concentrations using the CytoTox 96® Non-Radioactive Cytotoxicity Assay kit (Promega). Fresh culture media (50 pi) and media from wells with lysed neural cultures served as blank, and full -release of cellular LDH, control measurements, respectively. For LDH detection, 50 pL of reconstituted substrate mix was added to each 96-well and incubated in the dark, at room temperature for 30 minutes. After which reaction was stopped by adding 50 pi Stop Solution, raw LDH release was measured as single wavelength absorbance of converted formazan product at 490 nm using a Synergy TM 2 Microplate Reader (BioTek). Percentage of LDH release was calculated from the ratio of media-blanked release and full release of cellular LDH. Conditioned medium was sampled, and standard LDH (lactate dehydrogenase) fluorescence assay was performed to evaluate cell damage (Released LDH levels). These fluorescence readings aare positively correlated to compound cytotoxicity and were used to validate interpretations derived from electrophysiological results.

Example 2

In vitro PTX-Seizure Model

[0164] Chemically-induced seizure is widely employed in in vivo and in vitro systems to model acute status epilepticus (single episode of epileptic seizure). Picrotoxin (PTX), along with metrazol, pilocarpine, and kainic acid, are some of the most common convulsants used.

[0165] Current anti-epileptic drug (AED) screening is largely limited to rodent models which are high in cost and low in throughput despite considerable translational validity. No clinically relevant alternatives have been available from in vitro models. We have developed and validated a human-relevant in vitro seizure models for high-throughput, low-cost anticonvulsant screening (as disclosed in U.S. Provisional Patent Application / _ (Atty. Docket number 1106950.00012), titled “Assays For Assessing Anti seizure Activity Of Chemical Compounds”, and filed on date even with this application and which is incorporated by reference in its entirety). This new method can provide a translationally relevant culture of human neuronal network physiology for high-throughput, naive drug screening, as well as for efficacy and neurotoxicity testing during AED candidate discovery and optimization.

[0166] In human neuronal cultures composed of defined ratios of excitatory and inhibitory neuron types, picrotoxin induces acute hyperactivity of neural networks as measured by MEA recordings. This hyperactivity is counteracted in a dose-dependent manner by benchmark AEDs. There is a good correlation of the in vitro efficacy data (MEA EC50) and human plasma levels of these AEDs at therapeutic dose (Figure 2). The Human Total Plasma concentrations for each drug represent the plasma concentration produced by the recommended dosage according to the Prescribing Information for each of these approved drugs. These values serve as surrogates of the in vivo effective concentration of each of the AEDs. PTX EC50 is the weighted mean firing rate EC50 as determined in the in vitro PTX-Seizure Model. That PTX EC50 is generally proportional to Human Total Plasma concentration validates that the model is predictive of efficacy (anti-seizure activity) and the line fit to the data allows one to predict the effective concentration of an AED candidate in humans from the AED candidate’s PTX EC50. As compared to the other AEDs used in this validation study, safinamide and (-)cannabidiol have unusually high protein binding and brain permeability, that is, the ratio of plasma concentration to brain concentration is unusually low. This explains the deviation below the line in Figure 6 of these two compounds.

[0167] Gamma aminobutyric acid type A receptors (GABA_ARS) are ligand-gated chloride ion channels and represent the primary mediators of inhibitory neurotransmission, therefore playing an essential role in orchestrating CNS function. Blocking of GABA_ARS leads to disinhibition of neuronal circuits and excessive neuronal firing. Picrotoxin (PTX) is a potent antagonist of GABA_ARS and can induced severe tonic-clonic seizures upon application in vivo. The hPSC-derived neural co-cultures described herein, consisting of excitatory glutamatergic iN cells, inhibitory GABAergic iN cells, and primary astrocytes, exhibit spontaneous electrical activity within 12 days after seeding and develop coordinated network activity within 21-28 days, as measured on microelectrode arrays. During this time period, application of 10 mM PTX induces acute neuronal hyperactivity characterized by an increased rate of single action potentials as well as an increased frequency of network bursts and an elongation of network burst duration which resembles seizure-like neural activity during status epilepticus (Figure 8). This PTX-induced hyperactivity can therefore be regarded as a simplified proxy for seizure events in patients and be used as an in vitro model for testing anti-seizure effects of therapeutic interventions. As an alternative to PTX, other GABA_AR antagonists such as bicuculline (BIC) or pentylenetetrazol (PTZ) have demonstrated similar responses and can also be used to induce acute seizure-like activity in hPSC-derived neural co-cultures. Example 3

Compound Solution Preparation and Testing

[0168] A total 18 of antiepileptic drugs were tested on the in vitro PTX chemical -induced seizure model with Compound 003 (Table 2). None of the tested compounds has primary targets in GABAergic pathways, except stiripentol. Any anti-convulsant property depending on activating/enhancing GABAergic route may not suitable to evaluate in the PTX chemical-induced seizure model as this model relies on antagonism of GABA_AR by PTX.

[0169] Stock solutions of testing compounds were prepared at 100 mM with DMSO, and aliquoted at 30 pL per vial before stored at -20°C. Small aliquots prevent multiple freeze-thaw cycles and ensures the quality of testing compound. For all experiments, PTX (10 mM) was used to induce seizure-like events in induced neuron cultures, which is here referred to as the challenge or the challenge compound.

[0170] On the day of testing, a compound stock solution was serially diluted with culture media. 10 pL of diluted solution was added to culture wells, so that final working concentration is between 0.1 - 1000 pM. Depending on the potency of testing compounds reported in the literature, a dose-range was selected from one of the following three: low (0.1, 0.3, 1, 3, 10 pM), standard (1, 3, 10, 30, 100 pM), high (10, 30, 100, 300, 1000 pM). At least 5 doses were tested for every compound, and every dose had 6 replicates (Figure 3). For wells designated to vehicle control, 10 pL of 0.1% DMSO in culture media was added.

[0171] Data analysis

[0172] Using Axion NeuralMetricTool (Axion, version 2.5.1), recording files were segmented with 15- minute bins, and metrics of neuronal activity were extracted and exported to CSV files. Parameters for metric extraction is shown in Figure 5. Extracted data were then exported into an in-house built software for further analysis and visualization. Nine metrics were selected to assess neuronal activities: weighted mean firing rate, number of burst, duration of burst, number of events per burst, percent of events in bursts, number of network bursts, duration of network bursts, number of events per network burst, and synchrony index (Figure 4, example of MEA analysis plots, licarbazepine).

[0173] To ensure the quality and consistency of the assay, wells showing low basal activity were excluded from analysis. “Low activity” is defined as “less than 8 active electrodes per well”, and the criterion for an active electrode is having more than 5 events per minutes. Definitions were based on empirical testing and recommendations from the Maestro System manufacturer.

[0174] Compound efficacy was determined by fitting data with dose-response curve from which EC50, E_maX and Hill coefficient were obtained. Exemplary curves for each of the nine evaluated parameters are presented for licarbazepine (Figure 4). It was considered that the weighted mean firing rate best reflected the overall occurrence of seizure-like events. EC50 calculated from weighted mean firing rate was used to compare potency across tested compounds; corresponding published efficacious human total plasma concentrations (that is, the average concentrations achieved by the approved dosage) were also included for correlation plotting (Table 2).

Table 2. AEDs and Compound 003 assessments

*Mean Firing Rate

** Plasma concentration achieved with a 20 mg/kg dosage in cynomolgus monkeys; efficacy not evaluated.

[0175] The data in Table 2 was plotted in Figure 2 and fit to a line by least-squares regression. Example 4

Compound Dose Calculation for Epilepsy Treatment

[0176] Compound 003 is a small molecule which has shown a broad of anticonvulsant activities in animal models and in vitro model based on human induced pluripotent stem cells (HiPSC). Proper treatment dose was calculated based on animal model.

[0177] Use NOAEL to calculate MRSD (the maximum recommended starting dose]

[0178] There are five steps to calculate MRSD in entry into human studies. In brief, determine NOAEL’s in rodent and non-rodent animal species, then convert NOAEL to HED, select appropriate animal species most relevant to human metabolism, apply safety factor, and finally, convert to pharmacologically active dose. In general, animal species with the lowest HED are considered the most sensitive species for determining human risk and is usually selected.

[0179] Initial Compound 003 dose determination by “dose by factor”

[0180] In FDA recommended “dose by factor” dose extrapolation approach, an empirical equation for HED determination shown below has been adopted. (See Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, FDA, July 2005).

HED (mg/kg) = Animal NOAEL (mg/kg) x (Weight of animal [kg] /Weight of human [kg]) ^{(1 067)}

[0181] For Compound 003, the NOAEL value in SD rat (Sprague Dawley) weighing approximately 270 g is 200 mg/kg. To calculate the starting dose for human studies, HED (mg/kg) = 200 x (0.27/60)° ³³ = 33.6 mg/kg. Thus, for a 60 kg human, the dose is 2,017 mg. This HED value is further divided by a factor value of 10; thus, the initial maximum recommended starting dose in entry into human study is 201.7 mg, namely 3.4 mg/kg.

Example 5

Experimental procedure: Compound 003 ECso determination

[0182] A Compound 003 stock solution was prepared at 100 mM in DMSO, and aliquoted at 30 pL per vial before storage at -20 °C. Picrotoxin (PTX, 10 mM), which was referred to as the challenge or the challenge compound, was used to induce seizure-like events in induced neuron cultures.

[0183] 100 mM stock solution of Compound 003 and vehicle (DMSO) were diluted with culture media to the specific concentrations to be used for testing. 10 pL of diluted solution was added to culture wells to ensure Compound 003 reached the test concentrations in logarithm gradient scale, which was from 1.0 to 100 mM. Five concentrations were tested and every concentration was repeated 6 times (Figure 3). For wells designated as vehicle controls, 0.1% DMSO was used instead. Axion NeuralMetricTool (Axion, version 2.5.1) was used to record segmented fdes with 15-minute bin, then metrics of neuronal activities were extracted and exported to CSV fdes. Parameters for metrics extraction is shown in Figure 5. Next, extracted data were processed using in-house designed software for further analysis and visualization. Nine metrics were selected to assess neuronal activities, namely weighted mean firing rate, number of burst, duration of burst, number of events per burst, percent of events in bursts, number of network bursts, duration of network bursts, number of events per network burst, and synchrony index (Figure 6).

[0184] Compound 003 efficacy was determined by fitting data with dose-response curves where EC 50, E_max (maximum seizure-event inhibition) and Hill coefficient were obtained. EC50 calculated from weighted mean firing rate was used to compare potency across testing compounds (Table 2 and Figure 6).

Example 6

Dose determination by pharmacokineticallv-guided approach

[0185] In vitro efficacy data, rat brain permeability data, rat in vivo Maximal Electroshock (MES) efficacy data, and rat pharmacokinetics parameters were utilized to provide an estimated initial dose.

[0186] In rat MES model of generalized tonic -clonic epilepsy, Compound 003 showed an ED₅₀ of 20.1 mg/kg via oral dosing. In the pharmacokinetics study conducted in SD rat with the same dose and administration, Compound 003’s plasma and brain concentration reach 7.8 mM (Cmax) and 40 pM (Cbram). respectively, at an oral dose of 20 mg/kg. Therefore, the total brain concentration is approximately 5 times that observed in plasma. The brain concentration is also almost twice the 19.5 pM EC₅₀ obtained from the HiPSC-based epilepsy in vitro model (Figure 7). This result indicates that a dose of Compound 003 around 10 mg/kg p.o. would be sufficient to provide a concentration in rat brain corresponding to the in vitro EC₅₀. The ED₅₀ of AEDs vary considerably from one rat epilepsy model to another, and they are therefore not considered to be good predictors of efficacious doses in human. Instead, the in vitro MEA EC₅₀ is taken as the better predictor of effective concentration in human.

[0187] Based on the correlation between MEA EC50 and human efficacious plasma concentrations of 18 AEDs (antiepileptic drugs), which is established in HiPSC based epilepsy in vitro model (Figure 7), the plasma level of a drug with an in vitro EC50 of 19.5pM, such as Compound 003, should reach 30 - 50 pM in human to show efficacy. Assuming the brain permeability of Compound 003 in human is similar to SD rat (K_p = 5.1), it is reasonable to estimate that a total plasma concentration of 30-50 pM would correspond to a concentration of 150 - 250 pM in human brain, which is approximately 7 - 13 fold higher than the in vitro EC50 (19.5 pM). Considering the good brain permeability and extensive tissue binding of Compound 003, it is likely that the line fit to the data for the 18 known AEDs tested overestimated the necessary plasma concentration - as it does for safinamide and CBD. Thus, the human dose should be adjusted according to a similar drug approach, for example, the doses of safinamide (anti-Parkinson’s disease drug) used in phase I clinical trial for epilepsy, namely 100 and 300 mg/day (Safinamide and glutamate release: new insights. XXI World Congress on Parkinson's disease and related disorders at Milan, DOI: 10.13140/RG.2.1.3815.3043).

[0188] Interestingly, Compound 003 ’s plasma exposure level reached 25 mM at 20 mg/kg oral dose in the pharmacokinetic study carried out in cynomolgus monkey (Figure 7), which is approximately 3 times the exposure level in rat plasma that dosage achieves (7.8 pM) . Assuming similar brain penetration in monkey as in rat (K_p 5.1), Compound 003 would reach 125 pM in cynomolgus monkey brain with 20 mg/kg oral dose. Since Compound 003 EC50 as measured by the cell based model is 19.5 pM, the oral dose should be reduced 6.4-fold (20 mg/kg x 19.5/125), which equals to 3.1 mg/kg, 186 and 217 mg/kg/day for a 60 or 70 kg person, respectively. 3.1 mg.kg is in line with MRSD (3.4 mg/kg) derived from NOAEL in SD rat.

[0189] The dose extrapolation above indicated that Compound 003 doses for human clinical trial would be 100 (low), 200 (medium), and 400 (high) mg//kg/day. The high dose is further adjusted according to Compound 003 toxicity and adverse effects at low and medium doses, such as in the range of about 50 mg/day to 500 mg/day.

Example 7 Formulations

[0190] An intravenous dosing solution was prepared as follows:

The test substance was weighed and dissolved in the vehicle of PEG300:0.9% saline in a ratio of 2:1 (v/v). The resulting solution was filtered through a 0.22 pm membrane and used at a concentration of 2.5 mg/mL.

[0191] An oral dosing solution was prepared as follows:

Vehicle: Captex200P/CremophorEL (50:50, w/w)

[0192] 25 g of Captex200P and 25 g Cremophor EL were weighed, combined, and stirred (1000 rpm, 40-45 °C) for 30 min to obtain a clear solution, then stored at room temperature. Test substance was dissolved in the vehicle (Captex200P/CremophorEL50:50, w/w) by stirring (1000 rpm, 40-45 °C) for 30 min. The resulting clear solution was used at a concentration of 4 mg/mL [0193] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and/or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

[0194] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0195] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0196] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0197] The terms “a,” “an,” “the” and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. , “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0198] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of’ excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0199] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

Claims

1. A method for treating a subject diagnosed with epilepsy and in need of such treatment, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I,

Formula (I) wherein:

R¹ is selected from the group consisting of Ci-C₆ alkyl, C i -G, alkoxy, C i -G alkyl-ester, C i -G, alkyl-amide, Ci-C₆ alkyl-acid, C i -G haloalkyl, C i -G haloalkoxy, Ci-C₆ haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl, alkynyl, aryl- alkynyl, cycloalkenyl, heterocycloalkenyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O- heterocycloalkyl, and alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, each Ri group being optionally substituted with one or more independently-selected groups R₅;

R² and R³ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or

R² and R³ connect to form, together with the carbon atom to which they are attached, a three to seven- membered carbocyclic or heterocyclic ring; and

R⁴ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

X and Q are independently selected from CFF, O, NR₇, S, SO and SO₂;

R₅ is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO₂R₅, CONHR₅, CON(R_f,)₂. SO₂NHR₅, S0₂N(R_f,)₂. C₁-C₆ alkyl, C ₁ -G, alkoxy, C ₁ -G, lower alkyl-ester, C ₁ -G, alkyl-amide, C ₁ -G, lower alkyl-acid, C ₁ -G, lower haloalkyl, C ₁ -G, lower haloalkoxy, C₁-C₆ haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O- alkylene-cycloalkyl and alkylene-O-alkylene-heterocycloalkyl; and 5 and R₇ are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, provided that at least one of R¹, R² and R³ comprises a fluorine atom; wherein the dose of said compound is from 15 mg/day to 700 mg/day.

2. A composition comprising an orally administrable formulation comprising an effective dose of a compound of Formula I,

Formula (I) wherein:

R¹ is selected from the group consisting of Ci-Ce alkyl, C₁-C₆ alkoxy, Ci-Ce alkyl-ester, C₁-C₆ alkyl-amide, C₁-C₆ alkyl-acid, Ci-Ce haloalkyl, C₁-C₆ haloalkoxy, Ci-Ce haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, alkenyl, aryl-alkenyl, heteroaryl-alkenyl, alkynyl, aryl- alkynyl, cycloalkenyl, heterocycloalkenyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O- heterocycloalkyl, and alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, each Ri group being optionally substituted with one or more independently-selected groups R₅;

R² and R³ are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or

R² and R³ connect to form, together with the carbon atom to which they are attached, a three to seven- membered carbocyclic or heterocyclic ring; and R⁴ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

X and Q are independently selected from CTh, O, NR₇, S, SO and SO₂;

R5 is selected from the group consisting of hydroxy, halogen, cyano, nitro, CO2R5, CONHR5, (30N(I%)₂, SO2NHR5, S02N(R_<5)2, Ci-Ce alkyl, Ci-Ce alkoxy, C1-C6 lower alkyl-ester, C1-C6 alkyl-amide, C1-C6 lower alkyl-acid, C1-C6 lower haloalkyl, C1-C6 lower haloalkoxy, C1-C6 haloalkyl-ester, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl, heteroaryl, hydroxyalkyl, hydroxycycloalkyl, hydroxy-heterocycloalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkylenearyl, alkyleneheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O- alkylene -cycloalkyl and alkylene-O-alkylene-heterocycloalkyl; and 5 and R7 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, provided that at least one of R¹, R² and R³ comprises a fluorine atom; wherein the concentration of said compound is from 0.01% to 50% by weight.

3. The composition of claim 2, wherein the concentration of said compound is from 1% to 25% by weight.

4. The composition of claim 2, further comprising as excipients, one or more of:

0.01% to 70% by weight of one or more triglyceride lipids;

0.01% to 25% by weight of one or more surfactants;

0.01% to 95% by weight of one or more hydrophilic co-surfactants; and 0.01% to 50% by weight of saline or water.

5. The composition of claim 4, comprising 20% to 60% by weight of one or more triglyceride lipids.

6. The composition of claim 4, comprising 5% to 15% by weight of one or more surfactants.

7. The composition of claim 4, comprising 20% to 70 % by weight of one or more hydrophilic co surfactants.

8 The composition of claim 4 comprising:

20% to 60% by weight of one or more triglyceride lipids;

5% to 15% by weight of one or more surfactants;

20% to 70% by weight of one or more hydrophilic co-surfactants; and 0.01% to 50% by weight of saline or water.

9. The method of claim 1, wherein the epilepsy is focal epilepsy.

10. The method of claim 9, wherein the focal epilepsy is focal aware epilepsy.

11. The method of claim 9, wherein the focal epilepsy is focal impaired awareness epilepsy.

12. The method of claim 9, wherein the focal epilepsy is focal motor epilepsy.

13. The method of claim 9, wherein the focal epilepsy is focal non-motor seizure epilepsy.

14. The method of any one of claims 1 or 10-13, wherein the pharmaceutical composition is administered acutely.

15. The method of claim 14, wherein administration is by intravenous injection.

16. The method of claim 14, wherein as a result of the administration, the onset of seizure is prevented, or the severity or duration of seizure is reduced.

17. The method of any one of claims 1 or 10-13, wherein the pharmaceutical composition is administered chronically.

18. The method of claim 17, wherein administration is by oral administration, nasal administration, intramuscular injection, or subcutaneous injection.

19. The method of claim 17, wherein the frequency, severity, or duration of seizure is reduced.