Crystalline salts of T-type calcium channel modulators and methods of use thereof

Abstract

The present disclosure provides a crystalline form of Form D, i.e., a N-((1-(2-(tert-butylamino)-2-oxoethyl) piperidin-4-yl) methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (Compound 1). The disclosure also provides pharmaceutical compositions comprising Compound 1 in Form D, and methods of treating neurological and psychiatric disorders by administering Compound 1 in Form D or a pharmaceutical composition comprising Compound 1 in Form D to a subject in need thereof.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 449,461, filed March 2, 2023, the entire contents of which are hereby incorporated by reference. Background Technology

[0002] T-type calcium channels are low-pressure activated ion channels that mediate calcium influx into cells. Abnormal function of these ion channels is associated with several diseases or conditions, including mental disorders (e.g., mood disorders such as major depressive disorder), pain, tremors (e.g., essential tremor), and epilepsy or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, compounds that selectively modulate T-type calcium channels in mammals could be used to treat such disease states. Summary of the Invention

[0003] Therefore, in some aspects, this disclosure provides a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (compound 1), characterized in that its X-ray powder diffraction (XRPD) pattern contains at least one peak with a diffraction angle (°2θ) selected from the group consisting of: A peak at approximately 12.0°; A peak at approximately 15.6°; A peak of approximately 16.7°; A peak of approximately 19.8°; A peak at approximately 21.2°; A peak at approximately 24.1°; A peak at approximately 25.2°; A peak at approximately 27.3°; and The peak is approximately 30.2°.

[0004] In some embodiments, the crystalline form is characterized in that its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0005] In some embodiments, the crystalline form is characterized in that its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0006] In some embodiments, the crystalline form is characterized in that its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0007] In some embodiments, the crystalline form is characterized in that its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 12.0°; A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0008] In some embodiments, the crystalline form is characterized by its XRPD pattern being similar to... Figure 2 The XRPD maps depicted in the text are basically the same.

[0009] In some embodiments, the melting point of the crystalline form is approximately 75.2°C, as determined by differential scanning calorimetry (DSC).

[0010] In some embodiments, the crystalline form has a space group. The crystal structure. In some embodiments, the crystal structure is characterized by an asymmetric unit cell with a volume of 1213.0(10) Å. 3 The 3-D parameters are: a = 8.584(3) Å; b = 9.11(4) Å; c = 17.043 Å.

[0011] In some embodiments, this disclosure provides a pharmaceutical composition comprising the crystalline form of this disclosure and a pharmaceutically acceptable carrier.

[0012] In some embodiments, the pharmaceutical composition further comprises a release modulating polymer. In some embodiments, the release modulating polymer is selected from the group consisting of hydrophilic matrix polymers, hydrophobic matrix polymers, and polyacrylate polymers. In some embodiments, the hydrophilic matrix polymer is hydroxypropyl methylcellulose.

[0013] In some embodiments, the pharmaceutical composition is for oral administration.

[0014] In some embodiments, this disclosure provides a method for treating a neurological disorder, the method comprising administering to a subject in need a crystalline form of the present disclosure or a pharmaceutical composition thereof.

[0015] In some embodiments, the neurological disorder is a tremor. In some embodiments, the tremor is essential tremor, Parkinson's tremor, cerebellar tremor, or CACNA1G tremor. In some embodiments, the tremor is essential tremor.

[0016] In some embodiments, this disclosure provides a method for treating a mental disorder in a subject in need, the method comprising administering to the subject a crystalline form of the present disclosure or a pharmaceutical composition of the present disclosure. Attached Figure Description

[0017] Figure 1 These are the X-ray powder diffraction (XRPD) spectra of water activity experiments for comparison types C and D.

[0018] Figure 2 The XRPD spectrum is that of the new crystalline form of compound 1 (i.e., type D).

[0019] Figure 3 This is a polarization light microscope (PLM) image of type D.

[0020] Figure 4 The results of pyrolysis gravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis are shown for the new crystalline form of type D.

[0021] Figure 5 The following is a superimposed image of XRPD spectra: XRPD spectrum of type D heated to 90°C and cooled to room temperature; XRPD spectrum of type D heated to 150°C and cooled to room temperature; and reference spectra of type C and type D.

[0022] Figure 6 These are Type D images obtained using a hot stage microscopy (HSM) at temperatures of 90°C and 150°C.

[0023] Figure 7 It is the collected dynamic gas-phase adsorption (DVS) spectrum of type D.

[0024] Figure 8 It is the XRPD spectrum of the obtained DVS type D.

[0025] Figure 9 It is a superimposed image of the XRPD spectrum of the slurry of type D placed in H2O for 2 weeks and the reference of type D.

[0026] Figure 10 This is a thermal ellipsoid diagram of the compound in type D crystal.

[0027] Figure 11The hydrogen bond network in type D, formed by water and chloride anions, is shown.

[0028] Figure 12 The distances (angstroms, red) and angles (degrees, blue) in the solvent-anion network are shown.

[0029] Figure 13 The unit cell of compound 1 is shown, with hydrogen atoms omitted for clarity.

[0030] Figure 14 The stacking of compound 1 is shown as viewed along the b-axis.

[0031] Figure 15 The hydrogen bonds between molecules of compound 1 are shown, with hydrogen atoms omitted for clarity. Detailed Implementation

[0032] Crystallization form of compound 1 (formula D) In some aspects, this disclosure provides a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (compound 1). In some embodiments, compound 1 is represented by the following structure: .

[0033] Compound 1 is a novel selective T-type calcium channel blocker designed to block aberrant bursts of neuronal firing in the cerebellar-thalamic-cortical (CTC) circuit associated with tremor activity. Certain crystalline forms of Compound 1 are known and described, for example, in WO / 2021 / 007487, the entire contents of which are hereby incorporated by reference.

[0034] This disclosure provides a novel crystalline form of compound 1. As used herein, the term "crystalline" or "crystalline form" refers to the solid form of compound 1 in which atoms are arranged in a regular repeating pattern. In some embodiments, the term "crystalline" indiscriminately covers either the polymorphic form or the amorphous form of compound 1.

[0035] As used in this article, the term "amorphous" or "amorphous form" refers to the non-crystalline form of a substance, such as a solid form without a regular arrangement of atoms.

[0036] As used herein, the terms "polymorph" or "polymorphic form" refer to an organized structure involving only solute molecules and possessing characteristic crystalline features. These terms can refer to different crystalline forms of the same molecule. Due to differences in the arrangement or conformation of molecules in the crystal lattice, different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectra. The differences in the physical properties exhibited by different polymorphs can affect important parameters of pharmaceutical substances, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability).

[0037] Differences in stability among different polymorphs can also be caused by differences in chemical reactivity (e.g., different susceptibility to oxidation). Therefore, a dosage form composed of one polymorph may discolor more quickly than a dosage form composed of another polymorph of the same substance. Differences in stability among different polymorphs can also be caused by differences in mechanical properties (e.g., tablets may break during storage due to the conversion of a kinetically favorable polymorph to a thermodynamically more stable one); or by differences in both chemical and mechanical properties (e.g., tablets of one polymorph are more prone to decomposition at high humidity). Due to differences in solubility / dissolution, some polymorphic transformations can lead to loss of potency in extreme cases, or toxicity at the other extreme. Additionally, the physical properties of crystals can be important in processing. For example, different polymorphs of the same substance may exhibit differences in their tendency to form solvates or in particle shape and size distribution, thus affecting purification (e.g., one polymorph may be more difficult to filter and wash away impurities than another).

[0038] Polymorphs of molecules can be obtained by a variety of methods known in the art. These methods may include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Techniques used to characterize polymorphs may include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., IR and Raman spectroscopy), solid-state NMR, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. Specifically, XRPD is a technique used to characterize the crystal structure, size, and preferred orientation of polycrystalline or powdered solid samples. This diffraction is also used to characterize heterogeneous solid mixtures to determine the percentage of crystalline compounds present and can provide structural information about unknown materials. The term “X-ray powder diffraction pattern” is used interchangeably with the term “XRPD pattern” herein and refers to a graphical representation of data collected by XRPD analysis.

[0039] In some embodiments, this disclosure provides a new crystalline form of compound 1, which is also referred to herein as "type D".

[0040] In some embodiments, the novel crystalline form of compound 1, type D, is characterized by its X-ray powder diffraction (XRPD) pattern including at least one peak with a diffraction angle (°2θ) selected from the group consisting of, for example, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or nine peaks: A peak at approximately 12.0°; A peak at approximately 15.6°; A peak of approximately 16.7°; A peak of approximately 19.8°; A peak at approximately 21.2°; A peak at approximately 24.1°; A peak at approximately 25.2°; A peak at approximately 27.3°; and The peak is approximately 30.2°.

[0041] As used herein, the term "peak" refers to a peak in an XRPD spectrum that is at least 20% higher than the baseline noise, such as at least 30%, at least 40%, at least 50%, or at least 100%.

[0042] As used herein with respect to peaks in XRPD spectra, the term “approximately” or “about” means that the peak in the XRPD spectra appears within 0.5 °2θ of a given °2θ value, for example, within 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01 °2θ.

[0043] In some embodiments, the novel crystalline form of compound 1, type D, is characterized by its X-ray powder diffraction (XRPD) pattern including at least one peak with a diffraction angle (°2θ) selected from the group consisting of, for example, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or nine peaks: A peak of 12.0° ± 0.2°; A peak at 15.6° ± 0.2°; A peak at 16.7° ± 0.2°; A peak at 19.8° ± 0.2°; A peak at 21.2° ± 0.2°; A peak at 24.1° ± 0.2°; A peak at 25.2° ± 0.2°; The peak is at 27.3° ± 0.2°; and The peak is 30.2° ± 0.2°.

[0044] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least two peaks selected from the peak groups listed above.

[0045] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least three peaks selected from the peak groups listed above.

[0046] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least four peaks selected from the peak groups listed above.

[0047] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least five peaks selected from the peak groups listed above.

[0048] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least six peaks selected from the peak groups listed above.

[0049] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least seven peaks selected from the peak groups listed above.

[0050] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes at least eight peaks selected from the peak groups listed above.

[0051] In some embodiments, this disclosure provides a new crystalline form of compound 1, namely type D, characterized in that its X-ray powder diffraction pattern (XRPD pattern) includes all nine peaks in the peak group listed above.

[0052] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0053] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): The peak is at 25.2° ± 0.2°; and The peak is 27.3° ± 0.2°.

[0054] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0055] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak at 24.1° ± 0.2°; The peak is at 25.2° ± 0.2°; and The peak is 27.3° ± 0.2°.

[0056] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0057] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak at 16.7° ± 0.2°; A peak at 24.1° ± 0.2°; The peak is at 25.2° ± 0.2°; and The peak is 27.3° ± 0.2°.

[0058] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak at approximately 12.0°; A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

[0059] In some embodiments, the novel crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern containing peaks at the following diffraction angles (°2θ): A peak of 12.0° ± 0.2°; A peak at 16.7° ± 0.2°; A peak at 24.1° ± 0.2°; The peak is at 25.2° ± 0.2°; and The peak is 27.3° ± 0.2°.

[0060] In some embodiments, the new crystalline form of compound 1, i.e., type D, is characterized by its XRPD pattern being similar to... Figure 2 The XRPD maps depicted in the text are basically the same.

[0061] In some embodiments, the melting point of the new crystalline form of compound 1, type D, is approximately 75.2°C, as determined by differential scanning calorimetry (DSC).

[0062] In some embodiments, the new crystalline form of compound 1, i.e., type D, has a space group. Its crystal structure.

[0063] In some embodiments, the new crystalline form of compound 1, namely type D, is characterized by an asymmetric unit cell with a volume of 1213.0(10) Å. 3 The 3-D parameters are: a = 8.584(3) Å; b = 9.11(4) Å; c = 17.043 Å.

[0064] In some aspects, the new crystalline form of compound 1, namely type D, is at least 90% pure, expressed as a weight ratio (w / w%) of type D to the weight of the composition comprising type D. For example, type D may be at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.5% pure, or at least 99% pure. As used herein, the term "pure" or "purity" means that the compound is about 90-100% pure, such as about 95-100%, 98-100% pure, or about 99-100% pure. In some embodiments, pure type D contains less than about 10%, less than about 5%, less than about 2%, or less than about 1% impurities. The impurities may include one or more of, for example, degradation products, oxidation products, solvents, and / or other undesirable impurities.

[0065] Method for synthesizing the crystalline form (type D) of compound 1 The novel crystalline form, type D, of compound 1 provided in this disclosure can be prepared by crystallizing the amorphous form of compound 1 from a solvent system characterized by a water activity greater than about 0.6, for example, 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0. In some embodiments, type D can be prepared by crystallizing the amorphous form of compound 1 from a solvent system characterized by a water activity of 7.0 or greater. In some embodiments, type D can be prepared by crystallizing the amorphous form of compound 1 from a solvent system characterized by a water activity of 8.0 or greater.

[0066] As used in this article, the term "water activity (a)" w "Water activity" refers to the equilibrium water volume available for material hydration. In some embodiments, the term "water activity" is used... w "Water activity" refers to the ratio of the vapor pressure of water in a solvent system to the vapor pressure of pure water at the same temperature. Water activity is a function of water concentration and the properties of the cosolvent in the solvent system, and can be measured by methods known in the art.

[0067] In some embodiments, a solvent system with a water activity greater than about 0.6, such as 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises water. In some embodiments, a solvent system with a water activity greater than about 0.6, such as 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises only water and does not contain any organic solvent. In some embodiments, a solvent system with a water activity greater than about 0.6, such as 0.7 or greater, 0.8 or greater, 0.9 or greater, or 1.0, comprises water and an organic solvent, such as acetone, acetonitrile, benzene, chloroform, cyclohexane, n-hexane, diethyl ether, dimethyl sulfoxide, dimethylformamide, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, or an alcohol (e.g., methanol, ethanol, or isopropanol). In some embodiments, the solvent system comprises water and an organic solvent, such as acetone, with a water:acetone ratio greater than 1:3.

[0068] In some embodiments, this disclosure provides a new crystalline form of compound 1 prepared by the above method, namely type D.

[0069] Compositions containing the crystalline form (formula D) of compound 1 This disclosure also provides a pharmaceutical composition comprising a novel crystalline salt form of compound 1, namely, type D. The amount of compound 1 in the provided composition in the form of type D enables compound 1 to act as an effective T-type calcium channel blocker. For example, the amount of compound 1 in the pharmaceutical composition in the form of type D enables it to effectively treat, for example, neurological disorders, mental disorders, generalized epilepsy syndromes, or essential tremor.

[0070] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, the preparation method includes the following steps: associating compound 1 in form D with a carrier and / or one or more other excipients, and then, if desired and / or wishfully, shaping and / or packaging the product into desired single-dose or multi-dose units.

[0071] Pharmaceutically acceptable carriers used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. The compositions may also contain carriers such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents and aromatizers.

[0072] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0073] Exemplary granulating agents and / or dispersants include potato starch, corn starch, cassava starch, sodium glycolate starch, clay, alginate, guar gum, citrus pomace, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium glycolate starch), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0074] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, carrageenan, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), and carbomer. (e.g., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxylated vinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol monolaurate (Tween 20), polyoxyethylene sorbitol (Tween 60), polyoxyethylene sorbitol monooleate (Tween 80), sorbitol monopalmitate (Span 40), sorbitol monostearate (Span 60), sorbitol tristearate (Span 65), glyceryl monooleate, sorbitol monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj... 45) Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl lauryl ether, sodium lauryl sulfate, Pluronic F-68, poloxamer-188, cetrimonium bromide, hexadecylpyridine chloride, benzalkonium chloride, docusate sodium and / or mixtures thereof.

[0075] Exemplary adhesives include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), veegum, and larch arabinogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethyl methacrylate, waxes, water, alcohols, and / or mixtures thereof.

[0076] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0077] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0078] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzyl chloride, benzyl alcohol, bromonitrile glycol, cetrimide, hexadecylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, xylene, cresol, ethanol, glycerol, hexetidine, imidureurium, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0079] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0080] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0081] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0082] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0083] Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixture, thiamethoxam, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0084] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearoyl fumarate, and mixtures thereof.

[0085] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola seed oil, caraway oil, carnation oil, Brazil palm oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, flaxseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui nut oil, mixed lavender oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, and Atlantic sea bream oil. Roughy oil), palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, peppermint oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, tsubaki oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, caprylic triglyceride, cyclodimethylsiloxane, diethyl sebate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecyl alcohol, oleyl alcohol, polysiloxane oil, and mixtures thereof.

[0086] The pharmaceutical compositions provided herein can be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, buccally, transmucosally, or as ophthalmic preparations. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one aspect, the pharmaceutical compositions provided herein are administered orally in orally acceptable dosage forms, including but not limited to capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspensions and / or emulsions, the active ingredient may be suspended or dissolved in an oil phase in combination with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0087] The amount of compound 1 in form D, to be combined with a carrier material to produce a single-dosage composition, will vary depending on the subject to be treated and the specific administration regimen. For example, the specific dose and treatment regimen for any particular subject will depend on a variety of factors, including age, weight, general health condition, sex, diet, administration time, excretion rate, drug combination, physician's judgment, and the severity of the specific disease being treated. In one aspect, pharmaceutical compositions can be formulated such that a dose equivalent to about 0.001 to about 100 mg / kg body weight / day (e.g., about 0.5 to about 100 mg / kg of compound 1) can be administered to subjects receiving these compositions. Alternatively, doses equivalent to 1 mg / kg and 1000 mg / kg of compound 1 every 4 to 120 hours are also acceptable. As used herein, dose refers to the amount of compound 1 in form D.

[0088] In some embodiments, compound 1 in form D is formulated to be administered at doses equivalent to about 2 mg to about 3000 mg of compound 1, such as about 5 mg to about 350 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, or about 20 mg to about 40 mg of compound 1 in form D. In some embodiments, compound 1 in form D is formulated to be administered at doses equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of compound 1 in form D.

[0089] In some embodiments, compound 1 in form D is formulated to be administered at doses equivalent to about 2 mg to about 3000 mg of compound 1 daily, such as about 5 mg to about 500 mg, about 5 mg to about 200 mg, or about 20 mg to about 40 mg of compound 1 daily. In some embodiments, compound 1 in form D is formulated to be administered at doses equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of compound 1 daily. In some embodiments, compound 1 in form D may be administered once daily. In other embodiments, compound 1 in form D may be administered twice daily. In still other embodiments, compound 1 in form D may be administered every other day.

[0090] In some embodiments, compound 1 in form D may be formulated into a tablet composition together with a pharmaceutically acceptable carrier. Suitable carriers for use in the tablet composition may be selected from one or more of microcrystalline cellulose, mannitol, sodium croscarmellose, and sodium stearoyl fumarate. For example, in some embodiments, the carrier may be microcrystalline cellulose, for example, present in the tablet composition in an amount of about 40% w / w to about 80% w / w, for example, about 50% w / w to about 70% w / w, or about 55% w / w to about 65% w / w. In some embodiments, the carrier may be mannitol, for example, present in the tablet composition in an amount of about 20% w / w to about 45% w / w, for example, about 20% w / w to about 30% w / w. In some embodiments, the carrier may be sodium croscarmellose, for example, present in an amount of about 1% w / w to about 5% w / w. In some embodiments, the carrier may be stearoyl fumarate, for example, present in the tablet composition in an amount of about 1% w / w to about 5% w / w.

[0091] In some embodiments, compound 1 in the form of type D may be present in the tablet composition in amounts equivalent to about 1 mg to about 150 mg of compound 1, such as about 1 mg to about 100 mg, about 5 mg to about 50 mg, or about 20 mg to about 40 mg of compound 1.

[0092] In some embodiments, the pharmaceutical compositions provided in this disclosure may be administered to a subject once or more daily (e.g., twice, three, or four times daily).

[0093] In some embodiments, the method of this disclosure comprises administering a tuned dose of compound 1 in form D to a subject in need. In some embodiments, the maximum tuned dose is 60 mg or 100 mg per day. In one embodiment, the maximum tuned dose is 60 mg per day.

[0094] In one aspect, the pharmaceutical compositions provided in this disclosure comprise a single unit dosage form of compound 1 in form D. In some embodiments, the single unit dosage form comprises up to 200 mg of compound 1 in form D. In some embodiments, the length of the single unit dosage form is up to 16 mm, for example, from about 14 mm to about 16 mm, and / or the width is up to 7 mm, for example, from about 5 mm to about 7 mm. In some embodiments, the single unit dosage form is bioequivalent to a reference composition of the same dose strength administered in a multi-unit dosage form, such as a modulated release (MR) formulation comprising compound 1 in form D, which is a round and small-sized (e.g., about 6 mm in diameter) 5 mg and 20 mg tablet. In some embodiments, bioequivalence can be established by: (a) a 90% confidence interval for AUC, which is between about 80% and about 125%, and (b) C max The 90% confidence interval is between approximately 80% and approximately 125%.

[0095] Modified-release formulations and compositions In some embodiments, this disclosure also provides a pharmaceutical composition comprising compound 1 in the form of formula D and an excipient for altering the release rate of compound 1. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0096] The compositions disclosed herein may comprise compound 1 in the form of form D and a release modulating polymer. As used herein, the term "release modulating polymer" refers to any polymer that, when added to a composition comprising compound 1 in the form of form D, alters the release rate of compound 1. The release modulating polymer may be a hydrophilic polymer, such as a hydroxypropyl methylcellulose (HPMC) polymer; a hydrophobic polymer, such as ethylcellulose or ethocell; or a polyacrylate polymer, such as Eudragit RL100 or Eudragit RS100. In some embodiments, the release modulating polymer is present in the composition in an amount sufficient to alter the release rate of compound 1. In some embodiments, the composition is intended for oral administration.

[0097] In some embodiments, the compositions disclosed herein may comprise a modulating polymer and compound 1 in the form of formula D, in an amount of about 0.9% to about 40% by weight. (For example, about 0.9 wt% to about 30 wt%, about 1 wt% to about 25 wt%, about 2 wt% to about 25 wt%, about 3 wt% to about 20 wt%, about 4 wt% to about 20 wt%, about 5 wt% to about 20 wt%, about 5 wt% to about 15 wt%, about 5 wt% to about 10 wt%, or about 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 40 wt%.)

[0098] In some embodiments, the compositions disclosed herein may comprise a release polymer and compound 1 in the form of form D, in an amount of about 1 mg to about 40 mg, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0099] In some embodiments, the composition comprises about 55 mg to about 65 mg of a modulating polymer (e.g., HPMC polymer). In some embodiments, the composition comprises about 10% to about 70% by weight, for example about 50% to about 60% by weight of a modulating polymer (e.g., HPMC polymer).

[0100] In some embodiments, the composition may further comprise a diluent, such as microcrystalline cellulose. In some embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15 mg to 40 mg, for example, about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 40 mg. In some embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15% by weight to about 35% by weight, for example, about 15% by weight to about 20% by weight, about 20% by weight to about 25% by weight, 25% by weight to about 30% by weight, or 30% by weight to about 35% by weight.

[0101] In some embodiments, the composition may further comprise a flow aid, such as colloidal silica. In some embodiments, the composition may further comprise a lubricant, such as magnesium stearate. In some embodiments, the composition may further comprise a coating.

[0102] In some embodiments, the composition may be administered to a patient once or twice daily. In some embodiments, the composition may be in the form of tablets, capsules, or suspensions. In one embodiment, the composition is in the form of tablets.

[0103] Treatment using compound 1 in form D This disclosure also provides methods for treating diseases, conditions, or symptoms related to the function of T-type calcium channels. The methods comprise administering to a subject in need an effective amount of compound 1 in form D, as described herein, or a pharmaceutical composition comprising compound 1 in form D, as described herein. The ability of compound 1 to modulate T-type calcium channels has been described, for example, in WO 2021 / 007487, the entire contents of which are hereby incorporated by reference.

[0104] In some embodiments, the methods disclosed herein include administering a single-unit dosage form as described herein to a subject in need.

[0105] In some embodiments, this disclosure provides a method for treating a neurological disorder in a subject of need, the method comprising administering to the subject an effective amount of compound 1 in form D. In some embodiments, one or both of the subject's T-type calcium channel genes CACNA1H and CACNA1G are mutated. In some embodiments, the neurological disorder is epilepsy. In some embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is hereditary epilepsy. In some embodiments, the neurological disorder is absence seizures. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain, thalamic pain, or migraine). In some embodiments, the neurological disorder is tremor (e.g., essential tremor, or Parkinson's disease tremor). In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with a CACNA1G mutation). In some embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is arousal disorder.

[0106] In some embodiments, the compound 1 in form D described herein or a pharmaceutical composition comprising the compound 1 in form D is effective in treating tremor (e.g., essential tremor). In some embodiments, the compound 1 in form D described herein or a pharmaceutical composition comprising the compound 1 in form D is effective in treating epilepsy or epilepsy syndromes, such as absence seizures, juvenile myoclonic epilepsy, status epilepticus, or hereditary epilepsy. The compound 1 in form D described herein or a pharmaceutical composition comprising the compound 1 in form D may also modulate all T-type calcium channels, such as Cav3.1, Cav3.2, and / or Cav3.3. In some embodiments, the compound 1 in form D described herein or a pharmaceutical composition comprising the compound 1 in form D is effective in treating mental disorders, such as mood disorders, such as major depressive disorder.

[0107] In some embodiments, this disclosure also provides a method for treating a mental disorder in a subject in need, the method comprising administering to the subject an effective amount of compound 1 in the form of form D as described herein, or a pharmaceutical composition comprising compound 1 in the form of form D. In some embodiments, the mental disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0108] As used herein, the term "subject" for which medication is considered includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human" and "patient" are used interchangeably herein.

[0109] Epilepsy and Epilepsy Syndromes The compound 1 in form D described herein, or pharmaceutical compositions comprising compound 1 in form D, may be used to treat epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, resulting in seizures that can manifest as abnormal movements, staged abnormal behaviors, sensory disturbances, and sometimes loss of consciousness. The symptoms of epileptic seizures vary widely, ranging from a simple blank stare for a few seconds to repetitive twitching of the arms or legs during a seizure.

[0110] Epilepsy can involve generalized seizures or partial or focal seizures. Generalized seizures involve all areas of the brain. A person experiencing a generalized seizure may cry or make some noise, freeze for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are usually open, and the person may appear not to be breathing and actually turn blue. Recovery of consciousness is gradual, and the person may be confused for anywhere from a few minutes to a few hours. The main types of generalized seizures are as follows: tonic-clonic seizures, tonic seizures, clonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures, and absence seizures (typical seizures, atypical seizures, myoclonic seizures, eyelid myoclonic seizures), as well as epileptic spasms. In partial or focal seizures, only a part of the brain is involved, and therefore only a part of the body is affected. Symptoms may vary depending on the part of the brain with abnormal electrical activity.

[0111] As described in this article, epilepsy includes generalized seizures, partial seizures, complex partial seizures (e.g., seizures involving only a part of the brain but with impaired consciousness), tonic-clonic seizures, clonic seizures, tonic seizures, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe seizures.

[0112] Compound 1 in form D, or pharmaceutical compositions comprising compound 1 in form D, as described herein, may also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction, caused at least in part by certain aspects of epilepsy, are also called epileptic encephalopathy. These are associated with treatment-resistant, frequent seizures and severe cognitive impairment, such as West syndrome.

[0113] In some embodiments, the epilepsy syndrome includes epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 in hereditary generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 in non-acquired focal epilepsy (NAFE)). In some embodiments, the epilepsy syndrome is Doose syndrome or myoclonic anorexic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spikes and waves during sleep (CSWS). In some embodiments, the epilepsy syndrome is Landa-Cleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0114] Absence seizures Absence seizures are one of the most common types of seizures in patients with idiopathic generalized epilepsy (IGE). An absence seizure is a relatively brief, nonconvulsive seizure characterized by a sudden loss of consciousness and reflexes, typically lasting 10–30 seconds, followed by a rapid return of consciousness without postictal confusion. Accompanying EEG recordings show a characteristic onset and termination of generalized 1–6 Hz (e.g., 3 Hz) spikes and waves of discharge. Absence seizures often occur multiple times daily, disrupting learning and psychosocial functioning, and posing a risk of injury due to the frequent loss of consciousness. Typically, absence seizures begin in early childhood and remit during adolescence. However, in a minority of patients, seizures persist into adulthood, often becoming drug-resistant and potentially accompanied by other types of seizures, such as generalized tonic-clonic seizures. For these adult patients, absence seizures often result in severe disability, particularly preventing them from obtaining a driver's license or engaging in occupations and hobbies that pose a safety risk associated with the loss of consciousness during seizures and are accompanied by severe psychosocial impairment.

[0115] While absence seizures are generally considered relatively "easy" to treat, a randomized controlled trial in children with absence epilepsy showed that even the most effective antiepileptic drugs, ethosuximide and valproate, only achieved complete seizure control in 53% and 58% of patients, respectively, at 16 weeks, as assessed by video-EEG recordings, and only 45% and 44%, respectively, at 12 months. Lamotrigine, another commonly used AED for absence seizures, controlled seizures in only 29% of patients at 16 weeks and only 21% at 12 months. Furthermore, both ethosuximide and valproate are often accompanied by intolerable side effects (occurring in 24% of patients receiving either drug), and the latter is now generally considered contraindicated in girls and women of childbearing potential. Other treatment options for absence seizures are limited, with only benzodiazepines having proven efficacy, and these drugs are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat. Patients often require multiple medications, but these can cause serious side effects and fail to control seizures.

[0116] Extensive evidence suggests that low-threshold (T-type) calcium channels play a crucial role in the generation and maintenance of absence seizures, and are a key component of the oscillatory bursts of discharge occurring in thalamic cortical neurons during absence seizures. In some embodiments, this disclosure provides a method of treating absence seizures in a subject of need, the method comprising administering to the subject an effective amount of compound 1 in form D as described herein, or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the absence seizures are treatment-resistant absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0117] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizure is atypical absence seizure. In some embodiments, the absence seizure includes adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0118] In some embodiments, the method described herein further includes identifying a subject suffering from absence seizures.

[0119] In some embodiments, this disclosure provides a method for treating a subject with a generalized epilepsy syndrome accompanied by absence seizures, the method comprising administering to the subject an effective amount of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the method results in a reduction in the number of seizures.

[0120] In some embodiments, this disclosure provides a method for treating a subject with a generalized epilepsy syndrome accompanied by absence seizures, the method comprising administering to the subject an effective amount of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D.

[0121] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in the average or total duration of seizures.

[0122] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in the frequency, duration, or both of seizures, as measured by electroencephalography (EEG).

[0123] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in the average seizure duration, as measured by EEG.

[0124] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in the cumulative duration of seizures, as measured by EEG.

[0125] In some embodiments, the method of treating generalized epilepsy syndrome with absence seizures provided in this disclosure results in a reduction in the total duration of 2.5-4 Hz spike discharges following hyperventilation and photostimulation, as measured by EEG.

[0126] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in overall severity, as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) scores. CGI-S is a 7-point scale used to rate the severity of a patient's condition at assessment based on a clinician's past experience treating patients with the same diagnosis. CGI-I is a 7-point scale used to assess improvement in a patient's condition relative to baseline.

[0127] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndrome with absence seizures result in a reduction in the number of seizures.

[0128] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in seizure density, as measured by electroencephalography (EEG).

[0129] In some embodiments, the methods provided in this disclosure for treating generalized epilepsy syndromes with absence seizures result in a reduction in the average seizure duration, as measured by EEG.

[0130] Hereditary epilepsy In some embodiments, this disclosure provides a method for treating epilepsy or epilepsy syndrome in a subject in need, the method comprising administering to the subject an effective amount of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D.

[0131] In some embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or a hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is hereditary generalized epilepsy. In some embodiments, epilepsy or epilepsy syndrome includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Delavit syndrome, Delavit syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of children with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial epilepsy of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0132] In some embodiments, the methods described herein further include identifying a subject suffering from epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Delavit syndrome, Delavit syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of children with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infancy malignant migratory partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) before administering compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein.

[0133] In one aspect, this disclosure provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Delavit syndrome, Delavit syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of children with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infancy malignant migratory partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy), said method comprising administering to a subject in need an effective amount of compound 1 in form D described herein or a pharmaceutical composition comprising compound 1 in form D.

[0134] Compound 1 in form D, or a pharmaceutical composition comprising compound 1 in form D, as described herein, may also be used to treat epileptic encephalopathy in a subject in need, wherein the subject has one or more mutations in one of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB 1. KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN 8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0135] In some embodiments, the methods described herein further include, prior to administration of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D, identifying a subject having one or more of the following mutations: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRB2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KC NMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SI K1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H and CACNA1I.

[0136] The compound 1 in form D described herein, or a pharmaceutical composition comprising compound 1 in form D, may also be used to treat epileptic encephalopathy in a subject in need, wherein the subject has one or more mutations in one of the following: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2. (TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EH MT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR 2. GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ 10. KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF , NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PR IMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, S IK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SP ATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2,UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0137] In some embodiments, the methods described herein further include, prior to administration of compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein, identifying a subject having one or more of the following mutations: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2. (TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, E HMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOS R2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KC NJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEX MIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE 1. PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SG CE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX2 7. SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1,TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN and RANBP2.,

[0138] The compound 1 in form D described herein, or a pharmaceutical composition comprising compound 1 in form D, may also be used to treat epileptic encephalopathy in a subject in need, wherein the subject has one or more mutations in one of the following: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8 (CLN7), NALCN, NGLY1, NHLRC1 (EPM2B), NPRL3. NR2F1, NRXN1, PACS1, PCDH19, PIGA PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1 (CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0139] In some embodiments, the methods described herein further include, prior to administration of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D, identifying a subject having one or more of the following mutations: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8 (CLN7), NALCN, NGLY1, NHLRC1 (EPM2B), NPRL3. NR2F1, NRXN1, PACS1, PCDH19, PIGA PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1 (CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0140] The compound 1 in form D described herein, or a pharmaceutical composition comprising compound 1 in form D, may also be used to treat epileptic encephalopathy in a subject in need, wherein the subject has one or more mutations in one of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRB2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRN PU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NH LRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0141] In some embodiments, the methods described herein further include, prior to administration of compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D, identifying a subject having one or more of the following mutations: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRB2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, H NRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1 B. SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3 GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0142] Mood Disorders In some embodiments, this disclosure also provides a method for treating a mental disorder, the method comprising administering to a subject in need a compound 1 in form D described herein or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the mental disorder may be a mood disorder, such as clinical depression, postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicidal tendency, suicidal ideation, or suicidal behavior. The method comprises administering to a subject an effective amount of compound 1 in form D described herein or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the method described herein provides a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or conditions described herein (e.g., neuroendocrine disorders and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health conditions or symptoms).

[0143] Clinical depression, also known as major depressive disorder (MDD), severe depression, unipolar depression, unipolar affective disorder, and recurrent depression, is a mental disorder characterized by a generalized and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience difficulty sleeping, weight loss, and generalized anxiety and irritability. Clinical depression affects an individual's feelings, thoughts, and behaviors and can lead to a variety of emotional and physical problems. People with clinical depression may find it difficult to perform daily activities and may feel that life is meaningless.

[0144] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feeling alienated from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0145] Postpartum depression (PND), also known as postpartum depression (PPD), is a clinical depression affecting women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0146] In some embodiments, subjects with perinatal depression also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression have an increased risk of developing perinatal depression.

[0147] Atypical depression (AD) is characterized by mood responsiveness (e.g., anomalous anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also have excessive sleep or somnolence (hypersomnia), heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0148] Depressive disorder is characterized by loss of pleasure in most or all activities (anhedonia), no response to pleasurable stimuli, more pronounced depressive mood than sadness or loss, excessive weight loss, or excessive guilt.

[0149] Major psychotic depression (PMD) or psychotic depression refers to a severe depressive episode, particularly a melancholic one, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0150] Catatonic depression is a severe form of depression involving motor and behavioral disturbances as well as other symptoms. Individuals may become silent, comatose, unable to move, or make aimless or bizarre movements.

[0151] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals exhibit a seasonal pattern of depressive episodes during the fall or winter.

[0152] Dysphoria is a symptom associated with unipolar depression that presents with the same physical and cognitive problems. These problems are less severe and tend to be more persistent (e.g., at least 2 years).

[0153] Dual depression refers to a persistently low mood (dysthymia) lasting for at least 2 years, accompanied by a severe depressive episode.

[0154] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive features.

[0155] Recurrent transient depression (RBD) is a condition in which an individual experiences approximately one depressive episode per month, each episode lasting two weeks or less, usually less than two to three days.

[0156] Mild depressive disorder or mild depression is defined as depression characterized by the presence of at least two symptoms that last for two weeks.

[0157] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including elevated mood (mania or hypomania) and depressed mood (depression). During a manic episode, an individual may abnormally feel or exhibit euphoria, energy, or agitation. They often make ill-considered decisions with little regard for consequences. Sleep needs are typically reduced. During a depressive episode, crying, difficulty making eye contact, and negative outlooks on life may occur. People with this condition have a significantly higher 20-year suicide risk (greater than 6%), while the incidence of self-harm is 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are also commonly associated with bipolar disorder.

[0158] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0159] Treatment-resistant depression refers to a condition in which an individual receives treatment for depression, but their symptoms do not improve. For example, antidepressants or psychotherapy (psychotherapy) do not alleviate the depressive symptoms in a person with treatment-resistant depression. In some cases, an individual with treatment-resistant depression may experience symptom improvement, but the symptoms may relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics) and nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0160] Postoperative depression refers to depressive moods that occur after surgery (e.g., due to the need to face death). For example, an individual may experience persistent feelings of sadness or emptiness, lose enjoyment or interest in hobbies and activities they normally enjoy, or feel persistently worthless or hopeless.

[0161] Mood disorders associated with women’s health conditions or illnesses are mood disorders (e.g., depression) that are related to (e.g., caused by) women’s health conditions or illnesses (e.g., as described herein).

[0162] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual focus on suicide. The range of suicidal ideation varies greatly, from fleeting thoughts to broad ideas, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, acquiring means of suicide, avoiding social interaction, obsessing over death, feeling helpless or hopeless in a situation, increasing alcohol or drug use, engaging in dangerous or self-destructive activities, and saying goodbye to people as if they would never see them again.

[0163] Symptoms of depression include persistent anxiety or sadness, feelings of hopelessness, despair, pessimism, worthlessness, lack of energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, movement disorders, loss of interest in pleasant activities or hobbies, poor concentration, lack of energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, binge eating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary depending on the specific circumstances. The symptoms of depression and their remission can be determined by a physician or psychologist (e.g., through a mental status examination).

[0164] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysphoric disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0165] In some embodiments, the method includes monitoring subjects using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Overall Improvement Impression (CGI) scale, and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, treatment effectiveness can be determined by a reduction in the total HAM-D score performed by the subject. Treatment effectiveness can be assessed over a specified treatment period. For example, treatment effectiveness can be determined by a decrease in the total HAM-D score relative to baseline after administration of the composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or longer; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or lifetime).

[0166] In some embodiments, the subject has a mild depressive disorder, such as mild-severe depressive disorder. In some embodiments, the subject has a moderate depressive disorder, such as moderate-severe depressive disorder. In some embodiments, the subject has a severe depressive disorder, such as severe-major depressive disorder. In some embodiments, the subject has very severe depressive disorder, such as very severe-major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., prior to treatment with the composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18 and includes the extreme values. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 and includes the extreme values. In some embodiments, the subject's HAM-D total score prior to treatment with the composition described herein is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the total HAM-D score of a subject after treatment with the composition described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the total HAM-D score after treatment with the composition described herein is less than 10, 7, 5, or 3. In some embodiments, the decrease in the total HAM-D score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with the composition described herein. In some embodiments, the decrease from the baseline total HAM-D score to the total HAM-D score after treatment with the composition described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50. In some embodiments, the percentage decrease in the baseline HAM-D total score to the HAM-D total score after treatment with the composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the treatment effect is measured as the decrease in the HAM-D total score relative to the baseline HAM-D total score after treatment with the composition described herein.

[0167] In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in the Hamilton Depression Rating Scale (HAM-D)). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect within the first or second day of treatment with the composition described herein (e.g., as determined by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect within less than or equal to 28 days, such as less than or equal to 21 days or less than or equal to 14 days, since the commencement of treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein (e.g., as determined by a statistically significant reduction in the total HAM-D score).

[0168] In some embodiments, the therapeutic effect is a reduction in the overall HAM-D score relative to baseline after treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein. In some embodiments, prior to treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein, the subject's overall HAM-D score was at least 18, at least 24, or between 14 and 18. In some embodiments, the method of treating depressive disorders described herein results in a reduction in the overall HAM-D score of at least 10 or at least 15. In some embodiments, after treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein, the subject's overall HAM-D score was 8 or less, for example 7 or less, or 6 or less.

[0169] In some embodiments, the methods for treating depressive disorders provided herein provide a therapeutic effect (e.g., as measured by a reduction in the Clinical Overall Impression Scale (CGI)). In some embodiments, the reduction in CGI is achieved within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less after initiation of treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 as described herein. In some embodiments, the methods for treating depressive disorders (e.g., major depressive disorder) provide a therapeutic effect on the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction in the CGI score relative to baseline at the end of the treatment period (e.g., 14 days after initiation of administration of compound 1 in form D or a pharmaceutical composition comprising compound 1 as described herein).

[0170] In some embodiments, the methods for treating depressive disorders provided herein provide therapeutic effects, such as as measured by a reduction in the Montgomery-Asperger's Depression Rating Scale (MADRS) score exhibited by the subject. For example, the methods provided in this disclosure result in a reduction in MADRS score within 14 days, 4 days, 3 days, 2 days, or 1 day, or 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less after initiation of treatment with compound 1 in form D as described herein or a pharmaceutical composition containing compound 1 in form D. The MADRS is a ten-item diagnostic questionnaire (involving over apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, poor concentration, fatigue, loss of sensation, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0171] pain This disclosure also provides a method for treating pain, the method comprising administering to a subject in need a compound 1 in the form of form D described herein, or a pharmaceutical composition comprising compound 1 in the form of form D. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0172] In some embodiments, the methods provided in this disclosure further include identifying a subject suffering from pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain) or migraine) before administering compound 1 in form D as described herein or a pharmaceutical composition containing compound 1 in form D.

[0173] Tremor This disclosure also provides a method for treating tremor, the method comprising administering to a subject in need a compound 1 in the form of type D as described herein or a pharmaceutical composition comprising compound 1 in the form of type D. In some embodiments, the tremor may be cerebellar tremor or intention tremor, dystonia tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, or rubral tremor. Tremors can be caused by hereditary, degenerative, and idiopathic conditions, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders; peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy syndrome, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced tremors (tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremors can be classified as physiological tremor, enhanced physiological tremor, essential tremor syndromes (including classic essential tremor, essential orthostatic tremor, and task- and position-specific tremors), dystonia tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (i.e., rubra tremor), palatal tremor, neurogenic tremor, toxic or drug-induced tremor, and psychogenic tremor. In some embodiments, the tremor may be familial tremor.

[0174] A tremor is an involuntary, rhythmic contraction and relaxation of muscles that may involve oscillations or twitches in one or more body parts, such as the hands, arms, eyes, face, head, vocal cords, trunk, or legs.

[0175] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by cerebellar lesions or damage resulting from conditions such as tumors, stroke, or other focal diseases (e.g., multiple sclerosis) or neurodegenerative diseases.

[0176] Dystonic tremor occurs in individuals with dystonia, a movement disorder in which persistent, involuntary muscle contractions result in contorted and repetitive movements and / or pain and abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is usually relieved by complete rest or certain sensory movements.

[0177] Essential tremor, or benign essential tremor, is the most common type of tremor. In some people, essential tremor may be mild and non-progressive, or it may be slowly progressive, starting on one side of the body but usually affecting both sides. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease with age, but the severity may increase. Elevated mood, stress, fever, fatigue, or hypoglycemia may trigger tremors and / or increase their severity. Symptoms typically develop over time and are both visible and persistent after onset.

[0178] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur immediately after standing up in the legs and trunk. Patients may experience cramps in their thighs and calves, and may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can also occur in patients with essential tremor.

[0179] Parkinson's tremor is caused by damage to the structures in the brain that control movement. It is often described as a "rolling" motion of the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor typically begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0180] The characteristic feature of red nucleus tremor is a coarse, slow tremor that can occur at rest, in a posture, and intentionally. This tremor is associated with conditions affecting the red nucleus in the midbrain, such as stroke.

[0181] In some embodiments, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor. In some embodiments, the tremor is essential tremor.

[0182] In some embodiments, this disclosure also provides a method for treating essential tremor, the method comprising administering to a subject in need a compound 1 in form D as described herein or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the method results in a reduction of essential tremor, as assessed by the Essential Tremor Rating Assessment Scale (TETRAS) score. As used herein, the term “Essential Tremor Rating Assessment Scale (TETRAS)” refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities. It has an Activities of Daily Living (ADL) section and a Performance section. The ADL section has 12 items rated from 0 to 4, and the Performance section has 9 items rated from 0 to 4.

[0183] In some embodiments, reduction in essential tremor is assessed using the Essential Tremor Rating and Assessment Scale (TETRAS) upper limb score.

[0184] In some embodiments, reduction in essential tremor is assessed by TETRAS performance subscale scores or TETRAS performance individual items.

[0185] In some embodiments, subjects treated according to the methods provided in this disclosure have moderate essential tremor (i.e., a TETRAS score of 10-15). In some embodiments, prior to treatment according to the methods of this disclosure, subjects treated herein had a TETRAS score of about 10 to about 15 or about 12. Treatment with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein can reduce the subject's TETRAS score. In some embodiments, subjects treated with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein experience a mean TETRAS score reduction of about 2 to 5, for example, about 3. In some embodiments, subjects treated with compound 1 in form D or a pharmaceutical composition comprising compound 1 in form D as described herein experience a mean TETRAS score reduction of about 30% to about 50%, for example, about 40%.

[0186] In some embodiments, this disclosure also provides a method for treating essential tremor, the method comprising administering to a subject of need a compound 1 in form D as described herein, or a pharmaceutical composition comprising compound 1 in form D. In some embodiments, the method results in a reduction of essential tremor, as assessed by accelerometer-based scoring, such as an accelerometer-based upper limb score. In some embodiments, the method results in a reduction of essential tremor, as assessed by a CGI score.

[0187] In some embodiments, the idiopathic tremor is an upper limb tremor.

[0188] In some embodiments, subjects are selected to be treated with compound 1 in form D due to a clinical diagnosis of essential tremor. In some embodiments, subjects selected to be treated with compound 1 in form D have essential tremor but not intention tremor.

[0189] The efficacy of compound 1 in form D or pharmaceutical compositions containing compound 1 in form D for the treatment of essential tremor described in this article can be measured using the methods described in the following reference: Ferreira, JJ et al., “MDS Evidence-Based Review of Treatments for Essential Tremor”. Movement disorder (Mov. Disord.) July 2019;34(7):950-958; Elble, R. et al., “Task Force Report: Scales for Screening and Evaluating Tremor”, Movement disorders November 2013; 28(13):1793-800. Deuschl G. et al., “Treatment of patients with essential tremor”, Lancet Neurol. 2011; 10: 148-61. Reich SG et al., “Essential Tremor”, Med. Clin. N. Am. (North American Medical Clinic) 103 (2019) 351-356. The publicly available information in the references is incorporated herein by reference in its entirety.

[0190] Ataxia In some embodiments, this disclosure also provides a method of treating ataxia, the method comprising administering to a subject in need a compound 1 in the form of form D described herein or a pharmaceutical composition comprising compound 1 in the form of form D. Ataxia, including cerebellar ataxia and spinal ataxia (e.g., postspinal ataxia), generally involves a loss or failure of coordination. Patients exhibiting ataxia may have difficulty regulating the force, range, direction, speed, and rhythm involved in posture, balance, and limb movement. For example, trunk ataxia can lead to increased postural swaying and an inability to maintain the center of gravity above the support base. Primary or secondary symptoms of ataxia, as well as ataxia gait and limb tremors, may be accompanied by speech disturbances, dysphagia, ventilatory and speech abnormalities, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, thereby severely interfering with daily activities.

[0191] As noted above, ataxia can be caused by a variety of underlying diseases and conditions in patients, including cerebellar disorders and neurodegenerative diseases, as well as diseases resulting from chronic or long-term exposure to toxins. Symptoms of ataxia can be caused by a variety of diseases, conditions, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol), etc.; in one embodiment, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or a disease resulting from long-term or chronic exposure to toxins. Diseases, conditions, syndromes, and symptoms that may lead to ataxia and can be treated according to the methods described in this article include, but are not limited to: amyotrophic lateral sclerosis (ALS), benign paroxysmal positional vertigo (BPPV), type 1 cerebellar ataxia (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endostomy), and cerebellar hypoplasia (retinal blanket). Degeneration), cerebellar parenchymal autosomal recessive disorders 3, cerebellar parenchymal disorders V, cerebellar hypoplasia (hydrocerebrospinal fluid), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal disorders, autonomic dysfunction, balance disorder syndrome, sensory impairment, endocrine disorders, diseases caused by long-term exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, tranquilizers), fragile X / tremor ataxia syndrome, Friedreich's ataxia ataxia), frontal lobe dysfunction, hereditary diseases, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathy, hydrocephalus (e.g., low or normal pressure), hypotonia, congenital nystagmus, ataxia and aberrant auditory brainstem responses, infantile episodic spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus-ataxia, neurodegenerative diseases, olivopontocerebellar atrophy, paraneoplastic diseases, Parkinson's disease (atypical), peroneal muscular atrophy, phenytoin poisoning, posterior column ataxia with retinitis pigmentosa, post-poliomyelitis syndrome, severe brain injury (e.g.,Caused by head injury, brain surgery, multiple sclerosis or cerebral palsy, long-term alcohol / drug abuse, long-term exposure to toxins, viral infection or brain tumor), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia glaucoma-related precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-deafness), spinocerebellar ataxia (malformation), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal) Recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia (autosomal recessive 4), spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph disease type II), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia (X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency, etc. In one embodiment, the ataxia is a result of a disease selected from spinocerebellar ataxia, Friedreich ataxia, and fragile X-chromosome / tremor ataxia syndrome. In another specific embodiment, the ataxia is a result of spinocerebellar ataxia or fragile X chromosome / tremor ataxia syndrome.

[0192] tinnitus In some embodiments, this disclosure also provides a method of treating tinnitus, the method comprising administering to a subject in need a compound 1 in the form of form D as described herein, or a pharmaceutical composition comprising compound 1 in the form of form D. Tinnitus is a condition in which an affected person perceives sound in one or both ears or in the head when no external sound is present. Often referred to as “ringing” in the ears, tinnitus can occur intermittently or continuously, and the perceived volume ranges from low to distressingly high. However, the perceived volume of tinnitus can vary from patient to patient; what is objectively considered distressing in one patient may be considered subtle in another.

[0193] Sleep disorders In some embodiments, this disclosure also provides a method for treating a sleep disorder, the method comprising administering to a subject in need a compound 1 in the form of form D described herein or a pharmaceutical composition comprising compound 1 in the form of form D. For example, a sleep disorder may be a central sleep disorder, type I narcolepsy, type II narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a drug or substance, hypersomnia associated with a mental disorder, sleep deprivation syndrome, circadian rhythmic sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm disorder, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, and nonspecifically identified (NOS) circadian rhythmic sleep-wake disorder.

[0194] Combination therapy In some embodiments, the compound 1 in form D described herein, or a pharmaceutical composition comprising the compound 1 in form D, may be administered in combination with another agent or therapy. Subject to administration: In some embodiments, this disclosure also provides a method of treating ataxia, the method comprising administering to a subject in need the compound 1 in form D described herein, or a pharmaceutical composition comprising the compound 1 in form D, which may suffer from a disease, condition, or symptom or symptoms thereof that would benefit from treatment with another agent or therapy. These diseases or symptoms may be related to epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) or tremor (e.g., essential tremor).

[0195] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, and levetiracetam. Levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, aminohexenoic acid, and zonisamide.

[0196] Painkillers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine analogues, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. Given the ability of compound 1 to treat pain by inhibiting T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), a combination with analgesics is particularly envisioned.

[0197] Tremor drugs Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0198] Examples of the present invention Example 1. Preparation of a new crystalline form (formula D) of compound 1 The purpose of this study is to investigate the polymorphism of compound 1.

[0199] The starting material compound 1 was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), pyrolysis gravimetric analysis (TGA), and differential scanning calorimetry (DSC). Characterization results showed that the starting material is an anhydrous crystalline solid. DSC showed a single endothermic reaction with an onset point of 224.5 °C. The crystallinity of the starting material was determined to be type C, as previously characterized, as described, for example, in WO / 2021 / 007487, the entire contents of which are hereby incorporated by reference.

[0200] In the experiments, amorphous materials were produced by ball milling to obtain new crystalline forms. These experiments led to the discovery of a new crystalline form, designated type D. Additional experiments were conducted starting with crystalline type C, showing that type D crystallizes at water activities of 0.8 and higher. Type D was identified as a channel trihydrate, and its form was confirmed by single-crystal XRD. No form transformation was observed when type D was heated to 90°C, but a slight peak broadening was observed. When the sample containing type D was further heated to 150°C, it became amorphous.

[0201] Starting with amorphous ball-milled materials, polymorphs were screened under four different experimental conditions, resulting in type D. Tables 1 and 2 below show the experimental conditions used and the resulting crystalline forms.

[0202] Table 1. Screening experiments for polymorphs of amorphous APIs.

[0203] After the vial was left to stand for one week, crystalline material was obtained in the gel, which appeared as large crystals.

[0204] Table 2. Water activity experiments of amorphous APIs.

[0205] Figure 1 These are the X-ray powder diffraction (XRPD) spectra of water activity experiments for comparison types C and D.

[0206] Example 2. Characterization of the new crystalline form (formula D) of compound 1 Type D was observed under many conditions with a water activity of 0.8 or higher. Type D was characterized using various techniques.

[0207] Figure 2The XRPD spectrum of type D is shown. Table 3 below also shows a list of peaks observed in the XRPD spectrum of type D.

[0208] Table 3. List of XRPD peaks for type D.

[0209] Figure 3 This is a polarization light microscope (PLM) image of type D. Figure 3 Type D crystallization is a massive crystal.

[0210] Figure 4 The results of pyrolysis gravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis for type D are shown. Figure 4 The results show that the weight loss in TGA up to 125°C is 11.27% (approximately 3.09:1 H2O:API), and the DSC curve shows two broad endothermic curves with starting points of 74.5°C and 113.5°C. KF indicates a water content of 11.1% (approximately 3:1 H2O:API).

[0211] Figure 5 The following is a superimposed image of XRPD spectra: XRPD spectrum of type D heated to 90°C and cooled to room temperature; XRPD spectrum of type D heated to 150°C and cooled to room temperature; and reference spectra of type C and type D. Figure 5 This indicates that when type D is heated to 90℃, the peak broadens significantly, but there is no form transformation. When type D is further heated to 150℃, the sample becomes amorphous.

[0212] Figure 6 These are images of Type D obtained using a hot-stage microscope (HSM) heated to different temperatures. Figure 6 Confirmed Figure 5 The results are shown in the image.

[0213] Figure 7 It is the collected dynamic gas-phase adsorption (DVS) spectrum of type D. Figure 7 The results show that at 80% RH, the mass of the material increases by approximately 10.45%. When the RH approaches 0, the hydrate desolvates and loses the adsorbed water, and when the RH is 20%, the hydrate re-adsorbs approximately 10.5% of water molecules.

[0214] Figure 8 The obtained XRPD spectrum of D-type D after DVS shows no obvious form change.

[0215] Water solubility of type D The water solubility of type D was measured by HPLC to determine the decrease in water solubility between type C and type D. To measure the solubility of type D in H₂O, approximately 150 mg of type D was prepared into a slurry by placing it in 1 mL of H₂O at RT for 2 weeks. The solubility of type D in H₂O was found to be 77.24 mg / mL, compared to a solubility of type C greater than 154 mg / mL. Figure 9 This is a superimposed graph of the XRPD spectra of the slurry of type D placed in H2O for 2 weeks and the reference of type D, and no form transformation is shown.

[0216] Example 3. Crystal structure of type D The proposed structure of form D was verified by single-crystal X-ray structure analysis. Figure 10 This is a thermal ellipsoid diagram of the compound in type D crystal. A plate-shaped single crystal with high diffraction quality was immersed in Paratone-N (an oil-based cryoprotectant). The crystal was mounted on a polyester film ring with random orientation and immersed in a liquid nitrogen stream at 173 K. X-ray intensity data were measured on a Bruker D8VENTURE diffractometer (1 μS micro-focusing X-ray source, Cu Kα, λ = 1.54178 Å, PHOTON CMOS detector). Frames were integrated using the Bruker SAINT software package. Integration of the data using a triclinic unit cell yielded a total of 73495 reflections, with a maximum θ angle of 75.070° (0.83 Å resolution), of which 4988 reflections were independent (integrity = 99.9%, R0). int = 3.39%) and greater than 2σ(F 2 The final unit cell constant is a = 8.584(3)Å, b = 9.11(4)Å, c =17.043Å, α = 81.24(3)°, β = 88.90(3)°, γ = 67.176(16)°, cell volume = 1213.0(10)Å 3 These parameters are based on a refinement of the XYZ centroids of 4988 reflections above 20 σ(I), where 2.626° < θ < 75.070°. Data on absorption effects were corrected using the multi-scan method (SADABS). The absorption coefficient of the material at the wavelength (1.54178 Å) is... μ It is 2.761 mm -1 The calculated minimum and maximum transmittance (based on crystal size) are 0.6649 and 0.7538, respectively. The average uniformity factor is 4.74% based on intensity.

[0217] use ShelXTLThe structural analysis program uses the intrinsic phase method to solve the structure and employs... ShelXL (Sheldrick, GM SHELXTL-2014, Crystallographic Computation System Computing System (a) Bruker Analytical X-Ray Instruments: Madison, WI, 2014; (b) Sheldrick, GM A Short History of SHELX of SHELX) , Acta Crystallography (Acta Cryst.) 2008, A64, 112) (Version 2014 / 7) The refinement package uses the full matrix least squares method to refine the matrix. ShelXL (Sheldrick, GM SHELXTL-2014, a crystallography computer system Bruker Analytical X-ray Instruments, Inc.: Madison, WI, 2014; (b) Sheldrick, GM A Brief History of SHELX , Acta Crystallographica F contained in Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK and Puschmann, H. (2009), Journal of Applied Crystallography 42, 339-341 2 For fine-tuning, use space clusters For chemical formula unit C 19 H 27 ClFN3O2·HCl, 3(H2O), Z = 2. All non-hydrogen atoms underwent anisotropic refinement. The positions of hydrogen atoms bonded to carbon atoms were refined through geometric calculations using a riding model, but hydrogen atoms bonded to nitrogen (N13) and solvent water molecules were located in the difference Fourier map and allowed free refinement to their final positions. For F with 299 variables... 2 Final anisotropic full-matrix least-squares refinement was performed, converging to R1 = 4.74% for the observed data and wR2 = 13.28% for all data. The goodness of fit was 1.092. The maximum peak in the final differential electron density synthesis was 0.660 e. - / Å 3 And the maximum hole size is -0.910 e. - / Å 3 The density calculated based on the final model is 1.299 g / cm³. 3 And F(000) is 504 e -The contents of the asymmetric unit cell of the crystal structure and its thermal ellipsoidal representation are as follows: Figure 10 As shown in the image.

[0218] Structural details and explanation The structure of compound 1 is given as a hydrochloride obtained from an acetone / water solvent system. Three water molecules were identified, and their occupancy was allowed to be refined freely, but eventually converged to full occupancy, indicating that the water molecules formed a highly ordered structure. Figure 11 The hydrogen bond network in type D, formed by water and chloride anions, is shown. The API molecules are connected by nitrogen atoms shown on the periphery. This is further emphasized by observing the positions of hydrogen atoms in the Fourier peaks and assigning them as real atoms rather than geometrically idealized positions.

[0219] This level of order within the solvent network is highly unusual. Furthermore, the distances and angles within the hydrogen bond network are nearly idealized, such as... Figure 12 shown in . Specifically, Figure 12 The distances (Å, red) and angles (degrees, blue) in the solvent-anion network are shown. Only three solvent molecules and one anion per API unit are shown, along with the atoms interacting with them. The donor-acceptor distance of 2.8 Å indicates moderate hydrogen bonding between water molecules, and the gaps between water-water and water-chlorine hydrogen bonds correspond to the difference in atomic radii between oxygen and chlorine (approximately 0.3 Å). Additionally, the Fourier peak is located on the tertiary amine N16 corresponding to hydrogen, where the contact distance infers the presence of hydrogen bonding with O102 in the solvent water. Since the hydrogen atoms in the water molecules have been directly located and partitioned, this indicates protonation of the amine and has been refined accordingly.

[0220] The stacking of compound 1 is also of interest. With the hydrogen bond network in place, the solvent is very stable, but some still remain in the channels, such as... Figure 13 and 14 shown in . Specifically, Figure 13 The unit cell of compound 1 is shown, where hydrogen atoms are omitted for clarity. Figure 14 The stacking of compound 1 is shown as viewed along the b-axis. Figure 15 The hydrogen bonds between molecules of compound 1 are shown, with hydrogen atoms omitted for clarity. Figure 15 The results show that the API molecule itself also possesses a separate network of short contacts (2.899 and 2.922 Å contact distances) between amide groups, which organizes the API molecule into two-dimensional sheets. These sheets are then paired via slip π-stacking interactions on the disubstituted benzene rings. Solvent channels exist within the sheets between these bilayer structures and connect them together.

[0221] Chloride ions within the solvent channels bind only to water molecules—there is no direct API-anion contact in this configuration. The water molecules within these channels likely possess a variety of potential hydrogen-bonding motifs, depending on the amount of available water. Furthermore, the stability of the chloride ions may depend on maintaining a certain level of solvation. Although compound 1 crystallizes as a trihydrate, these water molecules within the channels are unlikely to possess the same degree of mobility, and their instability should be considered independent and iterative. If completely dehydrated, the channels would be entirely occupied by unbound and exposed chloride anions. Several potential pathways to stabilize this system can be envisioned, such as the deprotonation of API followed by the loss of unbound HCl gas. More likely, the channels will quickly refill with a certain degree of hydration upon exposure to air. In short, this crystal forms as a trihydrate with solvent channels but can behave as a monohydrate or dihydrate to maintain the hydration level required for stable chloride anions.

[0222] equivalent Those skilled in the art will recognize or be able to identify many equivalents of the specific embodiments and methods described herein using only conventional experiments. These equivalents are intended to be covered within the scope of this invention. All patents, patent applications, and references cited herein are hereby expressly incorporated by reference.

Claims

1. A crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride trihydrate (compound 1), characterized in that... Its X-ray powder diffraction (XRPD) pattern contains at least one peak with a diffraction angle (°2θ) selected from the following group: A peak at approximately 12.0°; A peak at approximately 15.6°; A peak of approximately 16.7°; A peak of approximately 19.8°; A peak at approximately 21.2°; A peak at approximately 24.1°; A peak at approximately 25.2°; A peak at approximately 27.3°; and The peak is approximately 30.2°.

2. The crystalline form according to claim 1, characterized in that... Its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 25.2°; and The peak is approximately 27.3°.

3. The crystalline form according to claim 1, characterized in that... Its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

4. The crystalline form according to claim 1, characterized in that... Its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

5. The crystalline form according to claim 1, characterized in that... Its XRPD pattern contains peaks at the following diffraction angles (°2θ): A peak at approximately 12.0°; A peak of approximately 16.7°; A peak at approximately 24.1°; A peak at approximately 25.2°; and The peak is approximately 27.3°.

6. The crystalline form according to claim 1, characterized in that... Its XRPD pattern is basically the same as the XRPD pattern depicted in Figure 2.

7. The crystalline form according to any one of claims 1 to 6, wherein the melting point of the crystalline form is approximately 75.2°C, as determined by differential scanning calorimetry (DSC).

8. The crystalline form according to any one of claims 1 to 7, wherein the crystalline form has a space group. Its crystal structure.

9. The crystalline form according to claim 8, wherein the crystal structure is characterized by an asymmetric unit cell with a volume of 1213.0(10) Å. 3 The 3-D parameters are: a = 8.584(3) Å; b = 9.11(4) Å; c = 17.043 Å.

10. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising a modulating polymer.

12. The pharmaceutical composition of claim 11, wherein the release-modifying polymer is selected from the group consisting of hydrophilic matrix polymers, hydrophobic matrix polymers, and polyacrylate polymers.

13. The pharmaceutical composition of claim 12, wherein the hydrophilic matrix polymer is hydroxypropyl methylcellulose.

14. The pharmaceutical composition according to any one of claims 10 to 13, wherein the pharmaceutical composition is for oral administration.

15. A method for treating a neurological disorder, the method comprising administering to a subject in need a crystalline form according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 14.

16. The method of claim 15, wherein the neurological disorder is tremor.

17. The method of claim 16, wherein the tremor is essential tremor, Parkinson's tremor, cerebellar tremor, or CACNA1G tremor.

18. The method of claim 17, wherein the tremor is an essential tremor.

19. A method for treating a mental disorder in a subject in need, the method comprising administering to the subject a crystalline form according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 14.

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