Treatment of epileptic conditions with GABAA receptor modulators

Abstract

Disclosed herein are GABA receptor antagonists for the treatment of epileptic conditions. A Receptor Modulators and GABA A Also disclosed herein are compositions comprising the GABA receptor modulators described herein. A A method of treating an epileptic condition in a subject by administering a receptor modulator or composition.

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 925,081, filed October 23, 2019, and U.S. Provisional Patent Application No. 62 / 950,674, filed December 19, 2019, each of which is incorporated herein by reference in its entirety. Statement of Federally Funded Research

[0002] This invention was made with government support under Award Number R43NS107051 awarded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The U.S. Government has certain rights in this invention. Summary of the Invention [Means for solving the problem]

[0002]

[0003] Disclosed herein are compounds of general formula (1a), general formula (1b) or general formula (1c):

[0003] [ka]

[0004] [where, X 1 , X 2 , X 1 , X 4 and X 5 are independently -C, -N, -S or -O, and X 1 , X 2 , X 3 , X 4 and X 5 At least two of the groups are -N, and Y 1 and Y 2 are independently -C or -N, and R 1 m m is 1, and R 1is unsubstituted phenyl, phenyl substituted with C1-C4 alkyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 and R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl, and R 2 n n is 1 or 2, and each R 2 are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen, or -O-CH2-R 4 and R 4 is a substituted or unsubstituted 5- or 6-membered heteroaryl, and Z 1 , Z 3 , Z 4 , and Z 5 are independently -C, -N, -S or -O, and A 1 , and A 2 and A 3 are independently -C, -N, or -(C=O)-OR 7 ,or

[0005] [ka]

[0006] and R 7 is alkyl, and B 1 , B 2 , B 3 , and B 4 are independently -C, -N, or -O, and R 21 s s is 1, 2, 3 or 4, and R 5 l l is 1 or 2, and each R 5 are independently C1-4 alkynyl or halogen, and R 6 k k is 1, 2, 3, or 4, and each R 6are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, or hydrogen; R 12 p p is 1 or 2, and each R 12 are independently substituted or unsubstituted C1-C4-alkyl, I, Br, Cl or F, and R 13 q q is 1, 2, 3 or 4, and each R 13 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen to treat the epileptic condition in the subject. In some embodiments, the compound is represented by the general formula (2), (3), (4), (5), (1c), or (7):

[0007] [ka]

[0008] It is of the type. In some embodiments, the compound has the general formula (2a), (3a), (4a), (5a), (5b), (1c), or (7a):

[0009] [ka]

[0010] It is of the type. In some embodiments, R 1 m is 1 and R 1 is unsubstituted phenyl, substituted phenyl containing C1-C4-alkyl, F, Cl, Br, I, -CN as a substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, substituted biphenyl containing at least one -CN as a substituent, or -(C=O)-R 3 and R 3is pyridine. In some embodiments, the compound has the general formula (2a'), (3a'), (4a'), (5a'), (5b'), (VI) or (7a'):

[0011] [ka]

[0012] [In the formula, R 10 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 alkyl, or hydrogen, and R 11 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 alkyl, or hydrogen, or R 12 p is 1 and R 12 is I, Br, Cl, or F. In some embodiments, the compound is of the general formula (2a"), (3a"), (4a"), (5a"), (5b"), (VIa"), or (7a")

[0013] [ka]

[0014] [In the formula, R 7 is an unsubstituted C1-C6 alkyl, an unsubstituted C3-C8 cycloalkyl, or an unsubstituted C1-C6 alcohol; R 8 , -O-CH2-R 4 and R 4 is a substituted or unsubstituted 5-membered heteroaryl or an unsubstituted C1-C6 alcohol, and R 9 is an unsubstituted C6 heteroaryl or halogen, or R 9 is an unsubstituted 6-membered heteroaryl in formula (4a") or a halogen in formula (5b"), R 10 is C1-C3 alkyl or hydrogen, and R 11 is a substituted or unsubstituted aryl or heteroaryl, and R 14 is a substituted or unsubstituted aryl or heteroaryl, and R 12is I, Cl, Br or F, or R 5 is C2 alkynyl or I. In some embodiments, the compound is an α1, α2, α3, or α5 GABA A In some embodiments, the compound is a positive allosteric α2 or α3 GABA receptor modulator. A In some embodiments, the compound is a receptor modulator. In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the subject is 0-17 years old. In some embodiments, the subject is 18-130 years old. In some embodiments, the therapeutically effective amount of the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the epileptic condition is selected from the group consisting of benign childhood epilepsy of the centrotemporal lobe, benign childhood occipital lobe epilepsy (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, West syndrome, Dravet syndrome, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS).

[0015] Also disclosed herein is a compound of general formula (1a), general formula (1b) or general formula (1c):

[0016] [ka]

[0017] [where, X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, -S or -O, and X 1 , X 2 , X 3 , X 4 and X 5At least two of the groups are -N, and Y 1 and Y 2 are independently -C or -N, and R 1 m m is 1, and R 1 is unsubstituted phenyl, phenyl substituted with C1-C4 alkyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 and R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl, and R 2 n n is 1 or 2, and each R 2 are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen, or -O-CH2-R 4 and R 4 is a substituted or unsubstituted 5- or 6-membered heteroaryl, and Z 1 , Z 3 , Z 4 , and Z 5 are independently -C, -N, -S or -O, and A 1 , and A 2 and A 3 are independently -C, -N, or -(C=O)-OR 7 ,or

[0018] [ka]

[0019] and R 7 is alkyl, and B 1 , B 2 , B 3 , and B 4 are independently -C, -N, or -O, and R 21 s s is 1, 2, 3 or 4, and R 5 l l is 1 or 2, and each R 5are independently C1-C4 alkynyl or halogen, and R 6 k k is 1, 2, 3, or 4, and each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, or hydrogen; R 12 p is 1 or 2, or each R 12 are independently substituted or unsubstituted C1-C4-alkyl, I, Br, Cl or F, and R 13 q is 1, 2, 3 or 4, and each R 13 and R is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen to treat epilepsy associated with sodium channel mutations. In some embodiments, the compound is represented by the general formula (2), (3), (4), (5), (1c), or (7):

[0020] [ka]

[0021] It is of the type. In some embodiments, the compound has the general formula (2a), (3a), (4a), (5a), (5b), (1c), or (7a):

[0022] [ka]

[0023] It is of the type. In some embodiments, R 1 m m is 1 and R 1is unsubstituted phenyl, substituted phenyl containing C1-C4-alkyl, F, Cl, Br, I, -CN as a substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, substituted biphenyl containing at least one -CN as a substituent, or -(C=O)-R 3 and R 3 is pyridine. In some embodiments, the compound has the general formula (2a'), (3a'), (4a'), (5a'), (5b'), (VI) or (7a'):

[0024] [ka]

[0025] [In the formula, R 10 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 alkyl, or hydrogen, and R 11 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 alkyl, or hydrogen, or R 12 p p is 1 and R 12 is I, Br, Cl, or F. In some embodiments, the compound is of the general formula (2a"), (3a"), (4a"), (5a"), (5b"), (VIa"), or (7a")

[0026] [ka]

[0027] [In the formula, R 7 is an unsubstituted C1-C6 alkyl, an unsubstituted C3-C8 cycloalkyl, or an unsubstituted C1-C6 alcohol; R 8 is -O-CH2-R 4 and R 4 is a substituted or unsubstituted 5-membered heteroaryl or an unsubstituted C1-C6 alcohol, and R 9 is an unsubstituted C6 heteroaryl or halogen, or R 9is an unsubstituted 6-membered heteroaryl in formula (4a") or a halogen in formula (5b"), and R 10 is C1-C3 alkyl or hydrogen, and R 11 is a substituted or unsubstituted aryl or heteroaryl, and R 14 is a substituted or unsubstituted aryl or heteroaryl, and R 12 is I, Cl, Br or F, or R 5 is C2 alkynyl or I. In some embodiments, the compound is an α1, α2, α3, or α5 GABA A In some embodiments, the compound is a positive allosteric α2 or α3 GABA receptor modulator. A In some embodiments, the compound is a receptor modulator. In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the subject is 0 to 17 years old. In some embodiments, the subject is 18 to 130 years old. In some embodiments, the therapeutically effective amount of the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the sodium channel mutation comprises a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene.

[0028] Also disclosed herein is a method for producing a medicament for the treatment of a pulmonary arthritis, comprising:

[0029] [ka]

[0030] and a polymorph thereof, wherein the compound is selected from the group consisting of:

[0031] [ka]

[0032] , a salt thereof, or a polymorph thereof. In some embodiments, the amount, when administered to a subject, is from about 0.003 mg / kg to about 10 mg / kg per day of the subject's body weight (e.g., from about 0.003 mg to about 100 mg per kg, from about 0.003 mg to about 95 mg, from about 0.003 mg to about 90 mg, from about 0.003 mg to about 85 mg, from about 0.003 mg to about 80 mg, from about 0.003 mg to about 75 mg, from about 0.003 mg to about 70 mg, from about 0.003 mg to about 65 mg, from about 0.003 mg to about 60 mg, from about 0.003 mg to about 55 mg, from about 0.003 mg to about 50 mg, from about 0.003 mg to about 45 mg, from about 0.003 mg to about 50 mg, from about 0.003 mg to about 65 ...0 mg, from about 0.003 mg to about 65 mg, from about 0.003 mg to about 50 mg, from about 0.003 mg to about 65 mg, from about 0.003 mg to about 50 mg, from about 0.003 mg to about 65 mg, from about 0.003 mg to about 60 mg, from about 0.003 mg to about 55 mg, from about 0.003 mg to about 50 mg, In some embodiments, the subject is effective in treating Dravet syndrome when administered at a dose of about 0.003 mg to about 40 mg, about 0.003 mg to about 35 mg, about 0.003 mg to about 30 mg, about 0.003 mg to about 25 mg, about 0.003 mg to about 20 mg, about 0.003 mg to about 15 mg, about 0.003 mg to about 10 mg, about 0.003 mg to about 9 mg, about 0.003 mg to about 8 mg, about 0.003 mg to about 7 mg, about 0.003 mg to about 6 mg, about 0.003 mg to about 5 mg, about 0.003 mg to about 4 mg, about 0.003 mg to about 3 mg, about 0.003 mg to about 2 mg, or about 0.003 mg to about 1 mg. In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the pharmaceutical composition comprises a carrier, and the carrier is methylcellulose. In some embodiments, the compound is

[0033] [ka]

[0034] , a polymorph thereof, or a salt thereof. In some embodiments, the pharmaceutical composition comprises a salt of the compound. In some embodiments, the salt is a phosphate salt. In some embodiments, the salt is a sulfate salt. In some embodiments, the pharmaceutical composition comprises a polymorph of the compound. In some embodiments, the polymorph is (a) Cu:K-α(

[0035] [ka]

[0036] (b) X-ray wavelength parameters of 40 kV and 40 mA; (c) a scanning scope of about 3° to about 40°; (d) a sample rotation rate of about 15 rpm; and (e) an X-ray powder diffraction (XRPD) having at least three characteristic peak positions of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2° 2-theta, when measured using a scan rate of 10° per minute. In some embodiments, administering comprises oral administration. In some embodiments, administration occurs at least once daily. In some embodiments, administration of an amount effective to treat Dravet Syndrome does not result in drowsiness or sedation in the subject.

[0037] Also disclosed herein is a compound of the formula:

[0038] [ka]

[0039] or a pharmaceutically acceptable salt thereof, or a polymorph thereof, to treat the epileptic condition in the subject, wherein the amount is from about 0.003 mg / kg to about 10 mg / kg (i.e., from about 0.003 mg / kg to about 100 mg / kg, from about 0.003 mg / kg to about 95 mg / kg, from about 0.003 mg / kg to about 90 mg / kg). g, about 0.003mg / kg to about 85mg / kg, about 0.003mg / kg to about 80mg / kg, about 0.003mg / kg to about 75mg / kg, about 0.003mg / kg to about 70mg / kg, about 0 .003mg / kg~about 65mg / kg, about 0.003mg / kg~about 60mg / kg, about 0.003mg / kg~about 55mg / kg, about 0.003mg / kg~about 50mg / kg, about 0.003 mg / kg~about 45mg / kg, about 0.003mg / kg~about 40mg / kg, about 0.003mg / kg~about 35mg / kg, about 0.003mg / kg~about 30mg / kg, about 0.003mg / k g~about 25mg / kg, about 0.003mg / kg~about 20mg / kg, about 0.003mg / kg~about 15mg / kg, about 0.003mg / kg~about 10mg / kg, about 0.003mg / kg~about 9 In some embodiments, administration reduces the amount of seizures to at least 20% less than the amount of seizures that would occur upon administration of an equivalent dose of clobazam. In some embodiments, the amount includes a dose of about 0.08 mg / kg to about 2.5 mg / kg. In some embodiments, the compound is in a shelf-stable formulation. In some embodiments, the compound is formulated in a non-drowsy formulation. In some embodiments, the non-drowsy formulation includes caffeine. In some embodiments, the compound, pharmaceutically acceptable salt, or polymorph thereof is a phosphate salt or a polymorph thereof.In some embodiments, the compound, pharmaceutically acceptable salt, or polymorph thereof is a sulfate salt or a polymorph thereof.

[0040] Disclosed herein is a compound of general formula (5a'):

[0041] [ka]

[0042] [In the formula, R 1 is unsubstituted phenyl, phenyl substituted with C1-C4 alkyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl, or -(C=O)-R 3 (In the formula, R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl; R 2 n n is 1 or 2, and each R 2 are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen, or -O-CH2-R 4 (In the formula, R 4 or a salt or polymorph thereof, wherein Administration is in an amount effective to treat an epileptic condition in a subject, which amount comprises a dose of about 0.003 mg to about 1 mg of the compound or a salt or polymorph thereof per kg of body weight of the subject per day.

[0043] [ka]

[0044] or a salt or polymorph thereof, wherein the administration is in an amount effective to treat the epileptic condition in the subject, the amount comprising a dose of about 0.0003 mg to about 1 mg of the compound or its salt or polymorph per kg of body weight of the subject per day. In some embodiments, the epileptic condition is generalized epilepsy or diathesis epilepsy. In some embodiments, the epileptic condition is Dravet syndrome. In some embodiments, the epileptic condition is focal seizures. In some embodiments, the epileptic condition is selected from the group consisting of benign childhood epilepsy of the centrotemporal lobe, benign childhood occipital lobe epilepsy (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, cerebral palsy, hypoxic encephalopathy, Down syndrome, hypoxic-ischemic encephalopathy (HIE), West syndrome, Dravet syndrome, focal seizures, progressive myoclonic epilepsy, focal seizures, or Lennox-Gastaut syndrome (LGS). In some embodiments, the compound, or a salt or polymorph thereof, is a phosphate salt or a polymorph thereof. In some embodiments, the compound, or a salt or polymorph thereof, is a sulfate salt or a polymorph thereof. In some embodiments, the compound, or salt or polymorph thereof, is a polymorph of a phosphate salt, wherein the polymorph of the phosphate salt has a 2-theta of about 6.4° when measured using (a) X-ray wavelength parameters of Cu:K-α (λ=1.54179 Å); (b) X-ray tube voltage setting of 40 kV and current of 40 mA; (c) a scanning scope of about 3° to about 40°; (d) a sample rotation rate of about 15 rpm; and (e) a scan rate of 10° per minute. , 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2°.In some embodiments, the pharmaceutical composition is formulated for oral or transdermal administration. In some embodiments, the amount comprises a dose of less than 0.3 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the amount comprises a dose of less than 0.1 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the amount comprises a dose of less than 0.03 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the epileptic condition is Dravet syndrome. In some embodiments, the epileptic condition is focal seizures. In some embodiments, the compound, or a salt or polymorph thereof, is not a phosphate salt or a polymorph thereof, and is not a sulfate salt or a polymorph thereof. In some embodiments, the subject is a human subject. In some embodiments, the compound is formulated in a non-drowsy formulation. In some embodiments, the non-drowsy formulation includes caffeine. In some embodiments, the subject is a human.

[0045] The novel features of the exemplary embodiments are set forth with particularity in the appended claims. A better understanding of these features and advantages will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the exemplary embodiments are utilized, and the accompanying drawings in which: [Brief explanation of the drawings]

[0046] [Figure 1]

[0009] Figure 1 shows the starting body temperatures (mean (±SEM)) of pretreated female mice before the onset of heat-induced seizures. The mean body temperatures of the female mice ranged from about 34.5°C to about 35.5°C before inducing heat-induced seizures. [Figure 2]

[0010] Figure 1 shows the starting body temperatures (mean (±SEM)) of pretreated male mice before the onset of heat-induced seizures. The mean body temperatures of the male mice ranged from about 34.5°C to about 35.5°C before inducing heat-induced seizures. [Figure 3]

[0011] Figure 1 shows the average starting body temperature (mean (±SEM)) of all pretreated mice prior to the onset of heat-induced seizures. The average body temperature (mean (±SEM)) of the mice ranged from about 34.5°C to about 35.3°C before inducing heat-induced seizures. [Figure 4]

[0012] Figure 1 shows the final body temperatures (mean (±SEM)) of female mice in the seizure study. Final body temperatures rose to approximately 42°C (ranging from about 40.5°C to about 42.5°C), which is sufficient to induce heat-induced seizures in mouse models without treatment with clobazam or GABAA receptor modulators. [Figure 5]

[0013] Figure 1 shows the final body temperature (mean (±SEM)) of male mice in the seizure test. Final body temperature rose to approximately 42°C (ranging from about 40.5°C to about 42.5°C), which is sufficient to induce heat-induced seizures in a mouse model without antiepileptic treatment. [Figure 6]

[0014] Figure 1 shows the average final body temperature (mean (±SEM)) of all mice in the seizure test. Final body temperature rose to approximately 42°C (ranging from about 40.5°C to about 42.5°C), which is sufficient to induce heat-induced seizures in a mouse model without antiepileptic treatment. Administration of vehicle resulted in the lowest overall body temperature in mice. [Figure 7]

[0015] Figure 1 shows the total change in body temperature (mean (±SEM)) of female mice during the seizure test. The body temperature of female mice was increased between 5°C and 8°C to induce heat-induced seizures in the mouse model. [Figure 8]

[0016] Figure 1 shows the total change in body temperature (mean (±SEM)) of male mice during the seizure test. The body temperature of male mice was increased between 5°C and 8°C to induce heat-induced seizures in the mouse model. [Figure 9]

[0017] Figure 1 shows the average total change in body temperature (mean (±SEM)) for all mice during the seizure study. Mouse body temperature was elevated between 5°C and 8°C to induce heat-induced seizures in the mouse model. Mice treated with the vehicle control experienced an overall body temperature increase of 5°C, which was lower than mice receiving the other treatments. [Figure 10]

[0018] Figure 1 shows the mean (±SEM) change in body temperature per minute for female mice during the seizure test. The change in body temperature per minute for female mice ranged from about 0.4°C / min to about 0.6°C / min. [Figure 11]

[0019] Figure 1 shows the mean (±SEM) change in body temperature per minute for male mice during the seizure test. The change in body temperature per minute for male mice ranged from about 0.4°C / min to about 0.6°C / min. [Figure 12]

[0020] Figure 1 shows the average change in body temperature per minute (mean (±SEM)) for all mice during the seizure test. The change in body temperature per minute for mice ranged from about 0.4°C / min to about 0.6°C / min. Mice administered vehicle had the highest rate of increase in body temperature per minute (about 0.6°C / min), while mice administered 100 mg / kg of the exemplary GABAA receptor modulator Compound 2 had the lowest rate of increase in body temperature per minute (about 0.4°C / min). [Figure 13]

[0021] Figure 1 shows a summary of the efficacy of each treatment in seizure testing. Exemplary GABAA receptor modulators Compound 1 and Compound 2 were each effective in preventing heat-induced seizures in a mouse model. Administration of GABAA receptor modulator Compound 2 prevented seizures in a dose-dependent manner. [Figure 14-1]

[0022] Figure 1 shows exemplary GABAA receptor modulators that are effective in treating epileptic conditions. [Figure 14-2] FIG. 1 shows exemplary GABAA receptor modulators that are effective in treating epileptic conditions. DETAILED DESCRIPTION OF THE INVENTION

[0047]

[0023] Definition The term "GABA receptor" may be used in its known sense in the field of biochemistry; the term "GABA receptor" may refer to a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A GABA receptors (ionotropic receptors) are ligand-gated ion channels, also known as metabotropic receptors. B The receptor is a G protein-coupled receptor. A GABA receptors are the most common and most important inhibitory receptors in the central nervous system. A There are eight classes of receptors: α 1~6 , β 1~3 , γ 1~3 , δ, ε, π, θ, and ρ 1~3 Contains five subunits, grouped into GABA A Most receptors contain two α, two β, and one γ subunit. Compounds, such as benzodiazepines, can bind to sites different from those of the endogenous ligand GABA. For example, benzodiazepines can bind to a binding site located between the α and γ subunits. The compounds described herein bind to GABA. A The different types of subunits can be allosteric modulators of the GABA receptor. A The α1 subunit is responsible for, among other functions, the sedative effects of benzodiazepines, while the α2 subunit is involved, among other things, in the anxiolytic function of those receptors, and the α3 subunit is responsible, among other things, for the GABA A It confers muscle relaxant properties to the receptor.

[0048] The term "allosteric modulator" can be used in its known sense in the fields of biochemistry and pharmacology; it can refer to a substance that indirectly modulates the effect of an agonist at a receptor. A positive allosteric modulator can induce an amplification of the effect of an agonist without having any effect by itself in the absence of an agonist. An allosteric modulator can bind to a site that is different from the (allosteric) binding site of an agonist.

[0049] As used herein, the terms "subject," "patient," or "individual" can encompass mammals and non-mammals. Mammals can be any member of the mammalian class, including, but not limited to, humans, non-human primates such as chimpanzees, apes, or other simian species; agricultural livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs (or canines), and cats (or felines); and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Non-mammals can include birds, fish, and the like. In some embodiments, the subject can be a mammal. In some embodiments, the subject can be a human. In some cases, the human can be an adult. In some cases, the human can be a child. In some cases, the human can be between 0 and 17 years of age. In some cases, the human can be between 18 and 130 years of age. In some cases, the subject can be a male. In some cases, the subject can be a female. In some cases, a subject can be diagnosed with a condition or disease, or can be suspected of having a condition or disease. In some cases, a disease or condition, or an epileptic condition. A subject can be a patient. A subject can be an individual. In some cases, subject, patient, or individual can be used interchangeably.

[0050]

[0027] As used herein, the terms "treat," "treating," "treatment," "improve," or "improving," and other grammatical equivalents, can include alleviating or relieving the symptoms of a disease or condition, inhibiting a disease or condition, for example, halting the occurrence of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or arresting the symptoms of a disease or condition.

[0051] "Alkyl" can mean, for example, a saturated, straight-chain or branched hydrocarbon having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms, wherein one carbon-carbon bond may be unsaturated and one CH moiety may be replaced with oxygen (ether bridge). Non-limiting examples of C1-C4 alkyl are methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, tert-butyl, but-3-enyl, prop-2-ynyl and but-3-ynyl. Unless otherwise specified in the specification, alkyl groups can be optionally substituted.

[0052] The term "alkynyl" can refer to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group can have from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Although this definition may encompass occurrences of the term "alkynyl" where a numerical range cannot be specified, whenever an alkynyl group appears herein, a numerical range, such as "C2-C6 alkynyl," can mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. In some embodiments, alkynyl can refer to any C1-C6 alkyl group. 10Alkynyl, C1-C9 alkynyl, C1-C8 alkynyl, C1-C7 alkynyl, C1-C6 alkynyl, C1-C5 alkynyl, C1-C4 alkynyl, C1-C3 alkynyl, C2-C 10 The alkynyl group can be alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkynyl can be optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkynyl can be optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkynyl can be optionally substituted with halogen.

[0053] The term "aryl" refers to a cyclic aromatic C-C 10 It can mean hydrocarbon. Examples of aryl can include, but are not limited to, phenyl, naphthyl, and heteroaryl. The term "heteroaryl" can mean an aryl compound in which at least one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom. Examples of heteroaryl can include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazine, quinoline, benzofuran, and indole. An aryl or heteroaryl can optionally be substituted. An aromatic hydrocarbon can be neutral or charged. As used herein, an aryl or heteroaryl group can optionally include one or more additional substituent groups.

[0054] "Cycloalkyl" can mean a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which can include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl can be attached through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (C3 to C6). 15 Cycloalkyl), 3 to 10 carbon atoms (C3 to C 10In some embodiments, cycloalkyl can be a 3- to 6-membered cycloalkyl. In some embodiments, cycloalkyl can be a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls can include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles can include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls can include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified specifically in the specification, cycloalkyls can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl can be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl can be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0055] "Halo" or "halogen" can refer to bromo (Br), chloro (Cl), fluoro (F), or iodo (I). In some embodiments, halogen can be Br, F, or Cl. In some embodiments, halogen can be F.

[0056] The term "about" can mean within an acceptable range of error for a particular value, as determined by the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within or more than 1 standard deviation, per practice in the art. Alternatively, "about" can mean within 20%, 10%, 5%, or 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of the value. Where specific values ​​are described in this application and claims, unless otherwise specified, the term "about" meaning within an acceptable range of error for the particular value should be assumed.

[0057]

[0034] Conditions Disclosed herein are compounds for the treatment of epileptic conditions. The compounds described herein (e.g., GABA A GABA receptor modulators can be used to at least partially ameliorate epileptic conditions. A Administration of a receptor modulator can effectively treat the onset of seizures associated with an epileptic condition. As used herein, the term epileptic condition can refer to a condition accompanied by seizures. In some embodiments, treatment includes reducing or preventing the onset of seizures associated with an epileptic condition. In some embodiments, the seizures are accompanied by convulsions. In some embodiments, an epileptic condition accompanied by seizures is also accompanied by convulsions. In some embodiments, an epileptic condition accompanied by seizures may not be accompanied by convulsions.

[0058] Seizures are often associated with many diseases or conditions. For example, seizures may be associated with Angelman syndrome, arteriovenous malformations, brain abscesses, brain tumors, cavernomas, cerebral palsy, Down syndrome, eclampsia, epilepsy, encephalitis, fragile X syndrome, meningitis, multiple sclerosis, systemic lupus erythematosus, and tuberous sclerosis. Additionally, seizures may be associated with adverse effects of several medications, including aminophylline, bupivicaine, bupropion, butyrophenones, excessive caffeine, chlorambucil, cyclosporine, clozapine, corticosteroids, diphenhydramine, enflurane, estrogens, fentanyl, insulin, lidocaine, maprotiline, meperidine, olanzapine, pentazocine, phenothiazines, prednisone, procaine, propofol, propoxyphene, quetiapine, risperidone, sevoflurane, theophylline, tramadol, tricyclic antidepressants, venlafaxine, isoniazid, lindane, metronidazole, nalidixic acid, penicillin, fluoroquinolones, and carbapenems.

[0059] In some cases, the epileptic condition is epilepsy. Epilepsy is a common, chronic neurological disorder characterized by recurrent, unprovoked seizures. These seizures are transient signs and / or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain. There are many different epileptic conditions, each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. In some embodiments, the epileptic condition is generalized epilepsy. In some embodiments, the epileptic condition is diathesis epilepsy.

[0060] Other exemplary epileptic conditions include those that occur with seizures, such as benign childhood epilepsy of the centrotemporal lobe, benign childhood occipital lobe epilepsy (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, cerebral palsy, hypoxic encephalopathy, Down syndrome, hypoxic-ischemic encephalopathy (HIE), West syndrome, Dravet syndrome, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS). Genetic, congenital, and developmental conditions are often associated with epilepsy in younger patients. Tumors may also be a cause in patients over the age of 40. Head trauma and central nervous system infections can cause epilepsy at any age. In some cases, GABA A receptor modulators can be administered to treat breakthrough seizures. "Breakthrough seizures" as described herein can refer to seizures that occur after a long period of seizure freedom. In some cases, breakthrough seizures can occur in subjects who are not taking medication. In some cases, breakthrough seizures can occur due to seizure resistance or refractoriness to existing therapeutic drugs, such as clobazam. Therefore, the GABA A receptor modulators described herein can be administered to treat breakthrough seizures. A Receptor modulators can be used as a replacement first line therapy to treat breakthrough seizures.

[0061] In some embodiments, the epileptic condition is a focal seizure. The focal seizure can be a simple focal seizure (aura). Simple focal seizures with motor symptoms affect muscle activity and can cause jerking of the legs, face, arms, or another part of the body. Simple focal seizures can cause sensory symptoms that affect the senses, such as hearing problems, hallucinations, and olfactory or other distortions. Simple focal seizures with autonomic symptoms can affect parts of the brain responsible for involuntary functions. These seizures can cause changes in blood pressure, heart rhythm, or bowel or bladder function. Some simple focal seizures can affect parts of the brain that trigger emotions or memories of previous experiences, causing feelings of fear, anxiety, or the imaginary feeling that something has happened before. The focal seizure can be a complex focal seizure. In some cases, a complex focal seizure is preceded by a simple focal seizure. In some cases, subjects experiencing complex focal seizures may stare blankly into space or experience motor autonomic movements (purposeless, repetitive movements such as lip smacking, eye blinking, moaning, gulping, or screaming).

[0062] In some cases, the disease or condition treatable by the GABA receptor modulators described herein is epilepsy associated with a mutation in a sodium channel in a subject. AOne such disease or condition treatable by receptor modulators is Dravet syndrome. Dravet syndrome is a rare epileptic encephalopathy. In some cases, Dravet syndrome is associated with a sodium channel mutation. For example, Dravet syndrome may be associated with a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene. Such mutations in SCN1A can include missense mutations, nonsense mutations, frameshift mutations, splice mutations, or in-frame deletions. For example, SCN1A mutations can include D79H, R101Q, R222X, I227S, R377X, R393C, R613X, R712X, R859C, R1596C, R1213X, R1648H, M1780T, A1783V, R1892X, or R1912X mutations.

[0063]

[0041] Dravet syndrome can begin in infancy and persist throughout a subject's life. Dravet syndrome can manifest as different seizure types, including myoclonic seizures, tonic-clonic seizures, absence seizures, atypical absence seizures, atonic seizures, focal clear seizures, or status epilepticus. GABA as described herein A Receptor modulators can be administered to a subject suffering from Dravet Syndrome to at least partially ameliorate the seizures associated with Dravet Syndrome.

[0064] As described in the examples of this application, GABA A Receptor modulators are effective in treating hyperthermia-induced seizures in the Scnla+ / - knockout mouse model, which is recognized in the art as a model for various epileptic conditions, including Dravet syndrome. Thus, GABA receptor modulators as a class of A Receptor modulators are expected to have efficacy in the treatment or prevention of seizures in the various epileptic conditions described herein.

[0065]

[0043] Compound Disclosed herein are compounds for the treatment of epileptic conditions. In some cases, the compounds for the treatment of epileptic conditions include GABA receptor antagonists. A In some embodiments, the compounds may be positive allosteric α2 and / or α3 GABA receptor modulators. A GABA receptor modulators that are specific for the α2 or α3 subunits while avoiding modulation of the α1 subunit. A Receptor modulators may be useful for treating the epileptic conditions described herein without causing the drowsiness associated with modulation of the α1 subunit. A Receptor modulators can be formulated as non-sedating or non-drowsy formulations. In some cases, non-drowsy formulations can contain other components, including stimulants (e.g., caffeine) that can further counteract any sedative effects associated with administration.

[0066]

[0045] GABAA receptor modulators, and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, may be included in exemplary embodiments and are expected to be effective in treating the epileptic conditions described herein.

[0067] GABA may be used in the treatment of epileptic conditions A The receptor modulator may be represented by the general formula (1a), (1b), or (1c):

[0068] [ka]

[0069] [In the formula, - X 1 , X 2 , X 3 , X 4 and X 5 are, independently of each other, -C, -N, -S, or -O, and X1 , X 2 , X 3 , X 4 and X 5 at least two of are -N; - Y 1 and Y 2 are, independently of each other, -C or -N, -R 1 m m is 1, -R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 (In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, -R 2 n n is 1 or 2, - Each R 2 is any other R 2 Independently, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, in some cases -F, or -O-CH2-R 4 (In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl; -Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are, independently of each other, -C, -N, -S or -O, -A 1 , and A 2 and A 3 are, independently of each other, -C, -N, -(C=O)-OR 7 and

[0070] [ka]

[0071] (In the formula, - R 7 is alkyl, -B 1 , B 2 , B 3 , and B 4 are, independently of each other, -C, -N, or -O; -R 21 s s is 1, 2, 3 or 4, - Each R 21 are independently hydrogen or C1-C6 alkyl, -R 5 l l is 1 or 2, - Each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl; -R 6 k k is 1, 2, 3, or 4, or in some cases, 1 or 2; - Each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0072] In some embodiments, compounds comprising the general formula (1a) are provided, wherein X 1 , X 2 , X 3 , X 4 and X 5 are, independently of each other, -C, -N, -S, or -O, and X 1 , X 2 , X 3 , X 4 and X 5 At least two of the groups are -N, and Y 1 and Y 2 are, independently of each other, -C or -N, and R 1 m m is 1 and R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 [In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, and R 2 nn is 1 or 2, and each R 2 is any other R 2 Independently, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, in some cases -F, or -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl.

[0073] In some embodiments, compounds comprising the general formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 are, independently of each other, -C, -N, -S or -O, and A 1 , A 2 and A 3 are, independently of each other, -C, -N or -(C=O)-OR 7 [In the formula, R 7 is alkyl, and R 5 l l is 1 or 2, and each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl, and R 6 k k is 1, 2, 3, or 4, and in some cases, is 1 or 2. 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0074] In some embodiments, a compound comprising the general formula (1c) is provided, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are, independently of each other, -C, -N, -S, or -O, and R 5 l l is 1 or 2, and each R 5are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl, and R 6 k k is 1, 2, 3, or 4, and in some cases, is 1 or 2. 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0075] In some embodiments, the compound comprises general formula (1a), general formula (1b), or general formula (1c), wherein X 1 , X 2 , X 3 , X 4 and X 5 are, independently of each other, -C, -N, and X 1 , X 2 , X 3 , X 4 and X 5 At least two of the groups are -N, and Y 1 and Y 2 are, independently of each other, -C or -N, and R 1 m m is 1 and R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 [In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, and R 2 n n is 1 or 2, and each R 2 is any other R 2 Independently, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, in some cases -F, or -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl; and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are, independently of each other, -C, -N, or -O, and A1 , A 2 and A 3 are, independently of each other, -C, -N or -(C=O)-OR 7 [In the formula, R 7 is alkyl, and R 5 l l is 1 or 2, and each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl, and R 6 k k is 1, 2, 3, or 4, and each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0076] In some embodiments, compounds comprising the general formula (1a) are provided, wherein X 1 , X 2 , X 3 , X 4 and X 5 are, independently of each other, -C or -N, and X 1 , X 2 , X 3 , X 4 and X 5 At least two of the groups are -N, and Y 1 and Y 2 are, independently of each other, -C or -N, and R 1 m m is 1 and R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 [In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, and R 2 n n is 1 or 2, and each R 2 is any other R 2 Independently, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, in some cases -F, or -O-CH2-R 4[In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl.

[0077] In some embodiments, compounds comprising the general formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 are, independently of each other, -C or -N, and A 1 , A 2 and A 3 are, independently of each other, -C, -N or -(C=O)-OR 7 [In the formula, R 7 is alkyl], and R 5 l l is 1 or 2, and each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl, and R 6 k k is 1, 2, 3, or 4, and in some cases, is 1 or 2. 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0078] In some embodiments, a compound comprising the general formula (1c) is provided, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are, independently of each other, -C, -N, or -O, and R 5 I is 1 or 2, and each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl, and R 6 k k is 1, 2, 3, or 4, and in some cases, is 1 or 2. 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0079] GABA may be used in the treatment of epileptic conditions. A The receptor modulator may be represented by the general formula (2), (3), (4), (5), (6) or (7):

[0080] [ka]

[0081] [In the formula, Y l , Y 2 , Z l , Z 4 , Z 5 , R 1 m m, R 1 , R 3 , R 2 n n, R 2 , R 4 , R 5 l l, R 5 , R 6 k k, R 6 , A l , A 2 and A 3 has the same meaning as defined above.

[0082] In some embodiments, the compound comprises the general formula (2), (3), (4), or (5), wherein Y 1 , Y 2 , R 1 m m, R 1 , R 3 , R 2 n n, R 2 and R 4 has the same meaning as defined above.

[0083] In some embodiments, the compound comprises the general formula (6), wherein Z 1 , Z 4 , Z 5 , R 5 l l, R 5, R 6 k k and R 6 has the same meaning as defined above. In some embodiments, the compound comprises the general formula (7), wherein Z 4 , Z 5 , R 5 l l, R 5 , R 6 k k, R 6 , A l , A 2 and A 3 has the same meaning as defined above.

[0084] GABA may be used in the treatment of epileptic conditions. A The receptor modulator may be represented by the general formula (2a), (3a), (4a), (5a), (5b), (6a), (6b), or (7a):

[0085] [ka]

[0086] [In the formula, R 1 m m, R 1 , R 3 , R 2 n n, R 2 , R 4 , R 5 l l, R 5 , R 6 k k and R 6 has the same meaning as defined above. In some embodiments, the compound comprises the general formula (2a), (3a), (4a), (5a), or (5b), and R 1 m m, R 1 , R 3 , R 2 n n, R 2 and R4 has the same meaning as defined above.

[0087] In some embodiments, the compound comprises the general formula (6a) or (6b), wherein R 5 l m of l of R 5 l ), R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0088] In some embodiments, the compound comprises the general formula (7a), wherein R 5 l l m, R 5 , R 6 k k and R 6 has the same meaning as defined above. In some embodiments, the compound comprises the general formula 1a, 1b, 1c, 2, 3, 4, 5, 6, 7, 2a, 3a, 4a, 5a, 5b, 6a, 6b, or 7a, and R 1 m is 1 and R 1 is unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl, in some cases containing at least one -CN as a substituent in the phenyl portion not connected to the parent moiety, or substituted biphenyl, in some cases containing at least one -CN as a substituent in the phenyl portion not connected to the parent moiety, in some cases one phenyl portion further containing at least one -F as a substituent, and in some cases each phenyl portion further containing at least one -F or -(C=O)-R as a substituent. 3 [In the formula, R 3 is pyridine, and R 5 I is 1 and R is 5 is Cl, Br, F, or C2 alkynyl.

[0089] In some embodiments, the compound comprises general formula 1a, 2, 3, 4, 5, 2a, 3a, 4a, 5a, or 5b, wherein R 1 m is 1 and R 1 is unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl, in some cases containing at least one -CN as a substituent in the phenyl portion not connected to the parent moiety, or substituted biphenyl, in some cases containing at least one -CN as a substituent in the phenyl portion not connected to the parent moiety, in some cases one phenyl portion further containing at least one -F as a substituent, and in some cases each phenyl portion further containing at least one -F or -(C=O)-R as a substituent. 3 [In the formula, R 3 is pyridine.

[0090] In some embodiments, the compound comprises general formula 1b, 7, or 7a, wherein R 5 1 is 1 and R 5 is Cl, Br, F, or C2 alkynyl. In some embodiments, the compound comprises general formula 1c, 6, 6a, or 6b, wherein R 5 1 is 1 and R 5 is Cl, Br, F, or C2 alkynyl.

[0091] In some embodiments, the compound comprises the general formula 1a, 1b, 1c, 2, 3, 4, 5, 6, 7, 2a, 3a, 4a, 5s, 5b, 6a, 6b, or 7a, and R 2 n is 1 or 2, and when n is 2, each R 2 are, independently of one another, unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl, or -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, and in some cases, R 4is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F; and when n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, in some cases pyridine; R 6 k is 1 or 4, and when k is 1, R 6 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and when k is 4, each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0092] In some embodiments, the compound comprises the general formula 1a, 1b, 1c, 2, 3, 4, 5, 6, 7, 2a, 3a, 4a, 5a, 5b, 6a, 6b, or 7a, and R 2 n is 1 or 2, and when n is 2, each R 2 are, independently of one another, unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl, or -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, and in some cases, R 4 is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F; and when n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, in some cases pyridine; R 6 k is 1 or 4, and when k is 1, R 6 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and when k is 4, each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0093] In some embodiments, the compound comprises general formula 1a, 2, 3, 4, 5, 2a, 3a, 4a, 5a, or 5b, wherein R 2 n is 1 or 2, and when n is 2, each R 2 are, independently of one another, unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl, or -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, and in some cases, R 4 is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F, and when n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, and in some cases a pyridine.

[0094] In some embodiments, the compound comprises general formula 1b, 7, or 7a, wherein R 6 k is 1 or 4, and when k is 1, R 6 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and when k is 4, each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0095] In some embodiments, the compound comprises general formula 1c, 6, 6a, or 6b, wherein R 6 k is 1 or 4, and when k is 1, R 6 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and when k is 4, each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, oxygen, or hydrogen.

[0096] In some embodiments, the compound comprises the general formula 1a, 1b, 1c, 2, 3, 4, 5, 6, 7, 2a, 3a, 4a, 5s, 5b, 6a, 6b, or 7a, and R 2 n is 2, while R 2 is unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, or unsubstituted C1-C6 alkyl, in some cases tert-butyl, and the other R 2 is -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or one R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and the other R 2 is a halogen, in some cases -F, and R 6 k is 4 and two R 6 is oxygen, and the other R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, or hydrogen.

[0097] In some embodiments, the compound comprises general formula 1a, 2, 3, 4, 5, 2a, 3a, 4a, 5s, or 5b, and R 2 n is 2, while R 2 is unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, or unsubstituted C1-C6 alkyl, in some cases tert-butyl, the other R 2 is O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or one R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and the other R 2 is a halogen, in some cases -F.

[0098] In some embodiments, the compound comprises general formula 1b, 7, or 7a, wherein R 6k is 4 and two R 6 is oxygen, and the other R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, or hydrogen.

[0099] In some embodiments, the compound comprises general formula 1c, 6, 6a, or 6b, wherein R 6 k is 4 and two R 6 is oxygen, and the other R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 alkyl, or hydrogen.

[0100] GABA may be used in the treatment of epileptic conditions A The receptor modulator may be represented by the general formula (2a'), (3a'), (4a'), (5a'), (5b'), (6a'), (6b') or (7a'):

[0101] [ka]

[0102] [In the formula, R 1 , R 3 , R 2 n n, R 2 , R 4 , R 5 , R 6 k k and R 6 has the same meaning as defined above. In some embodiments, the compound has the general formula (2a′), (3a′), (4a′), (5a′), or (5b′), wherein R 1 , R 3 , R 2 n n, R 2 and R 4 have the same meaning as defined above.

[0103] In some embodiments, the compound has the general formula (6a') or (6b'), where R 6 k k and R 6 have the same meaning as defined above. In some embodiments, the compound has the general formula (7a'), 6 k k and R 6 have the same meaning as defined above.

[0104] In some embodiments, the compound comprises the general formula (2a′), (3a′), (4a′), (5a′), (5b′), (6a′), (6b′), or (7a′), wherein R 1 is, in the case of formula (2a'), a substituted or unsubstituted C6 aryl, sometimes an unsubstituted phenyl, a substituted phenyl containing at least one -F as a substituent, in the case of formula (3a'), (5a') or (5b'), a substituted or unsubstituted biphenyl, sometimes an unsubstituted biphenyl, sometimes a substituted biphenyl containing at least one -CN as a substituent in the phenyl moiety not connected to the parent moiety, in sometimes one phenyl moiety further containing at least one -F as a substituent, in sometimes each phenyl moiety further containing at least one -F as a substituent, or in the case of formula (4a'), -(C=O)-R 3 [In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, and in some cases, R 3 is pyridine], and R 5 is Cl, Br or F in the case of formula (6a') or (6b'), is C2 alkynyl in the case of formula (7a'), and R 2 n and R 6 k has the same meaning as defined above.

[0105] In some embodiments, the compound comprises the general formula (2a′), (3a′), (4a′), (5a′), or (5b′), wherein R1 is, in the case of formula (2a'), a substituted or unsubstituted C6 aryl, sometimes an unsubstituted phenyl, a substituted phenyl containing at least one -F as a substituent, in the case of formula (3a'), (5a') or (5b'), a substituted or unsubstituted biphenyl, sometimes an unsubstituted biphenyl, sometimes a substituted biphenyl containing at least one -CN as a substituent in the phenyl moiety not connected to the parent moiety, in sometimes one phenyl moiety further containing at least one -F as a substituent, in sometimes each phenyl moiety further containing at least one -F as a substituent, or in the case of formula (4a'), -(C=O)-R 3 [In the formula, R 3 is a substituted or unsubstituted C6 heteroaryl, and in some cases, R 3 is pyridine], and R 2 n has the same meaning as defined above.

[0106] In some embodiments, the compound comprises the general formula (6a') or (6b'), wherein R 5 is Cl, Br or F, and R 6 k has the same meaning as defined above.

[0107] In some embodiments, the compound comprises the general formula (7a'), wherein R 5 is C2 alkynyl and R 6 k has the same meaning as defined above. GABA may be used in the treatment of epileptic conditions. A Receptor modulators may be of the general formula (2a"), (3a"), (4a"), (5a"), (5b"), (6a") or (7a")

[0108] [ka]

[0109] [In the formula, R 7 is unsubstituted C1-C6 alkyl, in some cases tert-butyl, unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, unsubstituted C1-C6 alcohol, in some cases C4 alcohol, and in some cases R 7 is, in the case of formula (2a"), unsubstituted C1-C6 alkyl, in some cases tert-butyl, or unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, or R 7 is an unsubstituted C1-C6 alcohol in the case of formula (5a") or (5b"), and in some cases a C4 alcohol; R 8 is -O-CH2-R 4 (In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol), and in some cases R 8 In the case of formula (2a"), -O-CH2-R 4 (In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole), or R 8 is, in the case of formula (3a"), an unsubstituted C1-C6 alcohol, and in some cases a C4 alcohol; R 9 is an unsubstituted C6 heteroaryl, in some cases pyridine, or halogen, in some cases -F; R 9 is, in the case of formula (4a"), an unsubstituted C6 heteroaryl, in some cases pyridine, or R 9 is, in the case of formula (5b"), a halogen, in some cases -F, and R 10 is C1-C3 alkyl or hydrogen, and R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and in some cases, R 11 is, in the case of formula (6a"), a substituted or unsubstituted aryl, in some cases a phenyl, and R 11is, in the case of formula (7a"), substituted or unsubstituted heteroaryl, in some cases pyridine, substituted or unsubstituted aryl, in some cases phenyl, and R 5 is Cl, Br or F in the case of formula (6a"), and is C2 alkynyl in the case of formula (7a").

[0110] In some embodiments, the compound comprises the general formula (2a"), (3a"), (4a"), (5a"), or (5b"), wherein R 7 is unsubstituted C1-C6 alkyl, in some cases tert-butyl, unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, unsubstituted C1-C6 alcohol, in some cases C4 alcohol, and in some cases R 7 is, in the case of formula (2a"), unsubstituted C1-C6-alkyl, in some cases tert-butyl, or unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl, or R 7 is an unsubstituted C1-C6 alcohol in the case of formula (5a") or (5b"), and in some cases a C4 alcohol; R 8 is -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol; and in some cases R 8 In the case of formula (2a"), -O-CH2-R 4 [In the formula, R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole; or R 8 is, in the case of formula (3a"), an unsubstituted C1-C6 alcohol, and in some cases a C4 alcohol; R 9 is an unsubstituted C6 heteroaryl, in some cases pyridine, or halogen, in some cases -F; R 9 is, in the case of formula (4a"), an unsubstituted C6 heteroaryl, in some cases pyridine, or R 9is halogen in the case of formula (5b"), and in some cases -F.

[0111] In some embodiments, the compound for the treatment of an epileptic condition comprises the general formula (6a"), wherein R 10 is C1-C3 alkyl or hydrogen, and R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and in some cases, R 11 is, in the case of formula (6a"), a substituted or unsubstituted aryl, in some cases a phenyl, and R 11 is, in the case of formula (7a"), a substituted or unsubstituted heteroaryl, in some cases pyridine, and R 5 is Cl, Br or F.

[0112] In some embodiments, the compound comprises the general formula (7a"), wherein R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and in some cases, R 11 In the case of formula (6a"), R is a substituted or unsubstituted aryl, in some cases a phenyl 11 is, in the case of formula (7a"), a substituted or unsubstituted heteroaryl, in some cases pyridine, and R 5 is a C2 alkynyl.

[0113] In some embodiments, the compound comprises the general formula (2a"), (3a"), (4a"), (5a"), or (5b"), and in the case of formula (2a"), R 1 is or is unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, and R 7 is unsubstituted C1-C6 alkyl, in some cases tert-butyl, or unsubstituted C3-C8 cycloalkyl, in some cases C4-cycloalkyl; R 8 is -O-CH2-R 4 [In the formula, R 4is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole; and in the case of formula (3a"), R 1 is an unsubstituted biphenyl, or in some cases a substituted biphenyl containing at least one -CN as a substituent in the phenyl moiety that is not connected to the parent moiety, in some cases one phenyl moiety further containing at least one -F as a substituent, in some cases each phenyl moiety further containing at least one -F as a substituent, and R 8 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and in the case of formula (4a"), R 1 is -(C=O)-R 3 [In the formula, R 3 is an unsubstituted C6 heteroaryl; and in some cases, R 3 is pyridine and R 9 is an unsubstituted C6 heteroaryl, in some cases pyridine, and in the case of formula (5a"), R 1 is an unsubstituted biphenyl, or in some cases a substituted biphenyl containing at least one -CN as a substituent in the phenyl moiety that is not connected to the parent moiety, in some cases one phenyl moiety further containing at least one -F as a substituent, in some cases each phenyl moiety further containing at least one -F as a substituent, and R 7 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and in the case of formula (5a"), R 1 is an unsubstituted biphenyl, or in some cases a substituted biphenyl containing at least one -CN as a substituent in the phenyl moiety that is not connected to the parent moiety, in some cases one phenyl moiety further containing at least one -F as a substituent, in some cases each phenyl moiety further containing at least one -F as a substituent, and R 7 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and R 9 is a halogen, in some cases -F.

[0114] GABA may be used in the treatment of epileptic conditions AThe receptor modulator has the general formula (8):

[0115] [ka]

[0116] [In the formula, -Z 4 and Z 5 are, independently of each other, -C, -N, -S or -O, -A 1 and A 2 are, independently of each other, -C, -N or -(C=O)-OR 7 (In the formula, R 7 is alkyl), -B 1 , B 2 , B 3 , and B 4 are, independently of each other, -C, -N, or -O; -R 5 l l is 1 or 2, - Each R 5 are, independently of each other, C1-C4 alkynyl or halogen, in some cases -Cl; -R 6 k k is 1, 2, 3, or 4, or in some cases, 1 or 2; - Each R 6 are, independently of each other, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 alkyl, oxygen or hydrogen, -R 21 s s is 1, 2, 3, or 4, or - Each R 21 are independently hydrogen or C1-C6 alkyl.

[0117] In some embodiments, the compound is selected from compounds shown in FIG. 14, e.g., L-838417, TPA023 (MK-0777), TPA123, MRK-409 (MK-0343), NS11394, ocinaplon (DOV-273547), TPA023B, TP003, N-desmethylclobazam 1, 2, 3, 4 and 5, Hz-166, MP-III-080, KRM-II-81, PF-06372865, SL65.1498, AZD7325, AZD6280, L-838417, and CTP-354.

[0118] In some cases, the compound is

[0119] [ka]

[0120] or a salt, prodrug, polymorph, solvate, ester, stereoisomer, or derivative thereof. In some cases, the compound is

[0121] [ka]

[0122] or a salt, prodrug, polymorph, solvate, ester, stereoisomer, or derivative thereof. As demonstrated in the examples below, exemplary GABA A The receptor modulators Compound 1 and Compound 2 are effective in preventing heat-induced seizures. The structures of Compound 1 and Compound 2 are listed below.

[0123] [ka]

[0124] As described herein, GABA AReceptor modulators, such as Compound 1 and Compound 2, inhibit GABA receptor activity. A Their modulation of receptors is expected to be effective in the treatment of epileptic conditions.

[0125] Also disclosed herein is a GABA A The receptor modulator is in the form of a pharmaceutically acceptable salt. The salt can include a counterion selected from the group consisting of acetate, benzoate, bitartrate, aspartate, formate, bromide, chloride, iodide, fumarate, citrate, maleate, nitrate, salicylate, succinate, sulfate, phosphate, besylate, hippurate, naphthoate, napsylate, sulfosalicylate, tosylate, octanoate, oleate, pamoate, stearate, propionate, hexanoate, decanoate, aspartate, bitartrate, salicylate, napsylate, or sulfite, and any combination thereof.

[0126] Also disclosed herein is a GABA A The polymorphs are polymorphs of the GABA receptor modulators described herein. A Free base polymorphisms of receptor modulators, or GABA A Salt polymorphs of the receptor modulators or GABA receptor modulators described herein A Polymorphs can include co-crystals of GABA receptor modulators. In some cases, polymorphism can improve solubility, improve oral bioavailability, provide more consistent oral bioavailability, improve stability, improve manufacturability, and accommodate improved formulations. Such polymorphs can be obtained by crystallizing GABA receptor modulators in a crystallization solvent, such as ethyl acetate, methyl ethyl ketone, 2-methylbutanone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetone, water, tetrahydrofuran (THF), 2-methyl-THF, isopropyl acetate (IPAC), acetonitrile, or dichloromethane. A The receptor modulators can be prepared by crystallizing or co-crystallizing the free base or salt forms.

[0127] Preparation of polymorphs can be confirmed by collecting a diffraction pattern of the crystal or co-crystal. In some cases, X-ray powder diffraction (XRPD) can be used to collect the diffraction pattern. Exemplary XRPD parameters are provided below:

[0128] [Table 1]

[0129] In some exemplary cases, polymorphs of Compound 1 may have XRPD patterns of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2° in 2-theta, and about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 15.9, 16.3, 16.4, 17.5° in 2-theta, and about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2° in 2-theta, A polymorph of Compound 1 having at least three characteristic peak positions of values ​​selected from the group consisting of about 7.0, 12.4, 12.6, 13.0, 14.1, 15.4, 15.7, 16.3, 17.5, 18.3, 19.0, 21.0, 22.3, 23.0, and 24.9±0.2 degrees two-theta can be administered.

[0130] Pharmaceutical composition Also disclosed herein are GABA receptors as described herein. AIn some embodiments, the pharmaceutical composition comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more GABA receptor modulators disclosed herein. A It may include a receptor modulator.

[0131] In some cases, the pharmaceutical composition comprises a GABA A In some cases, the GABA receptor modulator described herein may be administered in a medicament containing a GABA receptor modulator and at least one of an excipient, a diluent, or a carrier. A The receptor modulator can be dissolved or suspended in a diluent or carrier.

[0132]

[0101] In some embodiments, the pharmaceutical composition can include an excipient. The excipient can be an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

[0133]

[0102] Non-limiting examples of suitable excipients may include buffers, preservatives, stabilizers, binders, compaction agents, lubricants, chelating agents, dispersion enhancers, disintegration agents, flavoring agents, sweetening agents, and coloring agents.

[0134]

[0103] In some embodiments, the excipient may be a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. Buffering agents such as sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, and other calcium salts, or combinations thereof, may be used in the pharmaceutical composition.

[0135]

[0104] In some embodiments, the excipient may contain a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as α-tocopherol and ascorbate, and antimicrobial agents, such as parabens, chlorobutanol, and phenol. Antioxidants may further include, but are not limited to, EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, p-aminobenzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol, and N-acetylcysteine. In some cases, the preservative can include validamycin A, TL-3, sodium orthovanadate, sodium fluoride, Na-tosyl-Phe-chloromethylketone, Na-tosyl-Lys-chloromethylketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitors, phosphatase inhibitors, caspase inhibitors, granzyme inhibitors, cell adhesion inhibitors, cell division inhibitors, cell cycle inhibitors, lipid signaling inhibitors, protease inhibitors, reducing agents, alkylating agents, antibacterial agents, oxidase inhibitors, or other inhibitors.

[0136] In some embodiments, the pharmaceutical composition can include a binder as an excipient. Non-limiting examples of suitable binders include starch, pregelatinized starch, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.

[0137]

[0106] Binders that can be used in the pharmaceutical composition can be selected from starches, such as potato starch, corn starch, wheat starch; sugars, such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives, such as crystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols, such as sorbitol, xylitol, mannitol and water or combinations thereof.

[0138] In some embodiments, the pharmaceutical composition can include a lubricant as an excipient. Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. Lubricants that can be used in the pharmaceutical composition can be selected from metal stearates (e.g., magnesium stearate, calcium stearate, aluminum stearate, etc.), fatty acid esters (e.g., sodium stearyl fumarate, etc.), fatty acids (e.g., stearic acid, etc.), fatty alcohols, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol (PEG), metal lauryl sulfates (e.g., sodium lauryl sulfate, magnesium lauryl sulfate, etc.), sodium chloride, sodium benzoate, sodium acetate, and talc, or combinations thereof.

[0139] In some embodiments, the pharmaceutical composition can include a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersion enhancers can include starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0140]

[0109] In some embodiments, the pharmaceutical composition may include a disintegrant as an excipient. In some embodiments, the disintegrant may be a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches, such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose, alginates, sodium starch glycolate, gums, such as agar, guar, locust bean, karaya, pecitin, and tragacanth. In some embodiments, the disintegrant may be an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.

[0141]

[0110] In some embodiments, the excipient can include a flavoring agent. The flavoring agent incorporated into the outer layer can be selected from synthetic flavor oils and flavoring aromatic compounds; natural oils; extracts from plants, leaves, flowers, and fruits, and combinations thereof. In some embodiments, the flavoring agent can be selected from the group consisting of cinnamon oil; wintergreen oil; peppermint oil; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oils, such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences, including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0142] In some embodiments, the excipient may contain a sweetener. Non-limiting examples of suitable sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts, such as the sodium salt; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (stevioside); chloro derivatives of sucrose, such as sucralose; and sugar alcohols, such as sorbitol, mannitol, and sylitol.

[0143] In some cases, the pharmaceutical composition may contain a coloring agent. Non-limiting examples of suitable coloring agents include food, drug, and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C). Coloring agents may be used as dyes or their corresponding lakes.

[0144] In some cases, the pharmaceutical composition can include a diluent. Non-limiting examples of diluents include water, glycerol, methanol, ethanol, and other similar biocompatible diluents. In some cases, the diluent can be an aqueous acid, such as acetic acid, citric acid, maleic acid, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or the like. In some cases, the diluent can be used to titrate the pH of the compound to a certain pH, such as a physiological pH, that will produce the salts described above. In other cases, the diluent may be selected from the group comprising alkali metal carbonates such as, for example, calcium carbonate; alkali metal phosphates such as, for example, calcium phosphate; alkali metal sulfates such as, for example, calcium sulfate; cellulose derivatives such as, for example, cellulose, crystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, glucose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and / or anhydrous, hydrated and / or pharmaceutically acceptable derivatives thereof or combinations thereof.

[0145] In other embodiments, the pharmaceutical composition can include a surfactant, which can be selected from, but is not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycol (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, amino acids such as L-leucine, sugar esters of fatty acids, glycerides of fatty acids, or combinations thereof.

[0146] The pharmaceutical compositions disclosed herein can be formulated into various forms and administered by many different means. Pharmaceutical compositions can be administered orally, rectally, or parenterally, as desired, in formulations containing conventionally acceptable carriers, adjuvants, and vehicles. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, or intrasternal injection and infusion techniques. Administration can include injection or infusion, including intraarterial, intracardiac, intraventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical administration (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, and vaginal). In exemplary embodiments, the route of administration can be by injection, e.g., intramuscular, intravenous, subcutaneous, or intraperitoneal.

[0147]

[0116] Solid dosage forms for oral administration can include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules. Capsules can include a core material containing a nutritional protein or composition and a shell wall encapsulating the core material. In some embodiments, the core material can include at least one of a solid, a liquid, and an emulsion. In some embodiments, the shell wall material can include at least one of soft gelatin, hard gelatin, and a polymer. Suitable polymers include, but are not limited to, cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, and sodium carboxymethylcellulose; acrylic acid polymers and copolymers such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methacrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified lac). In some embodiments, at least one polymer can function as a taste masking agent.

[0148] Tablets, pills, and the like can be compressed, multiply compressed, multilayered, and / or coated. The coating can be single or multiple. In some embodiments, the coating material can include at least one of a saccharide, a polysaccharide, and a glycoprotein extracted from at least one of a plant, a fungus, and a microorganism. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, inulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, ghatti gum, tragacanth gum, funori, carrageenan, agar, alginate, chitosan, or gellan gum. In some embodiments, the coating material can include a protein. In some embodiments, the coating material can comprise at least one of a fat and / or an oil. In some embodiments, at least one of the fats and / or oils can be high-melting. In some embodiments, at least one of the fats and / or oils can be hydrogenated or partially hydrogenated. In some embodiments, at least one of the fats and / or oils can be derived from a plant. In some embodiments, at least one of the fats and / or oils can comprise at least one of a glyceride, a free fatty acid, and a fatty acid ester. In some embodiments, the coating material can comprise at least one edible wax. The edible wax can be derived from an animal, an insect, or a plant. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills can further be prepared with an enteric coating.

[0149] Liquid formulations can include syrups (e.g., oral formulations), intravenous formulations, intranasal formulations, ocular formulations (e.g., for treating eye infections), otic formulations (e.g., for treating ear infections), ointments, creams, aerosols, and the like. In some cases, combinations of various formulations can be administered. In some embodiments, tablets, pills, and the like can be formulated for an extended release profile. In some embodiments, the compositions can be formulated for enhanced shelf stability when stored in a sealed container under standard ambient conditions.

[0150] Dosage and Administration In one aspect, described herein is a GABA receptor antagonist, as described herein. A In some cases, the GABA receptor modulator compound or a pharmaceutical composition comprising the compound is administered to the subject. A a GABA receptor modulator, a salt thereof, or a AThe pharmaceutical composition containing the receptor modulator or a salt thereof may be administered in an amount of about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 0.2 mg to about 1000 mg, about 0.3 mg to about 1000 mg, about 0.4 mg to about 1000 mg, about 0.5 mg to about 1000 mg, about 0.6 mg to about 1000 mg, about 0.7 mg to about 1000 mg, about 0.8 mg to about 1000 mg, about 0.9 mg to about 1000 mg, about 1 mg to about 1000 mg, about 2 mg to about 1000 mg, about 3 mg ~ about 1000mg, about 4mg to about 1000mg, about 5mg to about 1000mg, about 6mg to about 1000mg, about 7mg to about 1000mg, about 8mg to about 1000mg, about 9mg to about 1000mg, about 10mg to about 1000mg, about 15mg to about 1000mg, about 20mg to about 1000mg, about 25mg to about 1000mg, about 30mg to about 1000mg, about 35mg to about 1000mg, about 40mg to about 1000mg, about 45mg to about 1000mg, about 50mg to about 100 0mg, about 55mg to about 1000mg, about 60mg to about 1000mg, about 65mg to about 1000mg, about 70mg to about 1000mg, about 75mg to about 1000mg, about 80mg to about 1000mg, about 85mg to about 1000mg, about 9 0mg to about 1000mg, about 95mg to about 1000mg, about 100mg to about 1000mg, about 150mg to about 1000mg, about 200mg to about 1000mg, about 250mg to about 1000mg, about 300mg to about 1000mg, about 35 In some embodiments, GABA may be administered at a dose of about 0 mg to about 1000 mg, about 400 mg to about 1000 mg, about 450 mg to about 1000 mg, about 500 mg to about 1000 mg, about 550 mg to about 1000 mg, about 600 mg to about 1000 mg, about 650 mg to about 1000 mg, about 700 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 850 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 950 mg to about 1000 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 1 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 1 mg to 3 mg. AThe GABA receptor modulator or salt thereof is administered at a dose of 1.5 mg to 2.5 mg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at a dose of 1.9 mg to 2.1 mg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at a dose of 1.8 mg to 2.2 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.5 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.5 mg to 4 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg to 10 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg to 10 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg to 20 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg to 15 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 1 mg to 8 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.5 mg to 10 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.25 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 2 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 2 mg to 10 mg. AThe GABA receptor modulator or salt thereof is administered at a dose of 3 mg to 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 2 mg to 4 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 6 mg to 7 mg. A The GABA receptor modulator or salt thereof is administered at a dose of 5 mg to 15 mg. A The receptor modulator or a salt thereof is administered at a dose of 10 mg to 20 mg.

[0151] In some cases, GABA A a GABA receptor modulator, a salt thereof, or a AA pharmaceutical composition comprising a receptor modulator or a salt thereof may comprise at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 4, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, It can be administered in doses of 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg. A a GABA receptor modulator, a salt thereof, or a AA pharmaceutical composition comprising a receptor modulator or a salt thereof may comprise at most about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 6, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 6, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 , 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, It can be administered in doses of 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 0.5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 1 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 1.5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 2 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 2.5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 3 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 3.5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 4 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 4.5 mg. AThe GABA receptor modulator or salt thereof is administered at a dose of about 5 mg. A The GABA receptor modulator or salt thereof is administered at a dose of about 10 mg. A The receptor modulator or a salt thereof is administered in a dose of about 15 mg.

[0152] In some embodiments, the GABA A In some embodiments, the GABA receptor modulator or salt thereof is administered daily. A In some embodiments, the GABA receptor modulator or salt thereof is administered once daily. A In some embodiments, the GABA receptor modulator or salt thereof is administered twice daily. A In some embodiments, the GABA receptor modulator or salt thereof is administered three times daily. A The GABA receptor modulator or salt thereof is administered 1 to 4 times daily. A The receptor modulator or a salt thereof is administered once a week.

[0153] In some cases, GABA A a GABA receptor modulator, a salt thereof, or a A The pharmaceutical composition containing the GABA receptor modulator or a salt thereof can be administered in a dose based on the body weight of the subject. A a GABA receptor modulator, a salt thereof, or a A The pharmaceutical composition comprising the GABA receptor modulator or a salt thereof may be administered at a dose of at least 0.0003 mg / kg. A a GABA receptor modulator, a salt thereof, or a AA pharmaceutical composition comprising a receptor modulator or a salt thereof may be administered in an amount of about 0.003 mg / kg to about 100 mg / kg, about 0.003 mg / kg to about 95 mg / kg, about 0.003 mg / kg to about 90 mg / kg, about 0.003 mg / kg to about 85 mg / kg, about 0.003 mg / kg to about 80 mg / kg, about 0.003 mg / kg to about 75 mg / kg, about 0.003 mg / kg to about 70 mg / kg, about 0.003 mg / kg to about 65 mg / kg, about 0.003 mg / kg to about 60 mg / kg, about 0.003 mg / kg to about 55 mg / kg, about 0.003 mg / kg to about 50 mg / kg, about 0.003 mg / kg to about 45 mg / kg, about 0.003 mg / kg to about 4 ...55 mg / kg, about 0.003 mg / kg to about 50 mg / kg, about 0.003 mg / kg to about 45 mg / kg, about 0.003 mg / kg to about 40 mg / kg, about 0.003 mg / kg to about 50 mg / kg, about 0.003 mg / kg to about 55 mg / kg, about 0.003 mg / kg to about 50 mg / mg / kg ~ approx. 35 mg / kg, approx. 0.003 mg / kg ~ approx. 30 mg / kg, approx. 0.003 mg / kg ~ approx. 25 mg / kg, approx. 0.003 mg / kg ~ approx. 20 mg / kg, approx. 0.003mg / kg ~ approx. 15mg / kg, approx. 0.003mg / kg ~ approx. 10mg / kg, approx. 0.003mg / kg ~ approx. 9mg / kg, approx. 0.003mg / kg ~ approx. 8mg / k g, about 0.003 mg / kg to about 7 mg / kg, about 0.003 mg / kg to about 6 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 4 mg / kg, about 0.003 mg / kg to about 3 mg / kg, about 0.003 mg / kg to about 2 mg / kg, or about 0.003 mg / kg to about 1 mg / kg. In some embodiments, GABA A The GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 10 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.0003 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.0005 mg / kg to 0.5 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.001 mg / kg to 0.5 mg / kg. AThe GABA receptor modulator or salt thereof is administered at a dose of 0.001 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.001 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.001 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.0003 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 0.3 mg / kg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.003 mg / kg to 0.03 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg / kg to 10 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.01 mg / kg to 1 mg / kg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at 0.01 mg / kg to 0.3 mg / kg. AThe GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg / kg to 0.05 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.01 mg / kg to 0.03 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.03 mg / kg to 10 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.03 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.03 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.03 mg / kg to 0.3 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.03 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.05 mg / kg to 10 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.05 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.05 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.05 mg / kg to 0.3 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.05 mg / kg to 0.1 mg / kg. A The GABA receptor modulator or salt thereof is administered at 0.1 mg / kg to 10 mg / kg.A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg / kg to 2 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg / kg to 1 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg / kg to 0.3 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg / kg to 0.5 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of 0.1 mg / kg to 0.05 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.01 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.02 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.03 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.04 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.05 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.06 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.07 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.08 mg / kg. A The GABA receptor modulator or salt thereof is administered at about 0.09 mg / kg. A The receptor modulator or salt thereof is administered at about 0.1 mg / kg.

[0154] In some cases, GABA A a GABA receptor modulator, a salt thereof, or a AThe pharmaceutical composition comprising the receptor modulator or a salt thereof may have a concentration of less than 0.0005 mg / kg, less than 0.001 mg / kg, less than 0.002 mg / kg, less than 0.003 mg / kg, less than 0.004 mg / kg, less than 0.005 mg / kg, less than 0.006 mg / kg, less than 0.007 mg / kg, less than 0.008 mg / kg, less than 0.009 mg / kg, less than 0.01 mg / kg, less than 0.02 mg / kg, less than 0.03 mg / kg, less than 0.04 mg / kg, less than 0.05 mg / kg, less than 0.06 mg / kg, less than 0.07 mg / kg, less than 0.08 mg / kg, less than 0.09mg / kg, less than 0.1mg / kg, less than 0.11mg / kg, less than 0.12mg / kg, less than 0.13mg / kg, less than 0.14mg / kg, less than 0.15mg / kg, less than 0.16mg / kg, less than 0.17mg / kg, less than 0.18mg / kg, less than 0.19mg / kg, less than 0.2mg / kg, less than 0.21mg / kg, less than 0.22mg / kg, less than 0.23mg / kg, less than 0.24mg / kg, less than 0.25mg / kg, less than 0.26mg / kg, less than 0.27mg / kg, less than 0.28mg / kg, 0.29 Less than 0.3mg / kg, less than 0.31mg / kg, less than 0.32mg / kg, less than 0.33mg / kg, less than 0.34mg / kg, less than 0.35mg / kg, less than 0.36mg / kg, less than 0.37mg / kg, less than 0.38mg / kg, less than 0.39mg / kg, less than 0.4mg / kg, less than 0.41mg / kg, less than 0.42mg / kg, less than 0.43mg / kg, less than 0.44mg / kg, less than 0.45mg / kg, less than 0.46mg / kg, less than 0.47mg / kg, less than 0.48mg / kg, less than 0.49mg / kg, 0. Less than 5mg / kg, Less than 0.51mg / kg, Less than 0.52mg / kg, Less than 0.53mg / kg, Less than 0.54mg / kg, Less than 0.55mg / kg, Less than 0.56mg / kg, Less than 0.57mg / kg, Less than 0.58mg / kg, Less than 0.59mg / kg, Less than 0.6mg / kg, Less than 0.61mg / kg, Less than 0.62mg / kg, Less than 0.63mg / kg, Less than 0.64mg / kg, Less than 0.65mg / kg, Less than 0.66mg / kg, Less than 0.67mg / kg, Less than 0.68mg / kg, Less than 0.69mg / kg, Less than 0.7mg / kg, Less than 0.Less than 71mg / kg, less than 0.72mg / kg, less than 0.73mg / kg, less than 0.74mg / kg, less than 0.75mg / kg, less than 0.76mg / kg, less than 0.77mg / kg, less than 0.78mg / kg, less than 0.79mg / kg, less than 0.8mg / kg, less than 0.81mg / kg, less than 0.82mg / kg, less than 0.83mg / kg, less than 0.84mg / kg, less than 0.85mg / kg, less than 0.86mg / kg, less than 0.87mg / kg, less than 0.88mg / kg, less than 0.89mg / kg, less than 0.9mg / kg, less than 0.91mg / kg, Less than 0.92mg / kg, Less than 0.93mg / kg, Less than 0.94mg / kg, Less than 0.95mg / kg, Less than 0.96mg / kg, Less than 0.97mg / kg, Less than 0.98mg / kg, Less than 0.99mg / kg, Less than 1mg / kg, Less than 2mg / kg, Less than 2.1mg / kg, Less than 2.2mg / kg, Less than 2.3mg / kg, Less than 2.4mg / kg, Less than 2.5mg / kg, Less than 2.6mg / kg, Less than 2.7mg / kg, Less than 2.8mg / kg, Less than 2.9mg / kg, Less than 3mg / kg, Less than 3.1mg / kg, Less than 3.2mg / kg, Less than 3.3mg g / kg, less than 3.4mg / kg, less than 3.5mg / kg, less than 3.6mg / kg, less than 3.7mg / kg, less than 3.8mg / kg, less than 3.9mg / kg, less than 4mg / kg, less than 4.1mg / kg, less than 4.2mg / kg, less than 4.3mg / kg, less than 4.4mg / kg, less than 4.5mg / kg, less than 4.6mg / kg, less than 4.7mg / kg, less than 4.8mg / kg, less than 4.9mg / kg, less than 5mg / kg, less than 5.1mg / kg, less than 5.2mg / kg, less than 5.3mg / kg, less than 5.4mg / kg, less than 5.5mg / kg, 5.6 Less than 5.7mg / kg, Less than 5.8mg / kg, Less than 5.9mg / kg, Less than 6mg / kg, Less than 6.1mg / kg, Less than 6.2mg / kg, Less than 6.3mg / kg, Less than 6.4mg / kg, Less than 6.5mg / kg, Less than 6.6mg / kg, Less than 6.7mg / kg, Less than 6.8mg / kg, Less than 6.9mg / kg, Less than 7mg / kg, Less than 7.1mg / kg, Less than 7.2mg / kg, Less than 7.3mg / kg, Less than 7.4mg / kg, Less than 7.5mg / kg, Less than 7.6mg / kg, Less than 7.7mg / kg, Less than 7.8mg / kg, 7.Less than 9mg / kg, Less than 8mg / kg, Less than 8.1mg / kg, Less than 8.2mg / kg, Less than 8.3mg / kg, Less than 8.4mg / kg, Less than 8.5mg / kg, Less than 8.6mg / kg, Less than 8.7mg / kg, Less than 8.8mg / kg, Less than 8.9mg / kg, Less than 9mg / kg, Less than 9.1mg / kg, Less than 9.2mg / kg, Less than 9.3mg / kg, Less than 9.4mg / kg, Less than 9.5mg / kg, Less than 9.6mg / kg, Less than 9.7mg / kg, Less than 9.8mg / kg, Less than 9.9mg / kg, Less than 10mg / kg, Less than 11mg / kg, Less than 12mg / kg, Less than 13mg / kg, Less than 14mg / kg, Less than 15mg / kg, Less than 16mg / kg, Less than 17mg / kg, Less than 18mg / kg, Less than 19mg / kg, 2 In some embodiments, GABA can be administered at a dose of less than 0 mg / kg, less than 21 mg / kg, less than 22 mg / kg, less than 23 mg / kg, less than 24 mg / kg, less than 25 mg / kg, less than 26 mg / kg, less than 27 mg / kg, less than 28 mg / kg, less than 29 mg / kg, less than 30 mg / kg, less than 31 mg / kg, less than 32 mg / kg, less than 33 mg / kg, less than 34 mg / kg, less than 35 mg / kg, less than 36 mg / kg, less than 37 mg / kg, less than 38 mg / kg, less than 39 mg / kg, less than 40 mg / kg, less than 41 mg / kg, less than 42 mg / kg, less than 43 mg / kg, less than 44 mg / kg, less than 45 mg / kg, less than 46 mg / kg, less than 47 mg / kg, less than 48 mg / kg, less than 49 mg / kg, or less than 50 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of less than 1 mg / kg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at a dose of less than 0.3 mg / kg. A The GABA receptor modulator or salt thereof is administered at a dose of less than 0.1 mg / kg. A In some embodiments, the GABA receptor modulator or salt thereof is administered at a dose of less than 0.03 mg / kg. A The receptor modulator or salt thereof is administered at a dose of less than 0.01 mg / kg.

[0155] In some embodiments, GABA A a GABA receptor modulator, a salt thereof, or a A The pharmaceutical composition comprising the GABA receptor modulator or a salt thereof can be administered as a liquid formulation. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.01 mg / ml to 100 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.001 mg / ml to 10 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.1 mg / ml to 10 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.001 mg / ml to 10 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.001 mg / ml to 1 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.001 mg / ml to 0.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.5 mg / ml to 5 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 1 mg / ml to 2 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.5 mg / ml to 2 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.2 mg / ml to 1 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.2 mg / ml to 0.5 mg / ml. AThe GABA receptor modulator or salt thereof is administered at a concentration of 0.2 mg / ml to 0.4 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.1 mg / ml to 0.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.1 mg / ml to 0.3 mg / ml. A The GABA receptor modulator or salt thereof is administered at a concentration of 0.05 mg / ml to 0.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 0.1 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 0.25 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 0.3 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 0.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 0.75 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 1 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 1.25 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 1.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 2 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 2.5 mg / ml. A The GABA receptor modulator or salt thereof is administered at about 5 mg / ml. AThe receptor modulator or salt thereof is administered at about 10 mg / ml. In some embodiments, 0.01 ml to 500 ml of the liquid formulation is administered per day. In some embodiments, 0.05 ml to 250 ml of the liquid formulation is administered per day. In some embodiments, 0.05 ml to 50 ml of the liquid formulation is administered per day. In some embodiments, 0.1 ml to 25 ml of the liquid formulation is administered per day. In some embodiments, 1 ml to 250 ml of the liquid formulation is administered per day. In some embodiments, 1 ml to 200 ml of the liquid formulation is administered per day. In some embodiments, 50 ml to 200 ml of the liquid formulation is administered per day. In some embodiments, 25 ml to 100 ml of the liquid formulation is administered per day. In some embodiments, 5 ml to 50 ml of the liquid formulation is administered per day. In some embodiments, 1 ml to 20 ml of the liquid formulation is administered per day. In some embodiments, 1 ml to 5 ml of the liquid formulation is administered per day.

[0156] In some embodiments, described herein are

[0157] [ka]

[0158] or a salt or polymorph thereof, wherein the administration is in an amount effective to treat the epileptic condition in the subject. In some embodiments, the amount effective to treat the epileptic condition comprises a dose of about 0.0003 mg to about 1 mg of the compound or its salt or polymorph per kg of the subject's body weight per day. In some embodiments, the amount comprises a dose of less than 0.3 mg of the compound or its salt or polymorph per kg of the subject's body weight per day. In some embodiments, the amount comprises a dose of less than 0.1 mg of the compound or its salt or polymorph per kg of the subject's body weight per day. In some embodiments, the amount comprises a dose of less than 0.03 mg of the compound or its salt or polymorph per kg of the subject's body weight per day.

[0159]

[0127] One skilled in the art can extrapolate an effective dose in one animal model to an equivalent dose in another model. For example, a dose shown to be effective in a mouse model can be divided by an allometric scaling factor (i.e., 12) to generate a human equivalent dose.

[0160] GABA A Administration of the receptor modulator, salt, or composition may occur at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times daily. A Administration of the receptor modulator, salt, or composition may occur at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times per week. AAdministration of the receptor modulator, salt, or composition may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, In some embodiments, the GABA A The receptor modulator or salt thereof is administered to the subject for a period of time. The period can be from 1 day to 30 years. In some embodiments, the period is from 1 day to 20 years, 1 week to 10 years, 1 month to 5 years, 1 month to 1 year, 1 week to 1 year, or any number or range therebetween.

[0161]

[0129] The present invention is further illustrated by the following examples, from which further embodiments and advantages can be derived. These examples are meant to illustrate the invention but not to limit its scope. This specification includes the disclosure of the following inventions. [Item 1] General formula (1a), general formula (1b) or general formula (1c) [ka] [In the formula, X 1 、X 2 、X 3 、X 4 and X 5 are independently -C, -N, -S or -O, and X 1 、X 2 、X 3 、X 4 and X5 at least two of are -N; Y 1 and Y 2 are independently -C or -N, R 1 m m is 1 and R 1 is unsubstituted phenyl, C 1 ~C 4 Phenyl substituted with alkyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 (In the formula, R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl; R 2 n n is 1 or 2, and each R 2 are independently substituted or unsubstituted C 3 ~C 8 Cycloalkyl, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 1 ~C 6 Alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen, or -O-CH 2 -R 4 (In the formula, R 4 is a substituted or unsubstituted 5- or 6-membered heteroaryl; Z 1 、Z 3 、Z 4 , and Z 5 are independently -C, -N, -S, or -O; A 1 , and A 2 and A 3 are independently -C, -N, or -(C=O)-OR 7 ,or

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[0162] Example 1 - Formulation

[0131] Exemplary GABA AThe receptor modulators were formulated prior to administration. Each modulator was combined with Tylose MH 300 (0.5% w / v), Tween 80 (final volume 1%), and 0.9% bacteriostatic saline (to final volume). The resulting suspension was then sonicated at 37°C for at least 10 minutes.

[0163]

[0132] A 0.9% bacteriostatic saline control solution of 0.5% Tylose MH 300 (w / v) and 1% Tween 80 (v / v) was also prepared. Example 2 - Test Design

[0134] Animal

[0135] Reasons for species selection: Scnla + / - Knockout mice ([129xB]F1.Scnla + / - ) is a model subject of DS with high translation value.

[0164]

[0136] Number: 1st generation Scnla + / - Heterozygous knockout mice ([129xB]F1.Scnla + / - ) 112 (56 males and 56 females)

[0137] Reserve animals: 112 wild-type littermates. A portion of the reserve animals was used to model GABA A The PK profile for the receptor modulator was determined.

[0165]

[0138] System / Hygiene:Scnla + / - Heterozygous knockout mice ([129xB]F1.Scnla + / - )

[0139] Breeder:Scnla + / - Breeding male mice (129S-Scnla + / - , n = 12) were obtained and set up as breeding trios with C57BL / 6J females (n = 24).

[0166]

[0140] Age / Weight: Between P14 and P16 + / - Heterozygous knockout mice were randomly assigned to treatment groups. Reception: Upon arrival, breeding female C57BL / 6J mice underwent a physical examination to ensure they were healthy. + / - Breeding male mice (129S-Scn1a + / - , n=12) were quarantined for two weeks until PCR testing revealed the presence of the virus.

[0167] Acclimation: No acclimation was required. + / - Heterozygous knockout mice were weaned, enrolled in the study, and treated. Group Allocation: After weaning, the required number of animals were randomly assigned (by sex) to treatment groups.

[0168]

[0144] Identification: Scnla from a breeding trio + / - Heterozygous knockout mice were numbered in each cage by toe clipping at ages P7-10. Cage cards indicated the number of animals in each cage. Wild-type littermates not designated for PK studies were euthanized. + / - Heterozygous knockout mice ([129xB]F1.Scnla + / - ) were enrolled in the hyperthermia-induced seizure study.

[0169]

[0145] Environmental conditions

[0146] From arrival, the animals were housed in an SPF-barriered rodent unit. Animal room conditions were set as follows: Temperature: 20~26℃ (68~79°F) Relative humidity: 50±20% Light / dark cycle: 12h / 12h; lights on starting at 07:00 Ventilation: Filtered, non-recycled air approximately 10-15 cycles per hour.

[0170]

[0147] The corresponding instruments and equipment were checked and calibrated at regular intervals. Temperature and relative humidity were continuously recorded (recording device with alarm system).

[0148] The animal room was disinfected before the animals' arrival and then cleaned regularly.

[0171]

[0149] Residence

[0150] Scnla + / - Breeding male mice (129S-Scnla + / - Upon arrival, C57BL / 6J and C67BL / 6J females were housed four per cage in autoclaved polycarbonate cages with stainless steel lids that had perforated holding devices containing Micro-Filter Tops and ¼-inch corncob bedding.

[0172]

[0151] One breeding male and two females were set up as a breeding trio. + / - Heterozygous knockout mice ([129xB]F1.Scnla + / - and wild-type) were housed with their mothers (C57BL / 6J females) until enrollment in the study. Unless otherwise specified for use in PK studies, wild-type littermates were euthanized after enrollment of [129xB]F1.Scnla+ / - littermates in the study.

[0173] Example 3 - Treatment of hypothermia-induced seizures Treatment Group

[0154] Rationale for Dose Level Selection - Dose levels were selected based on the results of previous studies.

[0174]

[0155] Between P14 and P16, Scnla + / - Heterozygous knockout mice were randomly assigned to treatment groups (n = 7 males, 7 females per treatment group). Scnla was used because it is a field-accepted animal model for epileptic conditions, including those with Dravet syndrome. + / - We chose a knockout mouse model. Treatment consisted of GABA A Receptor Modulator 1 ("Compound 1" as the phosphate salt at 0.1, 0.3, 1.0 mg / kg), GABA A Receptor Modulator 2 ("Compound 2" at 3, 10, 30, 100 mg / kg), vehicle, or clobazam ("CBZ") (10 mg / kg; positive control).

[0175]

[0156] Period

[0157] The dose regimen was administered singly for this study. Administration

[0159] GABA A Receptor modulators were administered intraperitoneally (ip) using a 0.5- or 1-ml plastic syringe fitted with a 27- or 30-gauge 0.5"-long bevel needle.

[0176]

[0160] Animals were administered 10 ml of the formulation per kg of body weight as measured on the day of the experiment.

[0161] The formulation was adjusted to and maintained at delivery conditions (temperature 37°C) throughout the procedure.

[0177]

[0162] Formulations were mixed immediately prior to administration by inverting their containers 2-3 times. To verify the dose concentration, mice were administered the test substance or control and placed in individual home cages. A temperature probe was gently inserted into the rectum of the mouse and secured by attaching the probe wire to the mouse's tail with the tag end facing dorsally. For each group, the probe was inserted as follows: a. For CBZ-treated mice, when a hyperthermic state was reached, the probe was inserted after 5 min to allow for 20–30 min of pretreatment. b. For mice administered Compound 1, when a hyperthermic state was reached, the probe was inserted after 35 minutes to allow for a 50-60 minute pretreatment period. c. For compound-treated mice, when a hyperthermic state was reached, the probe was inserted after 5 minutes to allow for 20-30 minutes of pretreatment.

[0178] Each mouse was allowed to acclimate to the temperature probe for 5 minutes before recording its baseline temperature. Figures 1-3 show the starting temperatures of female mice, male mice, and the average starting temperatures of all mice before inducing a heat-induced seizure.

[0179]

[0165] By keeping the mice on a heating pad, their core temperatures increased by approximately 0.5°C every 2 minutes until the first tonic-clonic onset accompanied by loss of posture was observed or until the body temperature reached 42.5°C. Figures 4-6 show the final core temperatures of female mice, the final core temperatures of male mice, and the average final core temperatures of all mice after warming. Figures 7-9 show the total temperature change for female mice, the total temperature change for male mice, and the average for all mice; Figures 10-12 show the average temperature change per minute for female mice, the average temperature change per minute for male mice, and the average for all mice. The mice's temperature was maintained at 42.5°C for 3 minutes. If no seizures occurred, the mice were considered seizure-free. Tables 1-9 below show the results of administration of control, CBZ, Compound 1, and Compound 2, and their ability to protect against seizures as a function of dose.

[0180] [Table 2]

[0181] [Table 3]

[0182] [Table 4]

[0183] [Table 5]

[0184] [Table 6]

[0185] [Table 7]

[0186] [Table 8]

[0187] [Table 9]

[0188] [Table 10]

[0189] A summary of the data is shown in Table 10 and FIG.

[0190] [Table 11]

[0191] As shown in Table 10, GABA A The receptor modulators Compound 1 and Compound 2 reduced the amount of seizures in animal models compared to vehicle administration. Furthermore, Compound 1 and Compound 2 performed at least as well as the clobazam positive control. Given that clobazam is the first-line treatment for seizures, GABA ... A Receptor modulators are promising therapeutic agents for treating seizures. Indeed, the present data show that Compound 2 treats seizures in a dose-dependent manner, with a 100 mg / kg dose completely preventing seizures in each animal (n=8).

[0192] In practice, administration of about 0.1 mg / kg to about 100 mg / kg of Compound 1 or Compound 2 has been shown to be effective in preventing seizures in mouse models. One skilled in the art should be able to extrapolate this effective amount to other animals. For example, using an allometric coefficient of 12 for humans, the equivalent human dose should be approximately 0.008 mg / kg to about 10 mg / kg.

[0193] Those skilled in the art will understand that the efficacy of Compound 1 and Compound 2 in treating seizures in hyperthermia-induced animal models is not limited to a particular compound. That is, those skilled in the art will understand the effectiveness of Compound 1 and Compound 2 in treating seizures in hyperthermia-induced animal models. A It would be reasonable to expect that receptor modulators should be effective in treating seizures in a manner comparable to the efficacy shown by Compound 1 and Compound 2. Furthermore, one skilled in the art would understand that efficacy may be comparable to that of Scnla. + / - It should be understood that the present invention is not limited to preventing seizures in knockout mice. In other words, the animal model is a well-established animal model for various epileptic conditions, including Dravet syndrome. Therefore, those skilled in the art will appreciate that the GABA A It would be reasonable to expect that the entire class of receptor modulators would be effective in treating epileptic conditions by preventing seizures.

[0194] These results therefore support the use of GABAergic drugs, as a class, in the treatment of epileptic conditions in general, as demonstrated in the mouse model of heat-induced seizures. A Demonstrate potential as a receptor modulator.

[0195] Example 4 - Pharmacokinetic Determinations To determine the pharmacokinetic parameters for Compound 1 and Compound 2, P14-P16 mice (n=7 groups) were administered 100 mg / kg of ethanol. -1 sex -1 time -1 ) Compound 1 and Compound 2 will be administered and terminal blood samples will be collected at the following time points: Compound 1: 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours b. Compound 2: 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours Blood collection: Mice were euthanized by CO2 inhalation immediately prior to blood collection. Blood was collected by cardiac puncture using a 27-gauge needle and transferred to 500 μL K3EDTA tubes and immediately placed on wet ice. These samples were centrifuged at 2900 g for 10 minutes under refrigerated conditions (set to maintain +4°C) within 2 hours of collection. Plasma was transferred to individual tubes within 2 hours and stored at -20°C.

[0196]

[0174] Dose prescription concentration verification

[0175] 0.3 ml aliquots of each formulation are collected from the mid-dose concentration location and stored in parafilm-wrapped, sealed vials at 2-4°C or colder until the completion of the study.

[0197]

[0176] A calibration curve consisting of at least six calibration standards is constructed using the LC / UV method.

[0177] The concentration of the test compound in the dose formulation samples is determined by the LC / UV method.

[0198] Determination of plasma levels of test items

[0179] An LC-MS / MS method for the quantitative determination of test compounds in biological matrices is developed under non-GLP compliance.

[0199]

[0180] A calibration curve with at least six non-zero calibration standards (STDs) is constructed for the LC-MS / MS method. Assay of test samples

[0182] Test samples are assayed in batches using LC-MS / MS after appropriate preparation. Generally, one set of calibration curves with two sets of QC samples at low, medium, and high concentrations is applied when the number of samples is 48 or less. Then, when the number of samples exceeds 48, two sets of calibration curves with two sets of QC samples are applied.

[0200]

[0183] Generally, one reagent blank, one plasma blank, and, if applicable, two plasma blanks containing only the internal standard are run.

[0184] Samples in the same matrix from different PK projects are quantified in the same analytical run.

[0201] Acceptance Criteria for Analytical Batches

[0186] Linearity: ≥75% of the STDs were back-calculated to within ±20% (±25% for LLOQ) of their nominal values ​​in biological fluids and to within 25% (30% for LLOQ) of their nominal values ​​in tissue homogenates and fecal samples.

[0202]

[0187] Precision: ≧67% of all QC samples were back-calculated to within ±20% of their nominal values ​​for biological fluids and within 25% of their nominal values ​​for tissue and fecal samples.

[0203] Specificity: The mean calculated concentration of the analyte in a single blank matrix should be less than 0.5 times the LLOQ. Pharmacokinetic analysis

[0190] Analysis of the pharmacokinetic data will be performed for each dose level, gender and sampling.

[0204] Generally, the following toxicokinetic parameters are used: C, C max , T max , T 1 / 2 , AUC 0-t , AUC 0-inf , MRT 0-t , MRT 0-inf , Cl and Vss were calculated / measured where possible.

[0205]

[0192] Values ​​within the lower limit of quantitation are reported as BLQ in individual tables, considered as 0 for descriptive statistics, and included in statistical calculations. If the mean of the individual concentrations is below the limit of quantitation, a BLQ is reported.

[0206]

[0193] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention herein. It should be understood that various alterations to the embodiments of the invention described herein can be made in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0207] Example 5 - Evaluation of the acute anticonvulsant efficacy of Compound 1 in mouse and rat models of acute seizures

[0195] Method: Compound 1 was tested for anticonvulsant efficacy in an acute 6 Hz seizure model in CF-1 mice at intensities of 32 and 44 mA. Compound 1 was evaluated for dose-related efficacy in the 6 Hz seizure test after acute administration at a single time point and compared to the efficacy of the positive control diazepam (DZP) (tested 0.5 hours after drug administration). The formulation vehicle (VEH) was used as a negative control.

[0208] After oral administration of the compounds, mice were subjected to 32 or 44 mA current delivered via corneal electrodes for 3 seconds, applied at the appropriate time point, to induce a typical seizure. A 6 Hz seizure was characterized by an initial momentary fainting, followed immediately by forelimb clonus, vibrissa twitching, and Straub's tail lift. Animals that did not exhibit all of these behaviors within the immediate (5-10 s) post-stimulus period were considered "protected" (N = number protected / F = number tested).

[0209] Compound 1 was administered and tested for anticonvulsant efficacy 3 hours later. The compound was administered at three doses (0.01, 0.03, and 0.1 mg / kg; n = 8 male CF-1 mice per dose group) in a volume of 0.01 mL / g. Testing was conducted over 1-2 days, with animals in each test cohort randomized to receive a single dose of the investigational compound or vehicle. For each test day, animals were tested in cohorts of 20-30 mice per session, and treatments were randomized across all groups and test days. The dose of compound required to produce the desired endpoint in 50% of animals (ED50) and 95% confidence intervals were calculated using a computer program based on the probit method. Groups of vehicle-treated and DZP-treated (1 mg / kg, PO) mice were also tested in parallel at the previously determined time of peak effect of DZP (0.5 hrs); all tests were performed by investigators blinded to treatment conditions. A statistically significant (P≦0.05) increase in the number of protected mice compared to the number of negative controls was considered to be effective. A summary of the results is shown in Table 11.

[0210] [Table 12]

Claims

【Request Item 1】 【Chemistry 1】 or a salt, solvate or polymorph thereof, wherein the epileptic condition is one of: selected from focal seizures, benign childhood epilepsy of the centrotemporal lobe, benign childhood occipital lobe epilepsy (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, West syndrome, Dravet syndrome, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS), generalized epilepsy, or diathesis epilepsy, A pharmaceutical composition for treating an epileptic condition or epilepsy associated with a sodium channel mutation in a subject.

2. The pharmaceutical composition of claim 1 , wherein the subject is a human or a dog.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein a therapeutically effective amount of the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier.

4. 4. The pharmaceutical composition of claim 1, wherein the sodium channel mutation comprises a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene.

5. below: 【Chemistry 2】 or a salt, solvate or polymorph thereof 1. A pharmaceutical composition for treating Dravet syndrome in a subject, comprising:

6. 6. The pharmaceutical composition of claim 5, comprising an amount effective to treat Dravet Syndrome when administered at a dose of about 0.003 mg / kg of a subject's body weight per day to about 10 mg / kg of a subject's body weight per day.

7. The pharmaceutical composition according to claim 5 or 6, wherein the subject is a human or a dog.

8. 8. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable excipient, diluent, or carrier. 【Request Item 9】 【Chemistry 3】 or a salt, solvate or polymorph thereof, wherein the pharmaceutical composition is in an amount effective to treat an epileptic condition in a subject, said amount comprising a dose of about 0.0003 mg to about 1 mg of the compound or its salt or polymorph per kg body weight of the subject per day, and wherein the epileptic condition is one of the following: selected from benign childhood epilepsy of the centrotemporal lobe, benign childhood occipital lobe epilepsy (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, cerebral palsy, hypoxic encephalopathy, Down's syndrome, hypoxic-ischemic encephalopathy (HIE), West syndrome, Dravet syndrome, focal seizures, progressive myoclonic epilepsy, Lennox-Gastaut syndrome (LGS), generalized epilepsy or diathesis epilepsy, A pharmaceutical composition for treating an epileptic condition in a subject.

10. wherein the compound, or salt, solvate, or polymorph thereof, is a polymorph of a phosphate salt, wherein said polymorph of the phosphate salt has a 2-theta of the following magnitude when measured using (a) X-ray wavelength parameters of Cu:K-alpha (λ=1.54179 Å); (b) an X-ray tube voltage setting of 40 kV and a current of 40 mA; (c) a scanning scope of about 3° to about 40°; (d) a sample rotation rate of about 15 rpm; and (e) a scan rate of 10° per minute: Approximately 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1 ± 0.2° 10. The pharmaceutical composition of claim 9, exhibiting an X-ray powder diffraction (XRPD) pattern having at least three, at least six, or at least nine characteristic peak positions of values ​​selected from:

11. 11. The pharmaceutical composition of claim 9 or 10, wherein the pharmaceutical composition is formulated for oral or transdermal administration, or is formulated as a non-drowsy formulation.

12. 12. The pharmaceutical composition of any one of claims 9 to 11, wherein the amount comprises a dose of less than 0.3 mg of the compound or its salt, solvate or polymorph per kg of subject body weight per day, less than 0.1 mg of the compound or its salt, solvate or polymorph per kg of subject body weight per day, or less than 0.03 mg of the compound or its salt, solvate or polymorph per kg of subject body weight per day.

13. The compound, or salt, solvate, or polymorph thereof, is a polymorph of a phosphate salt, wherein said polymorph of the phosphate salt has a 2-theta of the following magnitude when measured using (a) X-ray wavelength parameters of Cu:K-alpha (λ=1.54179 Å); (b) an X-ray tube voltage setting of 40 kV and a current of 40 mA; (c) a scanning scope of about 3° to about 40°; (d) a sample rotation rate of about 15 rpm; and (e) a scan rate of 10° per minute: Approximately 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1 ± 0.2° 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits an X-ray powder diffraction (XRPD) pattern having at least three, at least six, or at least nine characteristic peak positions selected from the group consisting of:

14. The pharmaceutical composition of claim 1 or 13, wherein the pharmaceutical composition is formulated for oral or transdermal administration, or is formulated as a non-drowsy formulation.

15. The pharmaceutical composition of any one of claims 1, 13 and 14, wherein the amount comprises a dose of less than 0.3 mg of the compound, or a salt, solvate or polymorph thereof, per kg of subject body weight per day, a dose of less than 0.1 mg of the compound, or a salt, solvate or polymorph thereof, per kg of subject body weight per day, or a dose of less than 0.03 mg of the compound, or a salt, solvate or polymorph thereof, per kg of subject body weight per day.

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