Crystalline forms of neuroactive steroids

Abstract

The present invention relates to crystalline forms of anhydrous Compound (1), and pharmaceutical compositions thereof. Also disclosed herein are methods of making the crystalline solid forms of Compound (1), and methods of using the crystalline forms of Compound (1) and pharmaceutical compositions thereof to modulate GABA activity (e.g., positive allosteric modulation of GABA activity) and treat CNS-related disorders. JPEG2024527992000012.jpg42165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of U.S. Provisional Application No. 63 / 226,374, filed July 28, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to solid forms (e.g., crystalline) of neurostimulant steroids that modulate (e.g., selectively modulate) the activity of certain GABA receptors and are useful for treating or reducing the severity of CNS-related disorders in a patient, and prophylactically preventing or reducing the incidence of symptoms of CNS-related disorders in a patient. [Background technology]

[0003] Brain excitability is defined as a continuum of an animal's level of arousal, ranging from coma to seizures, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across the nerve membrane. At rest, the nerve membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the inside of the cell being negative with respect to the outside of the cell. The electrical potential (voltage) is determined by the voltage of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When an excitatory chemical transmitter such as acetylcholine is released into the synaptic cleft, it causes membrane depolarization (a change in potential from -70 mV to -50 mV). This effect is stimulated by acetylcholine and Na + It is mediated by postsynaptic nicotinic receptors that increase the membrane permeability to ions. The decrease in membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0004] In the case of the gamma-aminobutyric acid receptor complex (GRC), its effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a major impact on overall brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the flow of chloride ions down the GRC's electrochemical gradient into the cell. Increased levels of this anion within the cell cause hyperpolarization of the transmembrane potential, making the neuron less sensitive to excitatory inputs (i.e., the neuron is less excitable). In other words, higher chloride ion concentrations within neurons result in less brain excitability (wakefulness).

[0005] There is a need for new and improved crystalline forms of neuroactive steroids that act as regulators of brain excitability as well as preventative and therapeutic agents for CNS-related disorders. The crystalline forms of such neuroactive steroids described herein are directed toward this end. Summary of the Invention [Means for solving the problem]

[0006] The present invention provides a crystalline form of compound (1), which is represented by the following structural formula: [ka] The above crystalline form is a crystalline anhydrous compound (1).

[0007] In some embodiments, the crystalline form is characterized by one or more peaks corresponding to 2-theta values ​​measured at 15.4±0.3, 15.6±0.3, 18.1±0.3, 18.8±0.3, and 22.6±0.3 degrees in an X-ray powder diffraction pattern. In other embodiments, the crystalline form is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.4±0.3, 11.9±0.3, 22.2±0.3, and 23.4±0.3 degrees in an X-ray powder diffraction pattern.

[0008] In some embodiments, the crystalline form is characterized by one or more peaks corresponding to 2-theta values ​​measured at 15.4±0.2, 15.6±0.2, 18.1±0.2, 18.8±0.2, and 22.6±0.2 degrees in an X-ray powder diffraction pattern. In other embodiments, the crystalline form is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.4±0.2, 11.9±0.2, 22.2±0.2, and 23.4±0.2 degrees in an X-ray powder diffraction pattern.

[0009] In some embodiments, the crystalline form has a T of about 146° C. to about 157° C. when heated at a rate of 10° C. / min starting at a temperature of about 30° C. 開始 It has an endotherm at

[0010] In some embodiments, the crystalline form further comprises: 13 In some embodiments, the crystalline form is further characterized by one or more peaks corresponding to 200.0±0.3 ppm, 164.3±0.3 ppm, 81.3±0.3 ppm, 70.5±0.3 ppm, and 62.2±0.3 ppm in a C SSNMR spectrum. 13 In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 60.9±0.3 ppm, 60.0±0.3 ppm, 56.7±0.3 ppm, 47.8±0.3 ppm, and 45.9±0.3 ppm in a C SSNMR spectrum. 13It is characterized by one or more peaks corresponding to 42.6±0.3 ppm, 39.3±0.3 ppm, 38.3±0.3 ppm, 35.5±0.3 ppm, 25.8±0.3 ppm, and 22.9±0.3 ppm in the C SSNMR spectrum.

[0011] In some embodiments, the crystalline form is characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 8.9±0.3, 14.6±0.3, 16.4±0.3, 18.0±0.3, and 20.0±0.3 degrees. In some embodiments, the crystalline form is further characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 11.6±0.3, 15.0±0.3, 17.4±0.3, 21.2±0.3, and 29.0±0.3 degrees. In other embodiments, the crystalline form is further characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 9.6±0.3, 12.9±0.3, and 29.6±0.3 degrees.

[0012] In some embodiments, the crystalline form is characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 8.9±0.2, 14.6±0.2, 16.4±0.2, 18.0±0.2, and 20.0±0.2 degrees. In some embodiments, the crystalline form is further characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 11.6±0.2, 15.0±0.2, 17.4±0.2, 21.2±0.2, and 29.0±0.2 degrees. In other embodiments, the crystalline form is further characterized by one or more peaks in an X-ray powder diffraction pattern corresponding to 2-theta values ​​measured at 9.6±0.2, 12.9±0.2, and 29.6±0.2 degrees.

[0013] In some embodiments, the crystalline form has a T of about 160° C. to about 166° C. when heated at a rate of 10° C. / min starting at a temperature of about 30° C. 開始 In another embodiment, the crystalline form (or compound (1)) decomposes at a temperature of about 200° C. or higher.

[0014] In some embodiments, the crystalline form further comprises: 13 In some embodiments, the crystalline form is further characterized by one or more peaks corresponding to 200.2±0.3 ppm, 199.1±0.3 ppm, 162.8±0.3 ppm, 82.9±0.3 ppm, 82.1±0.3 ppm, and 12.6±0.3 ppm in a C SSNMR spectrum. 13 In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 70.4±0.3 ppm, 63.6±0.3 ppm, 49.7±0.3 ppm, 35.5±0.3 ppm, and 15.5±0.3 ppm in a C SSNMR spectrum. 13 It is characterized by one or more peaks corresponding to 62.9±0.3 ppm, 61.4±0.3 ppm, 60.6±0.3 ppm, 45.4±0.3 ppm, and 37.9±0.3 ppm in the C SSNMR spectrum.

[0015] In some embodiments, the crystalline form of Compound (1) is substantially pure. For example, the crystalline form is substantially free of impurities (e.g., containing less than about 30% by weight of impurities, less than about 25% by weight of impurities, less than about 10% by weight of impurities, less than about 5% by weight of impurities, less than about 1% by weight of impurities, less than about 0.5% by weight of impurities, less than about 0.1% by weight of impurities, or less than about 0.05% by weight of impurities).

[0016] Another aspect of the present invention provides a pharmaceutical composition comprising a crystalline form described herein and a pharma- ceutically acceptable excipient.

[0017] Another aspect of the invention is a method for the treatment of GABAergic disorders comprising administering to a subject a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition described herein. A GABA receptors in subjects requiring modulation A A method for modulating a receptor is provided.

[0018] Another aspect of the invention is a method for the treatment of GABAergic disorders comprising administering to a subject a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition described herein. AGABA in subjects in need of regulating receptor-mediated CNS-related disorders A Methods are provided for modulating receptor-mediated CNS-related disorders.

[0019] Another aspect of the present invention provides a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition described herein.

[0020] In some implementations, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. For example, the CNS-related disorder is a mood disorder. In another example, the mood disorder is depression. For example, the depression is postpartum depression. In another example, the depression is major depressive disorder. For example, the major depressive disorder is moderate major depressive disorder. And, in another example, the major depressive disorder is severe major depressive disorder.

[0021] In some implementations, the CNS-related disorder is tremor (eg, essential tremor).

[0022] In some implementations, the CNS-related disorder is stroke.

[0023] In some implementations, the CNS-related disorder is epilepsy.

[0024] In some implementations, the CNS-related disorder is status epilepticus. For example, the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus. In some examples, the status epilepticus is a convulsive status epilepticus selected from early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus. In another example, the status epilepticus is a non-convulsive status epilepticus selected from generalized status epilepticus and complex partial status epilepticus.

[0025] Another aspect of the present invention provides a method for inducing sedation and / or anesthesia in a subject in need thereof comprising administering to the subject an effective amount of a crystalline form described herein or a pharmaceutical composition described herein.

[0026] The following figures are presented as examples and are not intended to limit the scope of the claimed invention. [Brief description of the drawings]

[0027] [Figure 1] 1 shows an exemplary XRPD pattern of form S1 of compound (1).

[0028] [Diagram 2] 1 shows exemplary thermograms of TGA / DSC thermal analysis of compound (1) form S1, including TG and DSC curves.

[0029] [Diagram 3] 1 shows an exemplary 13C solid-state NMR spectrum of Form S1 of Compound (1).

[0030] [Figure 4] 1 shows an exemplary DVS isotherm plot of Form S1 of Compound (1) at 25° C.

[0031] [Diagram 5]1 shows an exemplary XRPD pattern of form S4 of compound (1).

[0032] [Figure 6] 1 shows exemplary XRPD patterns of Form S1 (top) and Form S4 (bottom) of Compound (1).

[0033] [Figure 7] 1 shows exemplary thermograms of TGA / DSC thermal analysis of compound (1) form S4, including TG and DSC curves.

[0034] [Figure 8] FIG. 1 is an enantiotropy diagram showing the relationship between Forms S1 and S4 of Compound (1).

[0035] [Figure 9] 1 shows an exemplary 13C solid-state NMR spectrum of Form S4 of Compound (1).

[0036] [Figure 10] 1 shows an exemplary 13C solid-state NMR spectral overlay of Form S1 (solid line) and Form S4 (dashed line) of Compound (1).

[0037] [Figure 11] 1 shows an exemplary DVS isotherm plot of compound (1) form S4 at 25° C.

[0038] [Figure 12] FIG. 1 shows the interconversion conditions of Forms S1 and S4 of Compound (1). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] The present invention relates generally to crystalline forms (e.g., anhydrous crystalline forms) of Compound (1), pharma- ceutically acceptable formulations thereof, methods for preparing such crystalline forms of Compound (1), and uses of such crystalline forms for modulating GABA receptor activity (e.g., positive allosteric modulation) and / or treating CNS-related disorders.

[0040] I. Definition

[0041] As used herein, “compound (1)” refers to a compound having the following structure (or structural formula): [ka]

[0042] As used herein, "XRPD" refers to X-ray powder diffraction.

[0043] As used herein, the term "VT-XRPD" refers to variable temperature XRPD.

[0044] As used herein, the terms "XRPD pattern" and "X-ray powder diffraction pattern" are used interchangeably and refer to a plot of the intensity of X-rays scattered at different angles by a sample.

[0045] As used herein, "IPA" refers to isopropyl alcohol.

[0046] As used herein, "TGA" refers to thermogravimetric analysis.

[0047] As used herein, "DSC" refers to differential scanning calorimetry.

[0048] As used herein, "NMR" refers to nuclear magnetic resonance.

[0049] As used herein, "DVS" refers to dynamic vapor sorption.

[0050] As used herein, "DCM" refers to dichloromethane

[0051] As used herein, "EtOAc" refers to ethyl acetate.

[0052] As used herein, "MeOH" refers to methanol.

[0053] As used herein, "MTBE" refers to methyl tert-butyl ether.

[0054] As used herein, "RH" refers to relative humidity.

[0055] As used herein, "RT" refers to room temperature.

[0056] As used herein, "HPLC" refers to high pressure liquid chromatography.

[0057] As used herein, "crystalline" refers to a solid that has a highly ordered chemical structure, i.e., a solid that has long-range structural order within a crystal lattice. The molecules are regularly and periodically arranged in the three-dimensional space of the lattice. For the purposes of this application, the terms "crystal form", "single crystal form", "crystalline solid form", and "solid form" are synonymous and used interchangeably, and these terms distinguish between crystals with different properties (e.g., different XRPD diffraction patterns, different 13 C SSNMR spectrum, different DSC scan results, and / or different TGA scan results).

[0058] The term "substantially crystalline" refers to a form in which at least a particular weight percentage is crystalline. The particular weight percentage can be 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In certain embodiments, the particular weight percentage of crystallinity is at least 90%. In certain other embodiments, the particular weight percentage of crystallinity is at least 95%. In some embodiments, Compound (1) can be a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., Forms S1 and S4).

[0059] The term "substantially pure" refers to a composition of a particular crystalline solid form of Compound (1) (e.g., Form S2 or Form S4) and / or any other crystalline or solid form of Compound (1) that is substantially free of any impurities. In some examples, a substantially pure crystalline (or solid) form of Compound (1) (e.g., Form S1 or Form S4) or a sample thereof is at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least at least 99.5% pure by weight. In some embodiments, Compound (1) can be a substantially pure sample of any of the crystalline solid forms (e.g., Forms S1 and S4) described herein. In some embodiments, Compound (1) can be substantially pure Form S1. In some embodiments, Compound (1) can be substantially pure Form S4.

[0060] As used herein, the term "anhydrous" or "anhydrous" when referring to a crystalline form of Compound (1) means that solvent molecules, including those of water, do not form part of the unit cell of the crystalline form. Nevertheless, a sample of the anhydrous crystalline form may contain solvent molecules that do not form part of the unit cell of the anhydrous crystalline form, e.g., residual solvent left over from the production of the crystalline form. In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the sample of the anhydrous form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the sample of the anhydrous form. In some embodiments, a sample of the anhydrous crystalline form of Compound (1) does not contain (or has very low levels of) solvent molecules, e.g., does not contain detectable amounts of solvent.

[0061] As used herein, the term "solvate" when referring to a crystalline form of Compound (1) means that a solvent molecule, e.g., an organic solvent and / or water, forms part of the unit cell of the crystalline form. Solvates that include water as the solvent are also referred to herein as "hydrates."

[0062] As used herein, the term "isomorphic" when referring to a crystalline form of Compound (1) means that the form may contain different chemical components, e.g., different solvent molecules in the unit cell, but have the same XRPD pattern. Isomorphic crystalline forms are sometimes referred to herein as "isomorphs."

[0063] The crystalline anhydrous forms of Compound (1) described herein, e.g., Form S1 or Form S4, may undergo one or more transitions (e.g., melting, or melting and crystallizing into another crystalline form) over a particular temperature or temperature range. Such a particular temperature or temperature range may be characterized by one or more endotherms in the DSC curve of the crystalline form (each endotherm having an onset temperature (T 開始 )) at which the starting temperature is expressed as: In some embodiments, at such an onset temperature, a sample of the crystalline form of Compound (1) melts and undergoes a concomitant minor process, such as crystallization or chemical decomposition. In some embodiments, at such an onset temperature, the crystalline form of Compound (1) melts in the absence of other concomitant processes.

[0064] The term "characteristic peaks" when referring to peaks in an XRPD diffraction pattern of a crystalline form of Compound (1) refers to a particular collection of peaks whose 2θ values, spanning the range of 0° to 40°, are collectively uniquely assigned to one of the crystalline forms of Compound (1).

[0065] II. Crystalline (solid) form of compound (1)

[0066] In one aspect, the present invention provides crystalline forms of Compound (1), as demonstrated by the analytical methods described herein. In some embodiments, the crystalline forms of Compound (1) are anhydrous (e.g., Forms S1 and S4). Compound (1) and methods for preparing Compound (1) are disclosed in U.S. Patent Application Publication No. US20160083417 and PCT Application Publication No. WO2014169831.

[0067] A. Morphology S1

[0068] The present invention provides form S1 of compound (1), [ka] This is a stable anhydrous crystalline form of compound (1).

[0069] In some embodiments, Form S1 is characterized by one or more peaks corresponding to 2-theta values ​​measured at 15.4±0.3, 15.6±0.3, 18.1±0.3, 18.8±0.3, and 22.6±0.3 degrees in an X-ray powder diffraction pattern. In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.4±0.3, 11.9±0.3, 22.2±0.3, and 23.4±0.3 degrees in an X-ray powder diffraction pattern. In some embodiments, Form S1 is characterized by peaks corresponding to 2-theta values ​​measured at 15.4±0.3, 15.6±0.3, 18.1±0.3, 18.8±0.3, 22.6±0.3, 9.4±0.3, 11.9±0.3, 22.2±0.3, and 23.4±0.3 degrees in an X-ray powder diffraction pattern.

[0070] In some embodiments, Form S1 is characterized by one or more peaks corresponding to 2-theta values ​​measured at 15.4±0.2, 15.6±0.2, 18.1±0.2, 18.8±0.2, and 22.6±0.2 degrees in an X-ray powder diffraction pattern. In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.4±0.2, 11.9±0.2, 22.2±0.2, and 23.4±0.2 degrees in an X-ray powder diffraction pattern. In some embodiments, Form S1 is characterized by peaks corresponding to 2-theta values ​​measured at 15.4±0.2, 15.6±0.2, 18.1±0.2, 18.8±0.2, 22.6±0.2, 9.4±0.2, 11.9±0.2, 22.2±0.2, and 23.4±0.2 degrees in an X-ray powder diffraction pattern.

[0071] And, in some embodiments, Form S1 is characterized by an X-ray powder diffraction pattern having all or substantially all of the peaks shown in the XRPD pattern depicted in Figure 1. For example, Form S1 is characterized by an X-ray powder diffraction pattern having at least 15 (e.g., at least 20, at least 25, or at least 30) of the 33 characteristic peaks set forth in Table 2 below.

[0072] In some embodiments, Form S1, when heated at a rate of about 2° C. / min to about 15° C. / min (e.g., about 5° C. / min to about 12° C. / min, about 7° C. / min to about 10° C. / min) starting from a temperature of about 30° C., has a T of about 146° C. to about 157° C. (e.g., about 147° C. to about 156° C., about 148° C. to about 156° C., about 149° C. to about 156° C., or about 150° C. to about 156° C.). 開始 In some embodiments, Form S1, when heated at a rate of about 10° C. / min starting at a temperature of about 30° C., has a T of about 146° C. to about 157° C. (e.g., about 147° C. to about 156° C., about 148° C. to about 156° C., about 149° C. to about 156° C., or about 150° C. to about 156° C.). 開始 It has an endotherm at

[0073] In some embodiments, Form S1 is 13 In another embodiment, crystalline form S1 is further characterized by one or more peaks corresponding to 200.0±0.3 ppm, 164.3±0.3 ppm, 81.3±0.3 ppm, 70.5±0.3 ppm, and 62.2±0.3 ppm in a C SSNMR spectrum. 13 In some embodiments, crystalline form S1 is further characterized by one or more peaks corresponding to 60.9±0.3 ppm, 60.0±0.3 ppm, 56.7±0.3 ppm, 47.8±0.3 ppm, and 45.9±0.3 ppm in a C SSNMR spectrum. 13 In some embodiments, crystalline form S1 is further characterized by one or more peaks corresponding to 42.6±0.3 ppm, 39.3±0.3 ppm, 38.3±0.3 ppm, 35.5±0.3 ppm, 25.8±0.3 ppm, and 22.9±0.3 ppm in a C SSNMR spectrum. 13In some embodiments, crystalline form S1 is further characterized by one or more peaks corresponding to 200.0±0.3 ppm, 164.3±0.3 ppm, 81.3±0.3 ppm, 70.5±0.3 ppm, 62.2±0.3 ppm, 60.9±0.3 ppm, 60.0±0.3 ppm, 56.7±0.3 ppm, 47.8±0.3 ppm, and 45.9±0.3 ppm in a C SSNMR spectrum. 13 In some embodiments, crystalline form S1 is further characterized by one or more peaks corresponding to 42.6±0.3 ppm, 39.3±0.3 ppm, 38.3±0.3 ppm, 35.5±0.3 ppm, 25.8±0.3 ppm, and 22.9±0.3 ppm in a C SSNMR spectrum. 13 and one or more peaks corresponding to 200.0±0.3 ppm, 164.3±0.3 ppm, 81.3±0.3 ppm, 70.5±0.3 ppm, 62.2±0.3 ppm, 60.9±0.3 ppm, 60.0±0.3 ppm, 56.7±0.3 ppm, 47.8±0.3 ppm, 45.9±0.3 ppm, 42.6±0.3 ppm, 39.3±0.3 ppm, 38.3±0.3 ppm, 35.5±0.3 ppm, 25.8±0.3 ppm, and 22.9±0.3 ppm in a C SSNMR spectrum. And, in some embodiments, Form S1 has all or substantially all of the peaks shown in FIG. 13 For example, Form S1 has at least 13 (e.g., at least 15, at least 17, at least 20, or at least 22) of the 24 characteristic peaks set forth in Table 3 below. 13 Characterized by C SSNMR spectrum.

[0074] B. Form S4

[0075] The present invention provides Form S4 of Compound (1), which is a stable anhydrous crystalline form of Compound (1).

[0076] In some embodiments, Form S4 is characterized by one or more peaks corresponding to 2-theta values ​​measured at 8.9±0.3, 14.6±0.3, 16.4±0.3, 18.0±0.3, and 20.0±0.3 degrees in an X-ray powder diffraction pattern. In another embodiment, crystalline form S4 is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 11.6±0.3, 15.0±0.3, 17.4±0.3, 21.2±0.3, and 29.0±0.3 degrees in an X-ray powder diffraction pattern. In another embodiment, crystalline form S4 is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.6±0.3, 12.9±0.3, and 29.6±0.3 degrees in an X-ray powder diffraction pattern. In some embodiments, Form S4 is characterized by peaks corresponding to 2-theta values ​​measured at 8.9±0.3, 14.6±0.3, 16.4±0.3, 18.0±0.3, 20.0±0.3, 11.6±0.3, 15.0±0.3, 17.4±0.3, 21.2±0.3, and 29.0±0.3 degrees in an X-ray powder diffraction pattern.

[0077] In some embodiments, Form S4 is characterized by one or more peaks corresponding to 2-theta values ​​measured at 8.9±0.2, 14.6±0.2, 16.4±0.2, 18.0±0.2, and 20.0±0.2 degrees in an X-ray powder diffraction pattern. In another embodiment, crystalline form S4 is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 11.6±0.2, 15.0±0.2, 17.4±0.2, 21.2±0.2, and 29.0±0.2 degrees in an X-ray powder diffraction pattern. In another embodiment, crystalline form S4 is further characterized by one or more peaks corresponding to 2-theta values ​​measured at 9.6±0.2, 12.9±0.2, and 29.6±0.2 degrees in an X-ray powder diffraction pattern. In some embodiments, Form S4 is characterized by peaks corresponding to 2-theta values ​​measured at 8.9±0.2, 14.6±0.2, 16.4±0.2, 18.0±0.2, 20.0±0.2, 11.6±0.2, 15.0±0.2, 17.4±0.2, 21.2±0.2, and 29.0±0.2 degrees in an X-ray powder diffraction pattern.

[0078] And, in some embodiments, Form S4 is characterized by an X-ray powder diffraction pattern having all or substantially all of the peaks shown in Figure 5. For example, Form S4 is characterized by an X-ray powder diffraction pattern having at least 15 (e.g., at least 10, at least 12, or at least 15) of the 18 characteristic peaks set forth in Table 4 below.

[0079] In some embodiments, Form S4, when heated at a rate of about 2° C. / min to about 15° C. / min (e.g., about 5° C. / min to about 12° C. / min, or about 7° C. / min to about 10° C. / min) starting from a temperature of about 30° C., has a T of about 160° C. to about 166° C. (e.g., about 161° C. to about 166° C., about 162° C. to about 166° C., or about 163° C. to about 165° C.). 開始 In some embodiments, Form S4 has an endotherm at T of about 160° C. to about 166° C. (e.g., about 161° C. to about 166° C., about 162° C. to about 166° C., or about 163° C. to about 165° C.) when heated at a rate of about 10° C. / min starting at a temperature of about 30° C. 開始 and, in some embodiments, the crystalline form decomposes at a temperature of about 200° C. or greater.

[0080] In some embodiments, Form S4 is 13 In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 200.2±0.3 ppm, 199.1±0.3 ppm, 162.8±0.3 ppm, 82.9±0.3 ppm, 82.1±0.3 ppm, and 12.6±0.3 ppm in a C SSNMR spectrum. 13 In another embodiment, the crystalline form is further characterized by one or more peaks corresponding to 70.4±0.3 ppm, 63.6±0.3 ppm, 49.7±0.3 ppm, 35.5±0.3 ppm, and 15.5±0.3 ppm in a C SSNMR spectrum. 139. Form S4 is characterized by one or more peaks corresponding to 62.9±0.3 ppm, 61.4±0.3 ppm, 60.6±0.3 ppm, 45.4±0.3 ppm, and 37.9±0.3 ppm in a C SSNMR spectrum. And, in some embodiments, Form S4 has all or substantially all of the peaks shown in FIG. 13 For example, Form S4 has at least 12 (e.g., at least 15, at least 20, or at least 25) of the 34 characteristic peaks set forth in Table 5 below. 13 Characterized by C SSNMR spectrum.

[0081] III. Method for Producing Crystalline Forms of Compound (1)

[0082] Another aspect of the present invention provides a method for producing a crystalline anhydrous form of Compound (1), comprising: (a) dissolving Compound (1) in a polar organic solvent; (b) exchanging the polar organic solvent with a non-polar organic solvent to produce a slurry; (c) heating the slurry to a temperature of about 50° C. to less than 70° C. (e.g., about 55° C. to about 65° C.); (d) cooling the slurry to ambient temperature (e.g., about 20° C. to about 30° C.) to form a cooled slurry; and (e) filtering the crystalline Compound (1) from the cooled slurry to produce Form S1 of Compound (1).

[0083] Another aspect of the present invention provides a method for producing a crystalline anhydrous form of Compound (1), comprising: (a) dissolving Compound (1) in a polar organic solvent; (b) exchanging the polar organic solvent with a non-polar organic solvent to produce a slurry; (c) heating the slurry to a temperature of 70° C. or greater; (d) cooling the slurry to ambient temperature (e.g., about 20° C. to about 30° C.) to form a cooled slurry; and (e) filtering the crystalline Compound (1) from the cooled slurry to produce Form S4 of Compound (1).

[0084] In some implementations of these methods, the exchanging step (b) involves removing the polar organic solvent by partial vacuum distillation and adding a nonpolar solvent, wherein the total volume of the mixture of solvent(s) and compound (1) remains substantially constant (e.g., the total volume of the mixture changes by no more than ± about 20%, no more than ± about 15%, no more than ± about 10%, or no more than ± about 5% during the solvent exchange).

[0085] In some implementations of these methods, the polar organic solvent comprises tetrahydrofuran, isopropyl acetate, ethyl acetate, dichloromethane, or any combination thereof.

[0086] In some implementations of these methods, the non-polar solvent comprises n-heptane, cyclohexane, pentane, or any combination thereof.

[0087] Some implementations of these methods further include holding (or aging) the cooled slurry for a period of about 5 hours or less (e.g., about 5 hours or less, about 3 hours or less, about 2 hours or less, about 1 hour or less, or about 0.5 hours or less) before performing the filtering of step (e).

[0088] IV. Pharmaceutical Compositions

[0089] In another aspect, the present invention provides pharmaceutical compositions comprising a solid form of a compound of the present invention (i.e., Compound (1)), also referred to as the "active ingredient," "active pharmaceutical ingredient," or "API," and a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0090] The pharmaceutical compositions provided herein may be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, topical, transdermal, intradermal, intrathecal, subcutaneous (SC), intramuscular (IM), sublingual / buccal, ocular, otic, vaginal, and intranasal or inhalation administration.

[0091] In general, the solid form of Compound (1) provided herein is administered in an effective amount. The amount of the solid form of Compound (1) actually administered is typically determined by a physician depending on the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, response, and severity of the patient's symptoms of the individual patient.

[0092] When used to prevent the development of a CNS disorder, the solid forms of Compound (1) provided herein are typically administered to subjects at risk of developing the condition at the dosage levels described above under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0093] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a solid form of Compound (1) or a pharmaceutical composition thereof, which can be continued for an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is aimed at providing consistent levels of Compound (1) in the blood or brain, e.g., within the therapeutic range, over an extended period of time.

[0094] The pharmaceutical composition of the present invention can also be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition can be given as an injection, for example, to raise the concentration of compound (1) in the blood to an effective level. The placement of the injection dose depends on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous injection dose allows for a slow release of the active ingredient.

[0095] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like, in the case of solid compositions. In such compositions, the solid form of Compound (1) is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

[0096] For oral administration, a typical dosing regimen is 1 to 5 times, particularly 2 to 4 times, and usually 3 times per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg (e.g., about 0.1 to about 10 mg / kg, about 0.2 to about 5 mg / kg, about 0.1 to about 1 mg / kg, about 0.2 to about 0.8 mg / kg, about 0.2 to about 0.7 mg / kg, or about 0.2 to about 0.5 mg / kg) of the solid form of Compound (1) provided herein. In some examples, crystalline Compound (1) (e.g., Form S1 or Form S4) is administered at a dose of about 10 mg to about 70 mg (e.g., about 15 mg to about 60 mg, about 25 mg to about 55 mg, or about 30 mg to about 50 mg) per oral dose per day.

[0097] A transdermal dose is generally selected to provide blood levels equivalent to or lower than those achieved using an injected dose, and the amount is generally, for example, in the range of about 0.01 to about 20% by weight of the drug reservoir or drug adhesive reservoir of the transdermal patch, preferably in the range of about 0.1 to about 20% by weight, preferably in the range of about 0.1 to about 10% by weight, and more preferably in the range of about 0.5 to about 15% by weight.

[0098] The solid composition may, for example, contain any of the following ingredients, or solid forms of compound (1) of similar nature: binders, surfactants, diluents or fillers, buffers, anti-adherents, glidants, hydrophilic or hydrophobic polymers, retardants (e.g., delayed release agents), anti-degradants or stabilizers, disintegrants and super-disintegrants, dispersants, antioxidants, anti-foaming agents, fillers, flavors, colorants, lubricants, adsorbents, preservatives, plasticizers, coatings, or sweeteners, or mixtures thereof. For example, the excipient(s) may be a binder such as microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, low viscosity hydroxypropylmethylcellulose, gum tragacanth or gelatin, a diluent such as mannitol, microcrystalline cellulose, maltodextrin, starch or lactose, a disintegrant such as alginic acid, sodium starch glycolate (e.g., Primogel), croscarmellose sodium, crospovidone, or corn starch, a lubricant such as magnesium stearate, sodium stearyl fumarate, or glyceryl behenate, a glidant such as colloidal silicon dioxide or talc, a preservative such as potassium sorbate or methylparaben, sodium lauryl sulfate, docusate sodium, polysorbate 20, polysorbate 80, cetyltriethylammonium bromide, polyethylene oxide-polypropylene oxide copolymer, or Cremophor. the surfactant may be butylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid, citric acid, tocopherol or tocopherol acetate, an antioxidant such as sodium sulfite or sodium metabisulfite, a coating comprising one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, acrylate copolymers, cellulose acetate, ethyl acetate, hydroxypropyl methylcellulose acetate succinate, shellac, and the like, a sweetener such as sucrose, sucralose, acesulfame K, sodium aspartame or saccharin, or a flavoring such as peppermint, methyl salicylate, cherry, grape, lemon, or orange flavoring.Any of the well-known pharmaceutical excipients can be incorporated into the dosage form and are listed in FDA's Inactive Ingredients Guide, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); Handbook of Pharmaceutical Excipients, Sixth Ed. (Pharmaceutical Press, 2009), the contents of which are incorporated by reference in their entireties.

[0099] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is usually combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance skin penetration and stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein. Topical delivery compositions of interest include liquid formulations such as lotions (liquids containing insoluble materials in the form of a suspension or emulsion intended for external use, including spray lotions), and aqueous solutions, semi-solid formulations such as gels (colloids in which the dispersed phase combines with the dispersion medium to form a semi-solid, such as a jelly), creams (soft solids or thick liquids), and ointments (soft, viscous formulations), and solid formulations such as topical patches. Thus, delivery vehicle components of interest include, but are not limited to, oil-in-water (O / W) and water-in-oil (W / O) emulsions, dairy liquids, lotions, creams, ointments, gels, serums, powders, masks, packs, sprays, aerosols, sticks, and patches.

[0100] The solid forms of Compound (1) provided herein can also be administered by transdermal devices. Thus, transdermal administration can be accomplished using either reservoir or membrane type patches, or adhesive matrix or other matrix type patches. Delivery compositions of interest include liquid formulations such as lotions (liquids containing insoluble materials in the form of suspensions or emulsions intended for topical use, including spray lotions) and aqueous solutions, semi-solid formulations such as gels (colloids in which the dispersed phase is combined with the dispersion medium to form a semi-solid such as a jelly), creams (soft solids or thick liquids), and ointments (soft, viscous formulations), and solid formulations such as topical patches. Thus, delivery vehicle components of interest include, but are not limited to, oil-in-water (O / W) and water-in-oil (W / O) emulsions, milky liquids, lotions, creams, ointments, gels, serums, powders, masks, packs, sprays, aerosols, sticks, and patches. In the case of transdermal patches, the active agent layer contains one or more active agents, one of which is Compound (1). In certain embodiments, the matrix is ​​an adhesive matrix. The matrix may include a polymeric material. Polymers suitable for the adhesive matrix include, but are not limited to, polyurethanes, acrylates, styrenic block copolymers, silicones, and the like. For example, adhesive matrices include, but are not limited to, acrylate polymers, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, combinations thereof, and the like. Additional examples of adhesives are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989), the disclosure of which is incorporated herein by reference.

[0101] In certain embodiments, the active agent layer includes a penetration enhancer, which may be selected from the group consisting of fatty alcohols such as, but not limited to, saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol and lauryl alcohol; fatty acids such as, but not limited to, linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, and palmitic acid; fatty acid esters such as, but not limited to, isopropyl myristate, diisopropyl adipate, and isopropyl palmitate; alcohol amines such as, but not limited to, triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; glycerol, ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reduced sugars. Examples of suitable polyoxyethylene alkyl ethers include, but are not limited to, polyhydric alcohol alkyl ethers such as alkyl ethers of polyhydric alcohols such as saccharides (preferably, the number of carbon atoms in the alkyl group of the polyhydric alcohol alkyl ether is 6 to 20), polyoxyethylene alkyl ethers such as, but not limited to, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether, in which the number of carbon atoms in the alkyl group is 6 to 20 and the number of repeating units (e.g., -OCH2CH2-) in the polyoxyethylene chain is 1 to 9, glycerides (e.g., fatty acid esters of glycerol), such as, but not limited to, glycerol esters, diglycerides, and triglycerides of fatty acids having 6 to 18 carbon atoms, or combinations thereof. In some embodiments, the polymer matrix comprises polyvinylpyrrolidone. The composition may further comprise one or more fillers or one or more antioxidants. In some embodiments, the transdermal formulation described may have a multi-layer structure. For example, the transdermal formulation may have an adhesive matrix and a backing.

[0102] The above ingredients for orally administrable, injectable or topically administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0103] The solid forms of Compound (1) of the present invention can also be administered in sustained release form or from sustained release drug delivery systems. A description of representative sustained release materials is provided in Remington's Pharmaceutical Sciences.

[0104] V. Uses and Treatments

[0105] In other embodiments, the crystalline forms of Compound (1) may contain one or more isotopic substitutions. For example, hydrogen may be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and the oxygen may be, for example, 18 O, where the nitrogen can be, for example, 15 In another embodiment, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in a solid form of Compound (1).

[0106] A. Pharmaceutical Compositions

[0107] In one aspect, provided herein is a pharmaceutical composition comprising a solid form of Compound (1) described herein (e.g., Form S1 or Form S4) and a pharma- ceutically acceptable excipient. In certain embodiments, the solid form of Compound (1) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the solid form of Compound (1) is provided in a therapeutically effective amount.

[0108] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

[0109] The pharmaceutical compositions provided herein may be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, vaginal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0110] In general, the solid form of Compound (1) provided herein is administered in an effective amount. The amount of the solid form of Compound (1) actually administered is typically determined by a physician depending on the circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, response, and severity of the patient's symptoms, of the individual patient.

[0111] When used to prevent the onset of CNS disorders, the compounds provided herein are typically administered to subjects at risk of developing symptoms at the dosage levels described above under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as susceptible to developing the condition.

[0112] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof that can be continued for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, for example, for the remainder of the subject's life. In certain embodiments, chronic administration is aimed at providing a constant level of the compound in the blood, for example, within the therapeutic range, for an extended period of time.

[0113] The pharmaceutical composition of the present invention may also be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, for example, intramuscular or subcutaneous bolus administration allows for a sustained release of the active ingredient, whereas a bolus delivered directly into a vein (e.g., by intravenous drip) allows for a much faster delivery, and the concentration of the active ingredient in the blood rises quickly to an effective level. In another embodiment, the pharmaceutical composition may be administered as a continuous infusion, for example, by intravenous drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in another embodiment, the pharmaceutical composition may be administered as an initial bolus dose, followed by a continuous infusion.

[0114] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like, in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

[0115] For oral administration, a typical dosing regimen is 1 to 5 times, particularly 2 to 4 times, usually 3 times per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compounds provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0116] A transdermal dose is generally selected to provide blood levels equivalent to or lower than those achieved using an injected dose, and the amount is generally in the range of about 0.01 to about 20% by weight, preferably in the range of about 0.1 to about 20% by weight, preferably in the range of about 0.1 to about 10% by weight, and more preferably in the range of about 0.5 to about 15% by weight.

[0117] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. Maximum total doses are not expected to exceed about 5 g per day for human patients weighing 40 to 80 kg.

[0118] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin, excipients such as starch or lactose, disintegrating agents such as alginic acid, primogel, or corn starch, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0119] Injectable compositions are typically based on injectable sterile saline, phosphate buffered saline, or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0120] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is usually combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0121] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0122] The above ingredients for orally administrable, injectable or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0123] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials is found in Remington's Pharmaceutical Sciences.

[0124] The present invention also relates to pharma- ceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharma- ceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, paratoluenesulfonate, etc.).

[0125] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0126] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for the particular dosage form desired, e.g., injection, dispersion or suspension aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions drugs are described, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0127] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Examples of excipients that can be used include, but are not limited to, water, sterile saline, phosphate-buffered saline, or phosphate (buffered saline Ringer's solution).

[0128] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally containing one or more substituents on the linked sugar moieties, including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, US 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more particular embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0129] Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0130] In general, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by the physician depending on the circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, response, and severity of the patient's symptoms of the individual patient.

[0131] To facilitate accurate administration, the composition is provided in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage form for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight, preferably about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0132] The compounds provided herein can be administered as the sole active agent or can be administered in combination with other active agents.In one aspect, the present invention provides a combination of the compounds of the present invention with another pharma- ceutical active agent.The administration of the combination can proceed by any technique that is apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0133] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to any type of animal. Modifications to make pharmaceutical compositions suitable for administration to humans suitable for administration to various animals are well understood, and an ordinary skilled veterinary pharmacologist can design and / or implement such modifications using routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions are described, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0134] One embodiment provides a kit that includes a composition (e.g., a solid composition) comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0135] B. Combination Therapy

[0136] The crystalline forms of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) may be administered in combination with additional drugs or therapies. The subject to whom the compounds disclosed herein are administered may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another drug or therapy. Combination therapy may be achieved by administering two or more drugs, each of which is formulated and administered separately, or by administering two or more drugs in a single formulation. In some embodiments, two or more drugs in the combination therapy may be administered simultaneously. In another embodiment, two or more drugs in the combination therapy are administered separately. For example, administration of a first drug (or combination of drugs) may precede administration of a second drug (or combination of drugs) by minutes, hours, days, or weeks. Thus, two or more agents can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks of each other. In some cases, longer intervals are possible. In many cases, it is desirable for two or more agents used in a combination therapy to be present in the patient's body at the same time, but this is not required.

[0137] Combination therapy may also include more than one administration of one or more of the drugs used in combination, using different sequences of the component drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times in any combination, for example, sequentially in the order of XYX, XXY, YXY, YYX, XXYY, etc. Examples of additional drugs are described below.

[0138] 1. Selective serotonin reuptake inhibitors (SSRIs)

[0139] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with SSRI(s). SSRIs include antidepressants that increase levels of serotonin in the brain. Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

[0140] 2. MAO Inhibitors (MAOIs)

[0141] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with MAOI(s). MAOIs include antidepressants that inhibit monoamine oxidase activity in the brain. Exemplary MAOIs include, but are not limited to, isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (parnate).

[0142] 3. Norepinephrine reuptake inhibitors (NERIs)

[0143] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), is administered in combination with a NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Vestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amidaline (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivalan).

[0144] 4. Antipsychotics

[0145] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with an antipsychotic drug(s). Antipsychotic drugs include D2 antagonists that reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotics include, but are not limited to, asenapine (Saphris), aripiprazole (Abilify), cariprazine (Vrayar), clozapine (Clozaril), droperidol, fluperlapine, mesoridazine, quetiapine hemifumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperdal), ziprasidone (Geodon), mesothidazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0146] 5. Cannabinoids

[0147] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabidiol (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabidolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

[0148] 6. NMDA receptor antagonists

[0149] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with an NMDA receptor antagonist(s). NMDA receptor antagonists are a class of drugs that inhibit the action of N-methyl-d-aspartate receptors. Exemplary NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichlorokynurenic acid, ricotinel, memantine, gavestinel, phencyclidine, dextromethorphan, remacemide, selfotel, tiletamine, dextropropoxyphene, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxyphene, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

[0150] 7. GABA receptor agonists

[0151] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), is administered to a GABA receptor agonist(s) (e.g., GABA A GABA receptor agonists are a class of drugs or compounds that are agonists of one or more GABA receptors. Exemplary GABA receptor agonists include clobazam, topiramate, muscimol, progabide, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, pregabalin, phenytoin, carbamazepine, tipental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, midazolam, triazolam, lometazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazepam, lorazepam, temazepam, oxazepam, fludazepam, qrazolam ... Lordizaepoxide, Cloxazolam, Flutoprazepam, Alprazolam, Estazolam, Bromazepam, Flurazepam, Clorazepate potassium, Haloxazolam, Ethyl loflazepate, Cazepam, Clonazepam, Mexazolam, Etizolam, Brotizolam, Clotizaepam, Propofol, Fospropofol, Zolpidem, Zopiclone, Exopiclone, Muscimol, TFQP / Gaboxadol, Isoguvacine, Kodiamine, GABA, Homotaurine, Homohypotaurine, Trans-Aminocyclopentane-3-Carboxylic Acid, Trans-Amino-4-Crotonic Acid, β-Guanidinopropionic Acid, Homo-β-Proline, Isonipecotic Acid, 3-((Aminoiminomethyl)thio)-2-Propenoic Acid (ZAP A), imidazole acetic acid, and piperidine-4-sulfonic acid (P4S).

[0152] 8. Cholinesterase inhibitors

[0153] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered in combination with a cholinesterase inhibitor(s). In general, cholinergic agents are compounds that mimic the action of acetylcholine and / or butyrylcholine. Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine / donepezil (Namzaric), ambenonium (Mytelase), neostigmine (Bloxiverz), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

[0154] The present disclosure also contemplates administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject who has previously been administered an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, an antibody, and an antibacterial agent. In some embodiments, an additional agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, an antibody, and an antibacterial agent is administered to the subject prior to administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), is co-administered to a subject with an agent selected from a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, and an antibacterial agent.

[0155] C. Methods of Use and Treatment

[0156] In one aspect, it is contemplated that a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), is useful as one or more therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need of such treatment (e.g., a subject having Rett Syndrome, Fragile X Syndrome, or Angelman Syndrome). Exemplary CNS conditions related to GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD))], dysthymic disorders (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), treatment-resistant depression (TRD), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia ( Alzheimer's dementia, Lewis body dementia, vascular dementia]), movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophagy, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [e.g., stroke, ischemia, vascular malformation], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine, and / or alcohol addition], and tinnitus.

[0157] In certain implementations, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0158] In one aspect, a method is provided for reducing or preventing seizure activity in a subject, comprising administering to a subject in need of treatment an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the method reduces or prevents epileptogenesis.

[0159] Further, in another aspect, a combination of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) with another pharmacologically active agent is provided. The compounds provided herein can be administered as the sole active agent or can be administered in combination with the other agent. The administration of the combination can proceed by any technique apparent to one skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0160] In another aspect, there is provided a method for treating or preventing brain excitation in a subject susceptible to or afflicted with a condition associated with brain excitation, comprising administering to the subject an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0161] Further, in another aspect, there is provided a method for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of treatment an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a pharmaceutical composition thereof.

[0162] Additionally, in another aspect, there is provided a method for alleviating or preventing insomnia in a subject, comprising administering to a subject in need of treatment an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a pharmaceutical composition thereof.

[0163] Additionally, in another aspect, a method is provided for inducing sleep and substantially maintaining levels of REM sleep observed in normal sleep, the method not inducing substantial rebound insomnia, comprising administering an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0164] Additionally, in another aspect, there is provided a method of alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0165] Further, in another aspect, there is provided a method for treating or preventing a mood disorder in a subject, comprising administering to a subject in need thereof an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In certain embodiments, the mood disorder is depression.

[0166] Further, in another aspect, a method for treating cognitive enhancement or memory impairment is provided by administering a therapeutically effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0167] Further, in another aspect, there is provided a method for treating an attention disorder by administering to a subject a therapeutically effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In certain embodiments, the attention disorder is ADHD.

[0168] Inflammation of the central nervous system (CNS) (neuroinflammation) is recognized as a hallmark of all neurological diseases. Major inflammatory neurological disorders include multiple sclerosis (characterized by an immune-mediated response against myelin proteins) and meningoencephalitis (in which an infectious agent triggers an inflammatory response). Additional scientific evidence suggests a potential role for inflammatory mechanisms in other neurological conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury. In one aspect, the crystalline forms of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) are useful for treating neuroinflammation. In another embodiment, the crystalline forms of the present invention are useful for treating inflammation in neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury.

[0169] In certain embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is chronically administered to a subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to a subject.

[0170] 1. Neuroendocrine disorders and dysfunction

[0171] Provided herein are methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to a variety of conditions caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. The hypothalamus and pituitary are two areas of the brain that regulate hormone production, so damage to the hypothalamus or pituitary, such as from a traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a female health disorder or condition (e.g., a female health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a female health disorder or polycystic ovarian syndrome.

[0172] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive symptoms, and physical symptoms (including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, mood lability, lack of concentration, decreased attention span, decreased lipids, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, slow heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin).

[0173] 2. Neurodegenerative diseases and disorders

[0174] The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of neuronal structure or function, or death of neurons.Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment), amyotrophic lateral sclerosis (ALS), anoxic and ischemic injury, ataxia and seizures (including treatment and prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia), benign forgetfulness, cerebral edema, cerebellar ataxia including McLeod neuroepidermolysis syndrome (MLS), closed head injury, coma, contusion (e.g., spinal cord injury, and head injury), dementia including multi-infarct dementia and senile dementia, impaired consciousness, Down's syndrome, drug-induced or drug-induced parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor), epilepsy, fragile X syndrome, Gilles de la Tourette syndrome, head trauma, hearing impairment and hearing loss, Huntington's disease, Lennox syndrome, levodopa-induced dyskinesia, mental retardation, movement disorders including akinesia and akinesia (rigidity) syndromes (basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinson's disease-ALS dementia complex, Parkinson's disease, encephalitis) dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonucleus), tremor (including rest tremor, postural tremor, and intention tremor) and dystonia (axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, neurodegeneration due to viral infections (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy), eye injury, retinopathy, or neuronal damage including macular degeneration of the eye, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic damage following cardiac arrest, Parkinson's disease, seizures, status epilepticus, stroke, tinnitus, tubular sclerosis, and viral infections (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy).Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic damage following cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing loss of neurological function characteristic of neurodegenerative diseases.

[0175] 3. Mood disorders

[0176] Also provided herein are methods for treating mood disorders such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, mild depression, bipolar disorder or manic depression, depression caused by chronic illness, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect for subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0177] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, or recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression may have trouble sleeping, lose weight, and be generally agitated and irritable. Clinical depression can affect the way an individual feels, thinks, and behaves, and can cause a variety of emotional and physical problems. People with clinical depression may experience difficulties in their daily lives and feel as if life is not worth living.

[0178] Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, crying, restlessness, sleep problems, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of detachment from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0179] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after giving birth. Symptoms include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

[0180] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy.This depression is referred to herein as perinatal depression.In one embodiment, the subject who experiences perinatal depression is at higher risk of experiencing PND.

[0181] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, significant weight gain or increased appetite. Patients suffering from Alzheimer's disease may also develop significant social impairment as a result of excessive sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to interpersonal rejection.

[0182] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, a depressed mood that is more prominent than feelings of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0183] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0184] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become mute, stuporous, immobile, or exhibit aimless or bizarre movements.

[0185] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which individuals experience a seasonal pattern of depressive episodes in the fall or winter.

[0186] Dysthymia refers to a condition related to unipolar depression in which similar physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least 2 years).

[0187] Dual depression refers to a period of significant depression (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0188] Depressive personality disorder (DPD) refers to a personality disorder that has depressive features.

[0189] Recurrent brief depression (RBD) refers to a condition in which an individual experiences depressive episodes approximately once a month, with each episode lasting less than two weeks, usually less than two to three days.

[0190] Mild depressive disorder or mild depression refers to depression with at least two symptoms lasting for two weeks.

[0191] Bipolar disorder or manic depression causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During manic periods, a person may feel or behave unusually happy, energetic, or irritable. They often make decisions without thinking things through, with little consideration for the consequences. The need for sleep is usually decreased. During periods of depression, people may cry, make poor eye contact with others, and have a negative outlook on life. The risk of suicide for people with the disorder is high, at over 6% over a 20-year period, and self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are also commonly associated with bipolar disorder.

[0192] Depression due to a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0193] Treatment-resistant depression refers to a state in which depression is treated but symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the symptoms of depression in patients with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms but relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard drug treatments such as tricyclic antidepressants, MAOIs, SSRIs, double and triple uptake inhibitors and / or anxiolytics, as well as non-drug treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0194] Postoperative depression refers to feelings of depression that occur after surgery (e.g., as a result of having to deal with one's own mortality). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that are normally enjoyed, or persistent feelings of worthlessness or hopelessness.

[0195] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0196] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's suicidal tendencies. Suicidal ideation refers to thoughts about suicide or an abnormal obsession with suicide. The range of suicidal ideation varies widely, for example, from passing thoughts to widespread thinking, detailed plans, role-playing, and unfinished attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in situations, increased alcohol or drug use, doing dangerous or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0197] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, lack of energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, impaired mobility, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thinking or planning, oversleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief may be confirmed by a doctor or psychologist (e.g., by a mental status examination).

[0198] In some embodiments, the method includes monitoring the subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by the subject's reduction in the Hamilton Depression (HAM-D) total score. The reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day or less, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours or less. The therapeutic effect can be evaluated over a specified treatment period. For example, therapeutic efficacy can be determined by a decrease from baseline in HAM-D total score after administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) (e.g., 12, 24, 48 hours, or 24, 48, 72, or 96 hours or more, 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 lifelong).

[0199] In some embodiments, the subject has a mild depressive disorder, e.g., a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a very severe major depressive disorder. In some embodiments, the subject has a baseline HAM-D total score (i.e., before treatment with a crystalline form of Compound (1), e.g., Form S1, Form S4, or any combination thereof) of at least 24. In some embodiments, the subject has a baseline HAM-D total score of at least 18. In some embodiments, the subject has a baseline HAM-D total score of 14-18. In some embodiments, the subject has a baseline HAM-D total score of 19-22. In some embodiments, the subject has a HAM-D total score of 23 or greater before treatment with a crystalline form of Compound (1), e.g., Form S1, Form S4, or any combination thereof. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) 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 HAM-D total score after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is less than 10, 7, 5, or 3. In some embodiments, the reduction in the HAM-D total score is from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10, 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).In some embodiments, the reduction in baseline HAM-D total score after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold relative to the HAM-D total score. In some embodiments, the reduction in baseline HAM-D total score after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) of at least 10, 15, or 20 points relative to the baseline HAM-D total score (e.g., 12, 24, 48 hours, or 24, 48, 72, 96 hours or more, or 1 day, 2 days, 14 days or more after administration).

[0200] In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect in 14, 10, 4, 3, 2, or 1 day or less, or in 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) in 1 or 2 days or less of treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) in 14 days or less from the start of treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) 21 days or less after initiation of treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) 28 days or less after initiation of treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the therapeutic effect is a reduction in HAM-D total score from baseline after 14 days of treatment once daily with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, the subject's HAM-D total score prior to treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is at least 24. In some embodiments, the subject's HAM-D total score prior to treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is at least 18.In some embodiments, the subject's HAM-D total score prior to treatment with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is between 14 and 18. In some embodiments, the reduction in HAM-D total score after treatment of the subject with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) compared to the baseline HAM-D total score is at least 10. In some embodiments, the reduction in HAM-D total score after treatment of the subject with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treatment of the subject with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is only a numerical value in the range of 6 to 8. In some embodiments, treatment of a subject with a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) has a HAM-D total score associated with 7 or less.

[0201] In some embodiments, the method provides a therapeutic effect (e.g., measured by a reduction in the Clinical Global Impression (CGI) score) in 14, 10, 4, 3, 2, or 1 day or less, or in 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in CGI score at the end of the treatment period (e.g., 14 days after administration).

[0202] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) in 14, 10, 4, 3, 2, or 1 day or less, or in 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in the MADRS score at the end of the treatment period (e.g., 14 days after administration).

[0203] The effectiveness of treatment for major depressive disorder can be determined by a reduction in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score can be reduced to 4, 3, 2, or 1 day or less, or to 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (appearance sadness, reported sadness, inner tension, decreased sleep, decreased appetite, decreased concentration, fatigue, emotional helplessness, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0204] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 days or less, within 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic benefit is an improvement as measured by the EPDS.

[0205] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) for 4, 3, 2, 1 days or less, or for 24, 20, 16, 12, 10, 8 hours or less.

[0206] 4. Anxiety Disorders

[0207] Provided herein is a method for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder).Anxiety disorder is an umbrella term that includes several different forms of abnormal and pathological fear and anxiety.Current psychiatric diagnostic criteria recognize a variety of anxiety disorders.

[0208] Generalized anxiety disorder is a common chronic illness characterized by long-term anxiety that is not focused on any particular object or situation.People suffering from generalized anxiety experience non-specific persistent fear and worry, and become excessively worried about everyday things.Generalized anxiety disorder is the most common anxiety disorder that affects older adults.

[0209] In panic disorder, a person suffers from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sense of fear or discomfort that occurs suddenly and peaks in 10 minutes or less, may last for hours, and may be triggered by stress, fear, or even exercise, although a specific cause is not always evident. A diagnosis of panic disorder requires that, in addition to the unexpected recurrence of panic attacks, the attacks are also accompanied by chronic consequences, i.e., either worry about the potential impact of the attack, persistent fear of future attacks, or significant changes in behavior related to the attacks. Thus, people suffering from panic disorder experience symptoms outside of a particular panic episode. Often, panic sufferers notice normal changes in their heartbeat, leading them to believe that there is something wrong with their heart or that another panic attack is about to occur. In some instances, heightened awareness of bodily functions (hyperarousal) occurs during a panic attack, and the perceived physiological changes are interpreted as a possible life-threatening illness (extreme hypochondria).

[0210] Obsessive-compulsive disorder is a type of anxiety disorder that is primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform certain actions or rituals). OCD thought patterns may be likened to superstition, in that they involve belief in causal relationships that do not actually exist. Often the process is entirely illogical; for example, an obsession to walk in a particular pattern may be used to alleviate obsessions of imminent harm. And often the urges are entirely unexplained, merely a tension-induced urge to complete a ritual. In a minority of cases, OCD patients only experience obsessions and no overt compulsions, and a much smaller number experience only compulsions.

[0211] The largest category of anxiety disorders is phobia, which includes all instances in which fear and anxiety are triggered by a particular stimulus or situation. Sufferers usually expect a frightening outcome if they encounter the feared object, be it an animal, place, or even bodily fluid.

[0212] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme circumstances such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to severe stressors, such as soldiers who can withstand individual combat but not sustained combat. Common symptoms include flashbacks, avoidance behaviors, and depression.

[0213] 5. Women's health problems

[0214] Provided herein are methods of treating conditions or disorders related to women's health, including, but not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

[0215] Gynecological health and disorders affecting women include menstruation and menstrual irregularities, urinary tract health such as urinary incontinence and pelvic floor disorders, and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0216] Premenstrual syndrome (PMS) refers to the physical and mental symptoms that occur in a woman during the week or two before her period. Symptoms vary but can include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne and depression.

[0217] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, significant anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feeling out of control or overwhelmed, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint pain, muscle pain).

[0218] Pregnancy issues include preconception and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and congenital anomalies.

[0219] A miscarriage refers to a pregnancy that terminates naturally within the first 20 weeks or less of pregnancy.

[0220] Abortion refers to the intentional termination of a pregnancy and can take place up to the first 28 weeks of pregnancy.

[0221] Infertility and related disorders include uterine fibroids, polycystic ovarian syndrome, endometriosis, and primary ovarian insufficiency.

[0222] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms resulting from elevated levels of male hormones in women. Most women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual periods, heavy menstrual periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, dark, velvety skin. PCOS can be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0223] Other disorders and conditions that only affect women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0224] Issues related to women's overall health and wellness include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[0225] Menopause refers to the 12 months since a woman's last menstrual period, marking the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. Physical symptoms such as hot flashes and mental symptoms of menopause can disrupt sleep, reduce energy, and cause anxiety, sadness, or feelings of loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (hysterectomy, oophorectomy, cancer, etc.). It is induced when the ovaries are significantly damaged by radiation, chemotherapy, other medications, etc.

[0226] 6. Epilepsy

[0227] A crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a pharma- ceutically acceptable composition thereof, may be used in the methods described herein, e.g., for the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0228] Epilepsy is a brain disorder that causes repeated seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile nyoclonus epilepsy, morning grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0229] 7. Epilepsy induction

[0230] The crystalline forms of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) and the methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a stepwise process by which a normal brain develops epilepsy (a chronic disease in which seizures occur). Epileptogenesis is caused by neurological damage (e.g., status epilepticus) caused by an initial seizure.

[0231] 8. Status epilepticus (SE)

[0232] Status epilepticus (SE) may include, for example, convulsive status epilepticus (e.g., incipient status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus), non-convulsive status epilepticus (e.g., generalized status epilepticus, complex partial status epilepticus), generalized periodic epileptiform discharges, and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and includes incipient status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Incipient status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy, and second-line therapy is implemented. Refractory status epilepticus is characterized by persistent status epilepticus despite first-line and second-line treatment, typically with the administration of a general anesthetic. Super-refractory status epilepticus is characterized by persistent status epilepticus despite first-line, second-line, and general anesthetic treatment for 24 hours or more.

[0233] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus (e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus), generalized non-convulsive status epilepticus (e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus).

[0234] A crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a pharma- ceutically acceptable composition thereof, may be administered as a prophylactic to a subject having a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., incipient status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic unilateral epileptiform discharges, pre-seizure onset.

[0235] 9. Seizures

[0236] A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A seizure is when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0237] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized seizures and partial seizures (also called focal or localized seizures). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0238] Generalized seizures are caused by electrical impulses from throughout the brain, whereas partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that causes the seizure is sometimes called the focal point.

[0239] There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also called grand mal. In this type of seizure, the patient loses consciousness and usually collapses. After loss of consciousness, the whole body becomes rigid for 30-60 seconds (called the "tonic" phase of the seizure), followed by another 30-60 seconds of violent convulsions (the "clonic" phase), after which the patient goes into a deep sleep (the "postictal" or postictal phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0240] Absence seizures cause a brief (only a few seconds) loss of consciousness with few or no symptoms. The patient (most often a child) usually stops activity and stares blankly. These seizures start and end suddenly and can occur several times a day. Patients are usually unaware they are having a seizure other than that they are "losing time."

[0241] Myoclonic seizures consist of sporadic jerks that usually occur on both sides of the body. Patients sometimes describe the jolts as brief electric shocks. When these seizures become more severe, they may cause the patient to drop or throw objects involuntarily.

[0242] Clonic seizures are repeated rhythmic convulsions that occur simultaneously on both sides of the body.

[0243] Tonic seizures are characterized by muscle stiffness.

[0244] Cataplexy consists of a sudden, global loss of muscle tone, especially in the arms and legs, often resulting in a fall.

[0245] Seizures as described herein may include epileptic seizures, acute repetitive seizures, cluster seizures, ongoing seizures, incessant seizures, prolonged seizures, recurrent seizures, status epilepticus seizures (e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus seizures), refractory seizures, myoclonic seizures, tonic seizures, tonic-clonic seizures, simple partial seizures, complex partial seizures, secondary generalized seizures, atypical absence seizures, absence seizures, atonic seizures, benign rolandic seizures, febrile convulsions, emotional seizures, focal seizures, gelatinous seizures, generalized onset seizures, infantile spasms, Jacksonian seizures, severe bilateral myoclonic seizures, multifocal seizures, neonatal onset seizures, nocturnal seizures, occipital lobe seizures, post-traumatic seizures, subtle seizures, Sylvan seizures, visual reflex seizures, or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female childhood epilepsy.

[0246] 10. Movement disorders

[0247] Also described herein is a method for treating movement disorders.As used herein, "movement disorder" refers to various diseases and disorders related to hyperkinetic movement disorders and related abnormalities in muscle control.Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tic and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorder.

[0248] The methods described herein can be used to treat tremors, for example, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, psychogenic tremor, or rubral tremor. Tremor can be caused by genetic, degenerative, idiopathic diseases such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid, parathyroid, liver disease, hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Lucy-Lewy disease, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon dioxide, manganese, arsenic, toluene); drug-induced (narcoleptic drugs, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine), and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, task-specific tremor, and postural specific tremor), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0249] Tremor is the involuntary, sometimes rhythmic, contraction and relaxation of muscles, accompanied by vibration or spasms of one or more parts of the body (such as the hands, arms, eyes, face, head, vocal cords, trunk, or legs).

[0250] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, for example, due to tumors, stroke, or disease (e.g., multiple sclerosis, hereditary degenerative diseases).

[0251] Dystonic tremors occur in people with dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and are often relieved by complete rest.

[0252] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some people or it can be slow and progressive, starting on one side of the body and affecting both sides within three years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be affected. Tremors become less frequent as people age, but their severity can increase. Heightened emotions, stress, fever, physical fatigue, or hypoglycemia can cause tremors or increase their severity. Symptoms generally progress over time and may be visible or persistent after onset.

[0253] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk that occur immediately after standing. The thighs and legs are felt as spasms, and patients may shake uncontrollably when forced to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0254] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is usually seen as a "pill-rolling" movement of the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor typically begins after age 60. Movements may begin in one limb or on one side of the body and progress to include the other side.

[0255] Physiologic tremor can occur in normal individuals but has no clinical significance. It is found in all voluntary muscle groups. Physiologic tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions such as hyperthyroidism or hypoglycemia. Tremor frequency is classically around 10 Hz.

[0256] Psychogenic or hysterical tremor can occur at rest, or during posture or movement. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0257] Rubral tremor is characterized by a coarse, slow tremor that may be present at rest, in position, and with intent. This tremor is associated with conditions affecting the red nucleus of the midbrain, a classic abnormal stroke.

[0258] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms seen in Parkinson's disease, but is a complex condition rather than a progressive neurodegenerative disorder.

[0259] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions resulting in abnormal, often repetitive movements or postures. Dystonic movements may be patterned and include twisting and trembling. Dystonia is often initiated or exacerbated by voluntary actions and is associated with overflow muscle activity.

[0260] Chorea is a neurological disorder characterized by jerky, involuntary movements that usually affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes nerve cells in the brain to wear away. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, talking, and swallowing.

[0261] Ataxia refers to the loss of full control of body movements and can affect fingers, hands, arms, legs, torso, speech and eye movements.

[0262] Myoclonus and startle are responses to sudden, unexpected stimuli, including acoustic, tactile, visual, and vestibular.

[0263] Tics are usually sudden-onset, brief, repetitive but non-rhythmic involuntary movements that usually mimic normal behavior and often occur against a background of normal activity. Tics can be classified as motor or vocal, with motor tics being associated with movement and vocal tics being associated with sound. Tics are characterized as simple and complex; for example, simple motor tics involve only a few muscles confined to a specific part of the body. Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0264] Restless legs syndrome is a neurological sensorimotor disorder characterized by an overwhelming urge to move the legs while at rest.

[0265] Stiff person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually affecting the lower back and legs. A stiff-footed gait with excessive lumbar lordosis usually occurs. Characteristic abnormalities on EMG recordings are usually observed with sustained motor unit activity of the paraspinal axial muscles. Variants include "stiff limb syndrome" which causes localized stiffness that typically affects the distal legs and feet.

[0266] Gait disorders refer to abnormalities in gait or style due to neuromuscular, arthritic, or other bodily changes. Gaits are classified according to the system responsible for the abnormal movement and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0267] 11. Anesthesia / Sedation

[0268] Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that alone provides the appropriate combination of effects, or multiple drugs (hypnotics, sedatives, paralytics, analgesics, etc.) can be used in combination to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the discomfort and pain that would otherwise be experienced.

[0269] Sedation is the reduction of irritability or agitation, typically by administration of a drug, to facilitate a medical or diagnostic procedure.

[0270] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolytic) to general anesthesia.

[0271] Minimal sedation is also known as anxiolytic therapy. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are usually unaffected.

[0272] Moderate sedation / analgesia (conscious sedation) is the suppression of consciousness by drugs, with the patient responding purposefully to verbal commands alone or with light tactile stimulation. Usually no intervention is required to maintain a patent airway. Spontaneous ventilation is typically sufficient. Cardiovascular function is usually preserved.

[0273] Deep sedation / analgesia is a drug-induced suppression of consciousness from which the patient cannot be easily aroused, but responds purposefully after repetitive or painful stimulation (not a reflex withdrawal from the painful stimulus). Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0274] General anesthesia is a drug-induced loss of consciousness during which the patient is unable to awaken even to painful stimuli. The ability to maintain independent ventilatory function is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to reduced spontaneous ventilation or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0275] Sedation in the intensive care unit (ICU) reduces the patient's awareness of their environment and reduces their response to external stimuli. It can play a role in the care of critically ill patients, encompassing a wide range of symptom control that varies from patient to patient and from individual to individual throughout the course of the illness. Heavy sedation in critical care has been used, often with neuromuscular blockade, to facilitate tolerance of the endotracheal tube and ventilator synchrony.

[0276] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. The elimination half-life of sedatives in the ICU may be short.

[0277] Procedural sedation and analgesia, also called conscious sedation, is the technique of administering sedatives or dissociative agents, with or without analgesics, to induce a state that enables a subject to tolerate an unpleasant procedure while preserving cardiopulmonary function.

[0278] Also described herein are methods for ameliorating one or more symptoms of a respiratory condition in a subject, comprising administering to the subject an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a pharmaceutical composition described herein.

[0279] In one aspect, the description provides a method of treating a subject, wherein the subject exhibits one or more symptoms of a respiratory disorder and / or has been diagnosed with a respiratory disorder, the method comprising administering to the subject an effective amount of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0280] In some embodiments, the disclosure contemplates a method of treating a subject having a respiratory disease, comprising administering to the subject a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof).

[0281] In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), to a subject exhibiting symptoms of a respiratory disease may reduce the severity of one or more symptoms of the respiratory disease or may prevent or slow the progression of one or more symptoms of the respiratory disease.

[0282] In some embodiments, the subject with respiratory disease has been or is being treated with a ventilator or oxygen. In some embodiments, the subject with respiratory disease has been or is being treated with a ventilator.

[0283] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered to a subject who is being or has been treated with a ventilator. In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) continues during treatment of the subject with a ventilator. In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) continues after the subject has ceased treatment with a ventilator.

[0284] In some embodiments, a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) is administered to a subject undergoing or who has undergone treatment with a sedative agent. In some embodiments, the sedative agent is propofol or a benzodiazepine.

[0285] In some embodiments, the disclosure includes administering to a subject in need thereof a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) in an amount sufficient to increase blood oxygen saturation. In some embodiments, blood oxygen saturation is measured using pulse oximetry.

[0286] In some embodiments, the disclosure contemplates a method of treating a cytokine storm in a patient. In some embodiments, the method of treating a cytokine storm comprises administering to a patient a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof). In some embodiments, a symptom of a cytokine storm is pulmonary inflammation. In some embodiments, a patient suffering from a cytokine storm suffers from acute respiratory distress syndrome (ARDS).

[0287] 12. Respiratory status

[0288] In some embodiments, the subject with a respiratory disease suffers from dyspnea, hi some embodiments, the dyspnea comprises acute dyspnea.

[0289] In some embodiments, a subject with a respiratory disorder may exhibit one or more conditions selected from the group consisting of airway hyperresponsiveness, inflammation of lung tissue, pulmonary hyperresponsiveness, and lung pain associated with inflammation.

[0290] In some embodiments, the subject with a respiratory disease may exhibit inflammation of the lung tissue. In some embodiments, the inflammation of the lung tissue is bronchitis or bronchiectasis. In some embodiments, the inflammation of the lung tissue is pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia or hospital-acquired pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia.

[0291] In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a pharmaceutical composition thereof, to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of dyspnea in the subject with a respiratory disease, or prevents or slows the progression of dyspnea in a subject with a respiratory disease.

[0292] In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of airway hyperresponsiveness in a subject with a coronavirus-related disease or prevents or slows the progression of airway hyperresponsiveness in a subject with a respiratory disease.

[0293] In some embodiments, administering a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of inflammation of lung tissue in the subject with the respiratory disease or prevents or slows the progression of inflammation of lung tissue in the subject with the respiratory disease. In some embodiments, administering a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pneumonia in the subject with the respiratory disease or prevents or slows the progression of pneumonia in the subject with the respiratory disease.

[0294] In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pulmonary hypersensitivity in the subject with the respiratory disease or prevents or slows the progression of pulmonary hypersensitivity in the subject with the respiratory disease.

[0295] In some embodiments, administration of a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof), or a composition comprising a crystalline form of Compound (1) (e.g., Form S1, Form S4, or any combination thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pulmonary pain associated with inflammation in the subject with the respiratory disease, or prevents or slows the progression of pulmonary pain associated with inflammation in the subject with the respiratory disease.

[0296] In some embodiments, the subject with a respiratory disease is being treated or has been treated for an infection, fibrosis, a fibrotic episode, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma / asthma-related inflammation.

[0297] In some embodiments, the subject is exhibiting symptoms of asthma and / or has been diagnosed with asthma, hi some embodiments, the subject is experiencing or has experienced an asthma attack.

[0298] In some embodiments, the subject is undergoing or has undergone treatment for fibrosis or a fibrotic episode, hi some embodiments, the fibrosis is cystic fibrosis.

[0299] In some embodiments, the respiratory disease is selected from the group consisting of cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, sinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility due to congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies such as protein C deficiency, hereditary angioedema type 1, lipid processing deficiencies such as familial hypercholesterolemia, type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases such as I-cell disease / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Larond dwarfism, myeoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG or is the result of and / or associated with a disease or condition selected from the group consisting of neurodegenerative diseases such as type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neuropathies such as Huntington's, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluisian, and myotonic dystrophy, and hereditary Creutzfeldt-Jakob disease (due to prion protein processing defects), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or spongiform encephalopathies such as Sjogren's disease.

[0300] 13. Infectious diseases

[0301] The present disclosure contemplates, inter alia, the treatment of a subject suffering from an infectious disease. The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with an infectious disease. In some embodiments, the infectious disease is a viral infection or a bacterial infection. In some embodiments, the infectious disease is a viral infection. In some embodiments, the infectious disease is a bacterial infection.

[0302] In some embodiments, the viral infection is an infection with a virus selected from the group consisting of a coronavirus, influenza virus, human rhinovirus, human parainfluenza virus, human metapneumovirus, and hantavirus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and MERS-CoV.

[0303] The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with a coronavirus. In some embodiments, the disease associated with a coronavirus is selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). In some embodiments, the disease associated with a coronavirus is selected from the group consisting of COVID-19. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, the coronavirus is SARS-CoV-2.

[0304] In some embodiments, the bacterial infection is an infection with a bacteria selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae, hi some embodiments, the Staphylococcus aureus is Methicillin-resistant Staphylococcus aureus. EXAMPLES

[0305] VI. Working Examples

[0306] In order to more fully understand the invention described herein, the following examples are set forth. The examples described in this application are provided to illustrate the crystalline solid forms provided herein and should not be construed as limiting the scope thereof in any way.

[0307] Common analytical methods.

[0308] Unless otherwise stated herein, the following analytical methods were followed in the analysis and characterization of the solid (i.e., crystalline) forms of Compound (1).

[0309] A.XRPD analysis.

[0310] XRPD analysis was performed using a PANalytical X'pert pro with a PIXcel detector (128 channels) scanning the samples between 3 and 35°2θ. The solid compound (1) was gently ground to release aggregates and loaded into a multi-well plate with a Mylar polymer film supporting the sample. The multi-well plate was then placed in the diffractometer and analyzed using Cu K radiation (α1λ=1.54060 Å, α2=1.54443 Å, β=1.39225 Å, α1:α2 ratio=0.5) running in transmission mode (step size of 0.0130°2θ, step time of 18.87 s) using a 40 kV / 40 mA generator setting. Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017). The 2θ positions were calibrated monthly using an alumina powder reference standard.

[0311] B.TGA / DSC analysis.

[0312] TGA data was collected using a TA Instruments TA Q500 TGA and DSC was performed using a TA Instruments TA Q2000 DSC. The TGA and DSC operating parameters are shown in Table 1. The TGA was calibrated with a nickel reference standard and the DSC was calibrated with an indium reference standard.

[0313] [Table 1]

[0314] C. 13 C Solid-state NMR analysis.

[0315] Solid-state NMR (SSNMR) experiments are 13 C is 100.51MHz, 1 H was performed on a Bruker Avance I spectrometer (Bruker, Billerica, MA) operating at 399.67 MHz. Data were acquired using a Chemagnetics APEX probe refitted with a 7 mm magic angle spinning module (Revolution NMR, Fort Collins, CO). Each sample was packed into a 7 mm zirconia rotor. The magic angle spinning rate was 5 kHz. 13 C chemical shifts are reported with an accuracy of ±0.4 ppm relative to the methyl peak of 3-methylglutaric acid at 18.84 ppm.

[0316] Using saturation recovery, 1 H T1 relaxation times were measured. 13 C spectrum shows the period before saturation ( 1 H p / 2, no delay, loop 1x), variable delay list, 1 H p / 2 pulse, followed by a cross-polarized rotating sideband complete suppression (CPTOSS) sequence, and a pulse width of approximately 63.3 kHz (3.95 ms 1 H p / 2) 1 H was collected using SPINAL-64 decoupling. Samples were analyzed using the T1guide software package from Bruker Topspin 2.1 patch level 6. 1 The H T1 value was determined. 13 C CPTOSS spectra were acquired at 5 kHz MAS using a CPTOSS sequence, 624 acquisitions, a pulse delay of 20 seconds, a contact time of 1.5 ms, 3994 acquisition points (approximately 50 ms acquisition time), and an experiment time of approximately 3.46 hours. Data collection was performed at a nominal temperature of 18.5 °C. Data were processed with Topsin software.

[0317] E. Dynamic Vapor Sorption (DVS) analysis.

[0318] Approximately 10-20 mg of sample was placed on a mesh vapor sorption balance and loaded into a DVS Intrinsic / Advantage dynamic vapor sorption balance by Surface Measurement Systems. A ramp profile of 10% increments was applied to the sample ranging from 40-90% relative humidity (RH), with the sample maintained at each step until a stable weight was reached at 25 °C (dm / dt of 0.004%, minimum step length of 30 min, maximum step length of 500 min). After completion of the sorption cycle, the sample was dried to 0% relative humidity using the same procedure, then returned to 40% relative humidity for a second sorption cycle. Two cycles were performed. The weight change during the adsorption / desorption cycle was plotted, allowing the hygroscopic nature of the sample to be determined. XRPD analysis was then performed on any retained solids. The microbalance was calibrated monthly using certified calibration weights, and the relative humidity at 25 °C was calibrated against the deliquescence points of LiCl, MgCl, and NaCl. The data were not corrected for the initial moisture content of the samples and the data were presented according to the dry weight of the samples at 0% RH.

[0319] Example 1: Preparation of Form S1 of compound (1).

[0320] Method 1.

[0321] Crude compound (1) (431 g) is dissolved in tetrahydrofuran (3500 mL) with stirring under nitrogen. The solvent is exchanged by distilling under partial vacuum and slowly adding n-heptane (6500 mL) while keeping the temperature of the contents below 40 °C and maintaining the volume in the vessel at about 3500 mL. Compound (1) begins to crystallize during the distillation. At the end of the distillation, the vacuum is released to atmospheric pressure with nitrogen and the resulting slurry is heated to 55-60 °C. The slurry is then cooled to ambient temperature (15-25 °C) and held for 1 h. The anhydrous form S1 of compound (1) is collected by filtration and the vessel and filter cake are rinsed with n-heptane (1600 mL). The solid is dried under vacuum while maintaining the temperature below 40 °C.

[0322] Method 2.

[0323] Crude compound (1) (431 g) is dissolved in either dichloromethane (1600 mL) or tetrahydrofuran (2000 mL) with stirring under nitrogen. The solution is transferred to a second vessel through an abrasive filtration apparatus (pore size 1 μm or less). The solution is concentrated under partial vacuum to approximately 1000-1200 mL while maintaining the temperature of the contents below 40 °C. The resulting solution is diluted with 2000 mL of isopropyl alcohol and heated to reflux (45-55 °C if dichloromethane is used, 70-75 °C if tetrahydrofuran is used). Exchange the low boiling solvent by slowly adding isopropyl alcohol (5000 mL) while distilling, maintaining the contents in the vessel at approximately 3000 mL. After the end of distillation, keep the contents at reflux for at least 15 minutes to ensure that the solids are dissolved. The clear solution is cooled to 68-72°C and Compound (1) Form S1 seed crystals (4 g, 1% w / w) are added to induce crystallization. After holding for 1 hour to ensure crystallization has begun, the contents are cooled to 58-62°C and held for up to 2 hours. The contents are then slowly cooled to 20-25°C over approximately 2-3 hours, held for 1 hour, and then further cooled to 0-10°C. After holding for at least 15 minutes, Compound (1) anhydrous Form S1 is collected by filtration and the vessel and filter cake are washed with cold isopropyl alcohol (900 mL). The solid is dried under vacuum while maintaining the temperature below 40°C.

[0324] Form S1 of compound (1) was identified by XRPD, TGA / DSC, 13 It was characterized using C solid-state NMR and DVR analysis.

[0325] 1.XRPD analysis.

[0326] 1 shows the unnormalized X-ray powder diffraction pattern of Form S1 of Compound (1). Specific XRPD peaks and other XRPD data observed from the unnormalized X-ray powder diffraction pattern are summarized in Table 2 below.

[0327] [Table 2]

[0328] 2.TGA / DSC analysis.

[0329] As shown in Figure 2, TGA analysis of compound (1) form S1 showed a weight loss of 0.1% on the TGA curve up to 185°C. DSC analysis of compound (1) form S1 showed melting-crystallization-melting transitions at 155°C, 155.9°C, and 165.1°C. These thermal analysis results demonstrate that compound (1) form S1 converts to form S4 under heating conditions.

[0330] 3. 13 C Solid-state NMR analysis.

[0331] FIG. 3 shows the compound (1) in form S1. 13 The C solid-state NMR spectrum is shown. The specific peaks observed from the NMR spectrum are summarized in Table 3 below. 13 A single pure phase was observed during C solid-state NMR analysis.

[0332] [Table 3]

[0333] 4.DVS analysis.

[0334] As shown in Figure 4, DVS analysis of form S1 of compound (1) indicated that form S1 is substantially non-hygroscopic by DVS, with a mass uptake of approximately 0.6 wt% (0.14 equivalents of water) at 90% RH. No changes were observed in the XRPD patterns of the samples after DVS analysis, indicating that if the samples underwent a shape change during DVS analysis, they had reverted to form S1 prior to XRPD analysis.

[0335] Example 2: Preparation of Form S4 of Compound (1).

[0336] Crude compound (1) (431 g) is dissolved in tetrahydrofuran (2000 mL) with stirring under nitrogen. n-heptane (400 mL) is added and the solution is heated to reflux (70-75 °C) at atmospheric pressure and the solvent is exchanged by slowly adding n-heptane (5000 mL) while distilling, maintaining the volume in the vessel at about 2500 mL. When the temperature reaches 85-90 °C, compound (1) begins to crystallize. At the end of the distillation, the resulting slurry is cooled to ambient temperature (15-25 °C) and held for 1 h. The anhydrous form S4 of compound (1) is collected by filtration and the vessel and filter cake are rinsed with n-heptane (900 mL). The solid is dried under vacuum while maintaining the temperature below 40 °C.

[0337] Form S4 of compound (1) was identified by XRPD, TGA / DSC, 13 It was characterized using C solid-state NMR and DVR analysis.

[0338] 1.XRPD analysis.

[0339] 5 shows the unnormalized X-ray powder diffraction pattern of Form S4 of Compound (1). Specific XRPD peaks and other XRPD data observed from the unnormalized X-ray powder diffraction pattern are summarized in Table 4 below.

[0340] [Table 4]

[0341] FIG. 6 shows overlaid, non-normalized X-ray diffraction patterns of Forms S1 (top) and S4 (bottom) of Compound (1).

[0342] 2.TGA / DSC analysis

[0343] As shown in Figure 7, TGA analysis of Compound (1) form S4 showed a weight loss of 0.1% on the TGA curve up to 185°C. DSC analysis of Compound (1) form S4 showed a melting endotherm at 164.8°C before decomposition.

[0344] As shown in FIG. 8, the DSC data generated in the DSC analysis of Forms S1 and S4 indicates an enantiotropic relationship between Forms S1 and S4.

[0345] 3. 13 C Solid-state NMR analysis.

[0346] FIG. 9 shows the structure of compound (1) in form S4. 13 The C solid-state NMR spectrum is shown. Specific peaks observed from the NMR spectrum are summarized in Table 5 below. 13 A single pure phase was observed during C solid-state NMR analysis.

[0347] [Table 5]

[0348] FIG. 10 shows the comparative results of Form S1 of Compound (1) and Form S4 of Compound (1). 13 C SSNMR spectrum overlay is shown.

[0349] 4.DVS analysis.

[0350] As shown in Figure 11, DVS analysis of form S4 of compound (1) indicates that form S4 is non-hygroscopic by DVS, with a mass uptake of about 0.12 wt% (0.02 equivalents of water) at 90% RH. No changes were observed in the XRPD patterns of the samples after DVS analysis, indicating that if the samples underwent a shape change during DVS analysis, they reverted to form S4 before XRPD analysis.

[0351] Example 3: Slurry conversion of Compound (1) Forms S1 and S4.

[0352] To verify the transition temperatures between Forms S1 and S4 of compound (1) calculated from the DSC data, competitive slurry experiments of Forms S1 and S4 were performed.

[0353] For each experiment, approximately equal amounts of Forms S1 and S4 were used to generate slurries. The forms were suspended in 0.3 mL of solvent in 1.5 mL glass vials. The suspensions were magnetically stirred (1000 rpm) at the target temperature for 4 days. The remaining solids were isolated by centrifugation (10000 rpm, 3 min) and analyzed using the XPRD analysis method described above. The experimental conditions and results are summarized in Table 10.

[0354] [Table 10]

[0355] As shown in FIG. 12, the results of this experiment showed that at 60° C. and 70° C., form S4 was converted to form S1, and at 80° C., form S1 was converted to form S4.

[0356] Equivalence and Scope In the claims, articles such as "a," "an," and "the" may mean one or more, unless indicated to the contrary or clear from the context. A claim or description containing "or" between one or more members of a group is deemed satisfied when one, more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a particular product or process, unless otherwise indicated, unless indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which two or more, or all of the members of a group are present in, employed in, or otherwise relevant to a given product or process.

[0357] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, a claim that is dependent on another claim can be amended to include one or more limitations found in other claims that are dependent on the same base claim. When elements are presented as a list, for example in Markus group format, each subgroup of elements is also disclosed, and any element can be removed from the group. It should be understood that, generally, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, the particular embodiment of the invention or aspects of the invention consists of or consists essentially of such elements and / or features. For simplicity, these embodiments are not directly specifically described herein. It should also be noted that the terms "comprise" and "contain" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are specified, the endpoints are also included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can contemplate any specific value or subrange within the range described in different embodiments of the invention, down to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0358] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, the specification shall control. Furthermore, certain embodiments of the present invention that fall within the prior art may be expressly excluded from any one or more claims. Such embodiments are deemed known to those of skill in the art and may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0359] Alternative Embodiments Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. A crystalline form of compound (1), wherein the compound (1) is represented by the following structural formula: 【Chemistry 4】 The crystalline form of compound (1), wherein the crystalline form is crystalline anhydrous compound (1).

2. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured at 15.4±0.3, 15.6±0.3, 18.1±0.3, 18.8±0.3, and 22.6±0.3 degrees in a powder X-ray diffraction pattern.

3. 3. The crystalline form of claim 2, wherein the crystalline form is further characterized by one or more peaks corresponding to 2-theta values measured at 9.4±0.3, 11.9±0.3, 22.2±0.3, and 23.4±0.3 degrees in a powder X-ray diffraction pattern.

4. The crystalline form exhibits a T of about 146°C to about 157°C when heated at a rate of 10°C / min starting from a temperature of about 30°C. 開始 The crystalline form of any one of claims 1 to 3, having an endotherm at

5. The crystalline form is １３ 5. The crystalline form of any one of claims 1 to 4, characterized by one or more peaks corresponding to 200.0±0.3 ppm, 164.3±0.3 ppm, 81.3±0.3 ppm, 70.5±0.3 ppm, and 62.2±0.3 ppm in a C SSNMR spectrum.

6. The crystalline form may further comprise: １３ 6. The crystalline form of claim 5, characterized by one or more peaks corresponding to 60.9±0.3 ppm, 60.0±0.3 ppm, 56.7±0.3 ppm, 47.8±0.3 ppm, and 45.9±0.3 ppm in a C SSNMR spectrum.

7. The crystalline form may further comprise: １３ 7. The crystalline form of claim 6, characterized by one or more peaks corresponding to 42.6±0.3 ppm, 39.3±0.3 ppm, 38.3±0.3 ppm, 35.5±0.3 ppm, 25.8±0.3 ppm, and 22.9±0.3 ppm in a C SSNMR spectrum.

8. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by one or more peaks corresponding to 2-theta values measured at 8.9±0.3, 14.6±0.3, 16.4±0.3, 18.0±0.3, and 20.0±0.3 degrees in a powder X-ray diffraction pattern.

9. 9. The crystalline form of claim 8, wherein the crystalline form is further characterized by one or more peaks corresponding to 2-theta values measured at 11.6±0.3, 15.0±0.3, 17.4±0.3, 21.2±0.3, and 29.0±0.3 degrees in an X-ray powder diffraction pattern.

10. 10. The crystalline form of claim 9, wherein the crystalline form is further characterized by one or more peaks corresponding to 2-theta values measured at 9.6±0.3, 12.9±0.3, and 29.6±0.3 degrees in a powder X-ray diffraction pattern.

11. The crystalline form exhibits a T of about 160°C to about 166°C when heated at a rate of 10°C / min starting from a temperature of about 30°C. 開始 The crystalline form of any one of claims 1 or 8 to 10, having an endotherm at

12. 12. The crystalline form of any one of claims 1 or 8-11, wherein the crystalline form decomposes at a temperature of about 200°C or higher.

13. The crystalline form may further comprise: １３ 13. The crystalline form of any one of claims 1 or 8-12, characterized by one or more peaks corresponding to 200.2±0.3 ppm, 199.1±0.3 ppm, 162.8±0.3 ppm, 82.9±0.3 ppm, 82.1±0.3 ppm, and 12.6±0.3 ppm in a C SSNMR spectrum.

14. The crystalline form may further comprise: １３ 14. The crystalline form of claim 13, characterized by one or more peaks corresponding to 70.4±0.3 ppm, 63.6±0.3 ppm, 49.7±0.3 ppm, 35.5±0.3 ppm, and 15.5±0.3 ppm in a C SSNMR spectrum.

15. The crystalline form may further comprise: １３ 15. The crystalline form of claim 14, characterized by one or more peaks corresponding to 62.9±0.3 ppm, 61.4±0.3 ppm, 60.6±0.3 ppm, 45.4±0.3 ppm, and 37.9±0.3 ppm in a C SSNMR spectrum.

16. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. A composition comprising the crystalline form of any one of claims 1 to 15 or the pharmaceutical composition of claim 16, wherein the crystalline form is GABA. Ａ GABA receptor modulation in a subject in need thereof Ａ A composition or pharmaceutical composition for modulating a receptor.

18. A composition comprising the crystalline form of any one of claims 1 to 15 or the pharmaceutical composition of claim 16, wherein the crystalline form is GABA. Ａ GABA receptor-mediated CNS-related disorders in subjects in need of treatment Ａ A composition or pharmaceutical composition for treating a receptor-mediated CNS-related disorder.

19. A composition comprising the crystalline form of any one of claims 1 to 15 or the pharmaceutical composition of claim 16, for treating a CNS-related disorder in a subject in need thereof.

20. 20. The composition or pharmaceutical composition of claim 18 or 19, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

21. The composition or pharmaceutical composition of any one of claims 18 to 20, wherein the CNS-related disorder is a mood disorder.

22. 22. The composition or pharmaceutical composition of claim 21, wherein the mood disorder is depression.

23. 23. The composition or pharmaceutical composition of claim 22, wherein the depression is postpartum depression.

24. 23. The composition or pharmaceutical composition of claim 22, wherein the depression is major depressive disorder.

25. 25. The composition or pharmaceutical composition of claim 24, wherein the major depressive disorder is moderate major depressive disorder.

26. 25. The composition or pharmaceutical composition of claim 24, wherein the major depressive disorder is severe major depressive disorder.

27. 20. The composition or pharmaceutical composition of claim 18 or 19, wherein the CNS-related disorder is tremor.

28. 28. The composition or pharmaceutical composition of claim 27, wherein the tremor is essential tremor.

29. 20. The composition or pharmaceutical composition of claim 18 or 19, wherein the CNS-related disorder is seizures.

30. 20. The composition or pharmaceutical composition of claim 18 or 19, wherein the CNS-related disorder is epilepsy.

31. 20. The composition or pharmaceutical composition of claim 18 or 19, wherein the CNS-related disorder is status epilepticus.

32. 32. The composition or pharmaceutical composition of claim 31 , wherein the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus.

33. 33. The composition or pharmaceutical composition of claim 32, wherein the status epilepticus is a convulsive status epilepticus selected from incipient status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus.

34. 33. The composition or pharmaceutical composition of claim 32, wherein the status epilepticus is a non-convulsive status epilepticus selected from generalized status epilepticus and complex partial status epilepticus.

35. A composition comprising the crystalline form of any one of claims 1 to 15 or the pharmaceutical composition of claim 16, for inducing sedation and / or anesthesia in a subject in need thereof.

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