A crystalline 19-nor c3,3-disubstituted c21-n-pyrazolyl steroid

Abstract

This invention relates to crystalline 19-nor-C3,3-disubstituted C21-pyrazole steroids of formula (I), and compositions thereof. Methods for their preparation and use are also disclosed herein.

Description

Prior Technology

[0001] Brain excitability is defined as the level of arousal in an animal, a continuous state ranging from coma to convulsions, and is regulated by a variety of neurotransmitters. Generally, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, with the intracellular region being negative relative to the extracellular region. This potential (voltage) is a result of the balance of ions (K+, Na+, Cl-, and organic anions) across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. Upon release into the synaptic cleft, excitatory chemical transducers (such as acetylcholine) cause membrane depolarization (potential changes from -70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic acid receptors, which, when stimulated by acetylcholine, increase membrane permeability to Na+ ions. The decreased membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0002] In the case of the gamma-aminobutyric acid receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). GABA has a profound impact on overall brain excitability because up to 40% of neurons in the brain use GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by modulating the transmembrane conduction of chloride ions. GABA interacts with its recognition site on the GRC to promote the downward flow of chloride ions into the cell along the electrochemical gradient of the GRC. This increase in intracellular chloride ion content causes hyperpolarization of the transmembrane potential, making neurons less sensitive to excitatory input (i.e., reducing neuronal excitability). In other words, the higher the chloride ion concentration in neurons, the lower the brain excitability (level of arousal).

[0003] There is a need for new and improved crystalline forms of neuroactive steroids as modulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The crystalline forms of this steroid described in this article are for this purpose. Summary of the Invention

[0004] Part of this invention relates to novel forms of 19-normethyl (i.e., C19-demethyl) compounds (e.g., certain crystalline forms described herein). Typically, the efficacy of a solid compound as a drug is influenced by the properties of the solid it contains.

[0005] Therefore, in a one-state sample, this paper elucidates the formula ( [I]) Crystalline compounds: Mode( [I]) It is also referred to as "Compound 1" in this article.

[0006] In some embodiments, the soluble form of the crystalline form of compound 1 is transformed into different crystalline forms of compound 1 by slow evaporation, antisolvent addition, slow cooling, solution vapor diffusion, solid vapor diffusion, rapid evaporation, reverse antisolvent addition, and water activity experiments.

[0007] In some embodiments, the crystalline form of compound 1 is transformed into different crystalline forms of compound 1 through a slurry conversion process.

[0008] In some embodiments, the physical or chemical parameters of the solid form of compound 1 are evaluated using one or more of the following analytical techniques: X-ray powder diffraction (XRPD) analysis (e.g., variable temperature XRPD (VT-XRPD) analysis), single-crystal X-ray crystallography, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) spectroscopy or solid-state NMR spectroscopy, Raman spectroscopy or dynamic vapor adsorption (DVS).

[0009] In the embodiments, each solid form was characterized and identified using parameters obtained from one or more of the analytical methods mentioned above: An X-ray diffraction pattern plotted with 2-theta (2θ) as the abscissa and peak intensity as the ordinate, as determined by XRPD analysis. These patterns are also referred to herein as XRPD patterns. Properties of single-crystal structures in solid form, such as unit cell, crystal system, and space group, are determined by single-crystal X-ray crystallography. The calculated XRPD pattern of the crystal form, such as that determined using data from single-crystal X-ray crystallography; By initiating a specified endothermic reaction at a starting temperature T, it indicates solvent loss, transformation from one crystalline form to another, or melting point, as determined by DSC performed at a specific ramp rate; Weight loss values, such as those measured by TGA; Weight gain at 25°C and relative humidity between 5% and 95%, as determined by DVS; and An example 1H NMR spectrum of compound 1 dissolved in dimethyl sulfoxide (DMSO-d6).

[0010] In the embodiments, the solid form was determined to be crystalline by the presence of distinctive spikes found in the corresponding XRPD pattern.

[0011] In some embodiments, XRPD is used to determine whether the solid form of compound 1 transforms into another solid form at temperatures above room temperature.

[0012] In some embodiments, crystalline compound 1 is an anhydrous form.

[0013] In some embodiments, crystalline compound 1 is a solvate.

[0014] In some embodiments, the XRPD pattern of crystalline compound 1 has characteristic peaks centered approximately at the following 2θ values ​​(degrees): 11.8, 13.9, 14.2, 16.8, 19.1, 19.3, 20.1, 21.3, 22.1 and 23.2.

[0015] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [10A].

[0016] In some embodiments, the XRPD pattern of crystalline compound 1 has characteristic peaks centered approximately at the following 2θ values ​​(degrees): 9.5, 10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6, and 23.5.

[0017] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [1A].

[0018] In some embodiments, crystalline compound 1 comprises substantially as shown in Figure 1. The unit cell shown in [1B].

[0019] In some embodiments, the crystalline form of compound 1 changes to a different crystalline form when subjected to temperatures ranging from about 150°C to about 195°C, for example from 157°C to 170°C, as indicated by a DSC ramp rate of 10°C / min.

[0020] In some embodiments, crystalline compound 1 melts at a T starting point of about 200°C to about 225°C, for example about 205°C to about 225°C, for example about 208°C to about 215°C, as measured by DSC at a ramp rate of 10°C / min.

[0021] In some embodiments, the XRPD pattern of crystalline compound 1 has characteristic peaks centered approximately at the following 2θ values ​​(degrees): 9.9, 11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6.

[0022] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [3A].

[0023] In some embodiments, crystalline compound 1 comprises substantially as shown in Figure 1. The unit cell shown in [3B].

[0024] In some embodiments, the crystalline form of compound 1 changes to a different crystalline form when subjected to temperatures ranging from about 180°C to about 200°C, for example from about 184°C to about 200°C, for example from about 184°C to about 190°C, as indicated by a DSC at a ramp rate of 10°C / min.

[0025] In some embodiments, crystalline compound 1 melts at a T starting point of about 200°C to about 225°C, for example about 211°C to about 215°C, as measured by DSC at a ramp rate of 10°C / min.

[0026] In some embodiments, crystalline compound 1 has substantially the following characteristics: Any of the XRPD patterns shown in [2B].

[0027] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [4A].

[0028] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [5].

[0029] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [6A].

[0030] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [7A].

[0031] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [8A].

[0032] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [9A].

[0033] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [11A].

[0034] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in

[12] .

[0035] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [13A].

[0036] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure. As shown in [14A].

[0037] In some embodiments, the XRPD pattern of crystalline compound 1 is substantially as shown in the figure.

[16] any of them shown in the illustration.

[0038] In one embodiment, the present invention describes a method for converting a crystalline compound as described in technical solution 5 into a crystalline compound as described in technical solution 10, the method comprising crystallization or slurry conversion from the solution form of compound 1.

[0039] In some embodiments, the conversion is carried out using ethyl acetate as a solvent at a temperature of about 50°C to about 70°C, for example, 60°C to 65°C.

[0040] In some embodiments, the transformation is carried out in the presence of a seed crystal of the crystalline compound as described in technical solution 10, at a loading of about 0.1% to about 5.0%, for example, 0.2% to 1.0% of the total amount of the present compound 1.

[0041] In one embodiment, the present invention describes a pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable excipient.

[0042] In one embodiment, the present invention describes a method for treating CNS-related conditions in an individual in need, comprising administering to the individual an effective amount of compound 1, such as a crystalline solid form of compound 1 described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0043] In some embodiments, CNS-related conditions include sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, or tinnitus.

[0044] In some embodiments, crystalline compound 1 is administered orally, non-intestinally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, buccally, sublingually, rectally, topically, by inhalation, intranasally, or percutaneously.

[0045] In some embodiments, crystalline compound 1 is administered over a long period of time.

[0046] In this article, "XRPD" refers to X-ray powder diffraction. "VT-XRPD" refers to variable temperature X-ray powder diffraction. "TGA" refers to thermogravimetric analysis. "DSC" refers to differential scanning calorimetry. "NMR" refers to nuclear magnetic resonance. "DVS" refers to dynamic vapor adsorption. "DCM" refers to dichloromethane. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "MBTE" refers to methyl tributyl ether. "RH" refers to relative humidity.

[0047] As used herein, “crystal” refers to a solid with a highly regular chemical structure. Specifically, a crystalline form can be produced as one or more single crystalline forms. For the purposes of this application, the terms “crystalline form,” “single crystalline form,” “crystalline solid form,” “solid form,” and “polymorph” are synonyms and are used interchangeably; these terms are distinguished between different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0048] The term "substantially crystalline" refers to a form that can crystallize at least a specific weight percentage. A specific weight percentage is 10%, 20%, 30%, 40%, 50%, 60%, 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 10% and 100%. In some embodiments, compound 1 may be a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, and P).

[0049] The term "substantially pure" refers to the composition of a particular crystalline solid form of Compound 1 that is free from impurities and / or other solid forms of Compound 1 by at least a certain weight percentage. The specific weight percentage is 85%, 90%, 95%, or 99%. In some embodiments, Compound 1 may be a substantially pure sample of any of the crystalline solid forms described herein (e.g., forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, and P). In some embodiments, Compound 1 may be substantially pure form A. In some embodiments, Compound 1 may be substantially pure form B. In some embodiments, Compound 1 may be substantially pure form C. In some embodiments, Compound 1 may be substantially pure form D. In some embodiments, Compound 1 may be substantially pure form E. In some embodiments, Compound 1 may be substantially pure form F. In some embodiments, Compound 1 may be substantially pure form G. In some embodiments, Compound 1 may be substantially pure form H. In some embodiments, Compound 1 may be substantially pure form I. In some embodiments, Compound 1 may be substantially pure form J. In some embodiments, Compound 1 may be substantially pure form K. In some embodiments, compound 1 may be in a substantially pure form L. In some embodiments, compound 1 may be in a substantially pure form M. In some embodiments, compound 1 may be in a substantially pure form N. In some embodiments, compound 1 may be in a substantially pure form O. In some embodiments, compound 1 may be in a substantially pure form P.

[0050] As used herein, the terms "anhydrous" or "anhydrous" in relation to the crystalline form of Compound 1 mean that no solvent molecules (including water molecules) form a portion of the unit cell of the crystalline form. However, an anhydrous crystalline form may contain solvent molecules that do not form a portion of the unit cell of the anhydrous crystalline form, such as residual solvent molecules left over from the formation of the crystalline form. In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the sample in its anhydrous form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the sample in its anhydrous form. In some embodiments, the sample of the anhydrous crystalline form of Compound 1 contains no solvent molecules, such as no detectable amount of solvent. The term "solvent compound" in relation to the crystalline form of Compound 1 means that solvent molecules (e.g., organic solvents and water) form a portion of the unit cell of the crystalline form. Solvent compounds containing water as a solvent are also referred to herein as "hydrates". The term "isomorphic" in relation to the crystalline form of compound 1 means that the form may contain different chemical components in a unit cell, such as different solvent molecules, but has the same XRPD pattern. In this article, isomorphic crystalline forms are sometimes referred to as "isomorphic bodies".

[0051] The crystalline form of compound 1 described herein (e.g., form K) can melt at a specific temperature or across a temperature range. This specific temperature or temperature range can be represented by the onset temperature (Tstart) of the endothermic melting in the DSC trace of the crystalline form. In some embodiments, at this initial onset temperature, a sample of the crystalline form of compound 1 melts and undergoes concurrent side processes, such as recrystallization or chemical decomposition. In some embodiments, at this initial onset temperature, the crystalline form of compound 1 melts in the absence of other concurrent processes.

[0052] The term "characteristic peak" in the context of the XRPD pattern of the crystal form of compound 1 refers to the set of peaks spanning the 0°–40° range whose 2θ values ​​are as a whole assigned to only one crystal form of compound 1. Simple Explanation of the Diagram

[0053] picture [1A] An instance of an XRPD pattern of form A. picture [1B] An example unit cell of form A along the b-axis. picture [1C] Plot the instance TGA (top) and DSC (bottom) curves of form A. picture [1D] Plots the superposition of an instance VT-XRPD pattern of form A and an instance XRPD pattern of form K at the selected temperature. picture [1E] Plots an example DVS isotherm of form A at 25°C. picture [1F] Plots an example XRPD pattern of form A before and after an example DVS measurement at 25°C. picture [2A] An instance of an XRPD pattern of the same shape as form B. picture [2B] Instance XRPD pattern of three identical shapes in form B. picture [2C] Plot the TGA (top) and DSC (bottom) curves of the same shape in form B. picture [2D] Draws an instance of the VT-XRPD pattern of form B and an instance of the XRPD pattern of form K. picture [2E] Draw the instance TGA curve of the same shape as form B. picture [2F] Plot the instance DSC curve of the same shape as form B. picture [2G] shows an example 1H NMR spectrum of the isomorphic form B dissolved in DMSO-d6. picture [2H] illustrates an example 1H NMR spectrum of the isomorphic form B dissolved in DMSO-d6. picture [2I] An example 1H NMR spectrum of form B isomorphism dissolved in DMSO-d6 is shown. picture [3A] Instance XRPD pattern of drawing form C. picture [3B] The instance unit cell of form C along the b-axis. picture [3C] Plot the instance TGA (top) and DSC (bottom) curves of form C. picture [3D] Plots an overlay of an instance XRPD pattern of form C and an instance XRPD pattern of form K at a selected temperature. picture [3E] Plots the superposition of an instance XRPD pattern of form C at a selected temperature with or without N2 atmosphere. picture [3F] Plots an example DVS isotherm of form C at 25°C. picture [3G] illustrates the superposition of an example XRPD pattern of form C before and after DVS measurement at 25°C. picture [4A] Instance XRPD pattern of drawing form D. picture [4B] The superposition of an instance XRPD pattern of form D and an instance XRPD pattern of form A before and after drying under ambient conditions is illustrated. picture [5] Instance XRPD pattern of form E. picture [6A] Instance XRPD pattern of drawing form F. picture [6B] Plot the instance TGA (top) and DSC (bottom) curves of form F. picture [6C] Plots an overlay of an instance XRPD pattern of form F and an instance XRPD pattern of form K at a selected temperature. picture [6D] shows an example 1H NMR spectrum of form F dissolved in DMSO-d6. picture [7A] Instance XRPD pattern of drawing form H. picture [7B] Plots an instance XRPD pattern of form H and an instance XRPD pattern of form A before and after drying under ambient conditions. picture [8A] Instance XRPD pattern of drawing form I. picture [8B] The illustration shows an example XRPD pattern of Form I before and after drying for 3 days under ambient conditions, and an overlay of an XRPD pattern of Form A. picture [9A] Instance XRPD pattern of drawing form J. picture [9B] The illustration shows an instance of XRPD pattern of form J before and after drying for 3 days under ambient conditions, and an overlay of XRPD pattern of form A. picture [10A] Instance XRPD pattern of drawing form K. picture [10B] Plot the instance TGA (top) and DSC (bottom) curves of form K. picture [10C] An example DVS isotherm of form K at 25°C is drawn. picture [10D] illustrates the superposition of the instance XRPD pattern of form K before and after the instance DVS measurement at 25°C. picture [11A] Instance XRPD pattern of drawing form L. picture [11B] The superposition of the instance XRPD pattern of form L and the instance XRPD patterns of form M and form B is shown 3 days before and after. picture [11C] Plot an instance of the DSC curve of form L. picture

[12] An instance of an XRPD pattern of form M. picture [13A] Instance XRPD pattern of drawing form N. picture [13B] illustrates the superposition of an instance XRPD pattern of form N and an instance XRPD pattern of form A before and after drying overnight under ambient conditions. picture [13C] Plot the instance TGA (top) and DSC (bottom) curves of form N. picture [13D] shows an example 1H NMR spectrum of N dissolved in DMSO-d6. picture [14A] An instance of an XRPD pattern of form O. picture [14B] Plot the instance TGA (top) and DSC (bottom) curves of form O. picture [14C] Plots an instance XRPD pattern of form O and an instance XRPD pattern of form C superimposed at the selected temperature. picture [14D] illustrates an example 1H NMR spectrum of form O dissolved in DMSO-d6. picture

[15] The superposition of an instance XRPD pattern indicating the time-dependent transformation of form A to form C in ethyl acetate in the presence of seed crystals of form C under elevated temperature. picture

[16] An exemplary XRPD pattern is shown for form P corresponding to a wet sample (“wet cake”), a sample air-dried at room temperature (“air-dried”), and a sample oven-dried at 40°C (“oven-dried”). An exemplary XRPD of a reference sample of form A is also provided. picture [17A] An example 1H NMR spectrum of form P after air drying at room temperature is shown. picture [17B] An example 1H NMR spectrum of form P after oven drying at 40 °C is shown. picture [18A] Plots an example TGA curve for form P after air drying at room temperature. picture [18B] An example TGA curve of form P after oven drying at 40°C is shown. picture

[19] An example graph showing the solubility data of forms A, C and P in ethyl acetate. picture

[20] Plot the instance phase relationships between forms A, C and P. Implementation

[0054] [Cross-reference to related applications] [] This application claims priority to USSN 62 / 378,582, filed August 23, 2016, which is incorporated herein by reference in its entirety.

[0055] In one state, the present invention is described in the formula ( [I]) Compound, also referred to herein as "Compound 1", has been found to exist in various crystalline forms, as indicated by a variety of analytical methods. Compound 1 and its chemical synthesis were previously disclosed in U.S. Patent Application Publication No. US 20160083417 and PCT Application Publication No. WO 2014169831. Individual solid forms of the present invention and their compositions are provided in the following table: [surface] [1.] [Compound] [1] [Overview of Crystallization Forms] [] [Polymorphic] [type] [form] [A] Anhydrous [form] [B] solvates [form] [C] Anhydrous [form] [D] Intermediate stability [form] [E] Intermediate stability [form] [F] 1,4-Dioxane solvate [form] [H] Intermediate stability [form] [I] Intermediate stability [form] [J] Intermediate stability [form] [K] Anhydrous [form] [L] Solvates / Hydrates [form] [M] Solvates / Hydrates [form] [N] 1,4-Dioxane solvate [form] [O] Solvates / Hydrates [form] [P] EtOAc solvates Solid form of compound 1 and its preparation method

[0056] Forms B, C, D, E, F, G, H, I, J, K, N, and O were prepared from form A using various crystallization techniques described herein. Forms L and M were prepared from form B using other methods described herein. These forms were subsequently characterized by one or more of the following analytical techniques: X-ray powder diffraction (XRPD) (e.g., variable temperature X-ray powder diffraction (VT-XRPD)), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), or dynamic vapor adsorption (DVS). The single-crystal structures (including unit cells) of forms A and C were determined using data obtained using an X-ray diffractometer. Furthermore, the calculated XRPD patterns of forms A and C were obtained using their single-crystal X-ray diffraction data. In this invention, DSC and TGA data were obtained using a ramp rate of 10 °C / min.

[0057] Form A can be prepared by stirring crude compound 1 as a slurry in ethyl acetate below 10°C, followed by filtration and drying under vacuum; or by dissolving crude compound 1 in dichloromethane, followed by concentrating the solution twice under vacuum with ethyl acetate until dry. Form A can be determined by XRPD to be the crystalline form of compound 1. TGA, together with the single-crystal structure of form A, can be used to infer that form A is anhydrous. DSC can be used to indicate the presence of two endothermic events occurring at temperatures below 300°C: the first endothermic event, Ti, begins at 157.2°C, representing the transformation of form A to form K; and the second endothermic event, Ti, begins at 203.8°C, representing the melting point of form K. DVS can be used to show that form A exhibits a water uptake of less than 0.30% by weight at relative humidity (RH) less than or equal to 95%.

[0058] In some embodiments, the XRPD pattern of form A can be substantially as shown in the figure. As shown in [1A]. Furthermore, the representative peaks of the XRPD pattern of form A can be indicated by, for example, the values ​​of 2θ, d-spacing, and relative intensity in Table 2 below: [surface] [2.] [form] [A] [Selected Experiment] [XRPD] [Image data.] [] 2θ (degrees) d-Spacing (Å) Relative Intensity (%) 9.494611 9.31518 40.49 10.78823 8.20093 46.5 13.22776 6.69345 37.69 14.89123 5.94927 10.18 15.99324 5.54174 15.09 18.28113 4.85302 31.96 18.93233 4.68754 100 21.05207 4.2201 10.38 21.64548 4.10573 24.16 23.50505 3.78495 15.37

[0059] In some embodiments, the XRPD pattern of crystalline compound 1 has characteristic peaks centered approximately at the following 2θ values ​​(degrees): 9.5, 10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6 and 23.5.

[0060] The calculated XRPD data for the selected peak can be obtained from the X-ray diffraction data of the single crystal of form A, as shown in Table 3 below, supplemented by experimental data in Table 2. [surface] [3.] [form] [A] [Selected Calculation] [XRPD] [Image data.] 2θ (degrees) d-interval (Å) Relative Intensity (%) 10.9265 8.09076 21.14 13.32097 6.64132 48.56 14.11329 6.27021 20.36 14.94619 5.92262 24.95 16.05232 5.5169 49.72 17.42404 5.08555 48.28 18.40825 4.81581 100 19.2493 4.60725 18.47 24.23572 3.66943 19.02 24.3725 3.64915 19.56

[0061] Form B exists as the crystalline form of compound 1 as determined by XRPD and can be prepared using various techniques described herein, such as slow evaporation, slurry conversion, antisolvent addition, solid vapor diffusion, or slow cooling. Furthermore, isoforms of form B can be prepared from different solvent systems, such as dichloromethane (DCM) / n-heptane, tetrahydrofuran (THF) / n-heptane, or chloroform (CHCl3) / methyl tributyl ether (MBTE). Table 4 summarizes the properties of these isoforms, as determined by various instrumental methods, such as TGA, DSC, and 1H NMR spectroscopy. [surface] [4.] [] [form] [B] [An overview of instances of isomorphic forms] [] [isomorphic body] [Solvent System] [crystallization] [, , ] [method] [TGA] [weight] [, , ] [loss(%)] [DSC] [Absorbing heat] [, , T] [, 開始 , (] [℃)] [Compound] [1:] [solvent] [(] [Moll ratio] , ] [Types of Solvates] Form B-1 DCM / n-Heptane Slurry conversion 5.7 to 8.5 87.2, 211.7 1:0.4 n-Heptane solvates Form B-2 THF / n-Heptane Antisolvent addition 4.6 to 8.5 85.4, 212.2 1:0.3 n-Heptane solvates Form B-3 CHCl3 / MBTE Antisolvent addition 10.2 69.2, 211.6 1:0.5 CHCl3 solvate

[0062] Form C is the anhydrous crystalline form of compound 1 as determined by XRPD, and can be prepared from form A in isopropanol and isopropyl acetate using slurry conversion crystallization at 50 °C. The absence of solvent in form C can be confirmed using TGA and single-crystal X-ray crystallography. DSC can be used to indicate two endothermic events below 300 °C: a broad peak at T0 begins at 183.8 °C, corresponding to the transformation of form C to form K, and a sharp peak at T0 begins at 211.0 °C, corresponding to the melting of form K. DVS can be used to show that form C exhibits a water uptake of less than 0.32 wt% at RH less than or equal to 95%.

[0063] In some embodiments, the XRPD pattern of form C can be substantially as shown in the middle figure. As shown in [3A]. Furthermore, the representative peaks of the XRPD pattern from form C can be indicated by their values ​​for 2θ, d-spacing, and relative intensity, as shown in, for example, Table 5 below: [surface] [5.] [form] [C] [Selected Experiment] [XRPD] [Image data.] [] 2θ (degrees) d-Spacing (Å) Relative Intensity (%) 22.60955 3.93279 26.76 20.65623 4.30006 27.84 13.36358 6.62573 28.42 14.81188 5.98097 33.78 21.50066 4.12963 36.7 21.54634 4.12439 36.94 9.889125 8.94443 41.85 11.79075 7.50579 65.73 14.41313 6.14552 65.89 16.99542 5.21715 100

[0064] In some embodiments, the XRPD pattern of form C may have characteristic peaks centered approximately at the following 2θ values ​​(degrees): 9.9, 11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6.

[0065] The calculated XRPD data for the selected peaks can be obtained using X-ray diffraction data from single crystals of form C, as provided in Table 6 below. These simulated peaks supplement the experimental data in Table 5. [surface] [6.] [form] [C] [Selected Calculation] [XRPD] [Image data.] 2θ (degrees) d-Spacing (Å) Relative Intensity (%) 9.861923 8.96162 19.41 11.75959 7.51938 37.75 13.33554 6.6341 31.9 14.38478 6.15248 43.36 14.79021 5.98473 26.68 16.96659 5.22162 100 19.61234 4.52277 17.69 20.60123 4.30785 30.39 21.48653 4.13232 25.6 22.57956 3.93469 27.32

[0066] Form D can be prepared in tetrahydrofuran (THF) / water (H2O) using an antisolvent addition crystallization technique, and can be identified by XRPD analysis as the crystalline form of compound 1. After drying at room temperature, it is converted back to form A.

[0067] Form E can be prepared at room temperature in 1,4-dioxane / n-heptane using a self-reverse solvent crystallization technique and can be determined by XRPD as a crystalline wet sample of compound 1.

[0068] Form F was prepared from 1,4-dioxane / n-heptane at ambient room temperature using an antisolvent addition crystallization technique and was determined by XRPD to be the crystalline form of compound 1. TGA of the sample of form F showed a 19.7% weight loss at a maximum temperature of 200 °C. DSC revealed two endothermic peaks for form F at the initial temperatures of 63.1 °C and 210.7 °C, corresponding to solvent loss (conversion to form K) and the melting point of form K, respectively. The conversion of form F to form K was further confirmed by VT-XRPD measurements. Based on 1H NMR spectroscopy, form F was a 1,4-dioxane solvate with a molar ratio of 1:0.9 to the remaining n-heptane.

[0069] Form H can be prepared in n-heptane at room temperature by solution vapor diffusion crystallization. This form is crystalline as determined by XRPD, but it transforms into the metastable form A after drying under ambient conditions for 3 days.

[0070] Form I can be manufactured using a slow cooling crystallization technique carried out in methanol at room temperature. Like Form H, Form I can be determined to be a crystalline material by XRPD analysis, but it is found to be metastable because it transforms into Form A after drying under ambient conditions for 3 days.

[0071] Form J can be prepared in methanol at room temperature using solid vapor diffusion crystallization. XRPD analysis can be used to infer that form J is a metastable crystalline sample that transforms into form A after drying under ambient conditions for 3 days.

[0072] Form K can be prepared by heating various forms of compound 1 (e.g., forms A, B, C, E, and F) to elevated temperatures. The sample analyzed in this form can be determined to be crystalline by XRPD analysis. TGA can be used to indicate no weight loss before the decomposition temperature and to show that form K is anhydrous. DSC can be used to show that form K exhibits a single endothermic reaction, with a T0 starting at 211.6 °C, corresponding to the melting point of the analyzed sample. DVS measurements are performed to show that form K exhibits less than 0.35% by weight water uptake at RH less than or equal to 95%.

[0073] In some embodiments, the XRPD pattern of form K can be substantially as shown in the figure. As illustrated in [10A]. Furthermore, representative peaks from the XRPD pattern of form K can be indicated by their values ​​of 2θ and relative intensity, as shown in, for example, Table 7 below: [surface] [7.] [form] [K] [Selected Experiment] [XRPD] [Image data.] [] 2θ (degrees) d-Spacing (Å) Relative Intensity (%) 13.9471 6.3498 19.12 20.09767 4.41829 20.68 23.20826 3.83268 23.69 22.05504 4.0304 24.27 19.10905 4.64459 24.93 21.32362 4.16697 26.68 19.33614 4.59055 28.07 14.16125 6.25426 47 16.84678 5.26284 61.56 11.75077 7.53124 100

[0074] In some embodiments, the XRPD pattern of form K may have characteristic peaks centered approximately at the following 2θ values ​​(degrees): 11.8, 13.9, 14.2, 16.8, 19.1, 19.3, 20.1, 21.3, 22.1 and 23.2.

[0075] Form L can be prepared by storing form B in a sealed vial under ambient conditions for one month. This form can be determined to be the metastable crystalline form of compound 1. XRPD analysis indicates that form L transforms into a mixture of forms B and M under ambient conditions 3 days after preparation.

[0076] Form M can be manufactured by storing Form B in a sealed vial under ambient conditions for one month. The sample analyzed for this form was determined to be poor crystallization by XRPD analysis.

[0077] Form N can be prepared by a reverse antisolvent addition crystallization technique in 1,4-dioxane / n-heptane and is determined to be the crystalline form of compound 1 by XRPD. TGA can be used to determine that form N is a solvate, exhibiting a 2.5% weight loss at a maximum of 60 °C, followed by a 7.1% weight loss at a maximum of 200 °C. DSC can be used to show two endothermic events, one corresponding to the solvent loss starting at T0 of 75.4 °C and the other starting at T0 of 210.4 °C, which represents the melting point of form K. VT-XRPD can be used to confirm that form N transforms into form K at 100 °C. Based on 1H NMR spectroscopy, form N is a 1,4-dioxane solvate, with a molar ratio of compound 1:1,4-dioxane of 1:0.3.

[0078] Form O was prepared at room temperature in a water / acetonitrile mixture (0.041 water: 0.959 acetonitrile, volume / volume; aw = 0.6) using a water activity assay and determined by XRPD to be the crystalline form of compound 1. TGA of the sample of form O indicated a weight loss of 5.3% at a maximum of 55.1 °C and then 5.9% at a maximum of 200 °C. DSC was used to show that form O exhibited three endothermic phases: once at Tstart = 65.0 °C, corresponding to solvent loss to form C; once at Tstart = 168.5 °C, corresponding to the conversion from form C to form K; and once at Tstart = 210.8 °C, corresponding to the melting of form K. Form O could be further characterized by 1H NMR spectroscopy dissolved in DMSO-d6.

[0079] Furthermore, form P is a solvate of compound 1 in ethyl acetate (EtOAc) and can be detected in: (a) a slurry of form A in EtOAc at 5°C (after 1 h) and 20°C (after 2 days), and (b) a slurry of form C in EtOAc at 5°C (after 1 h) and 20°C (after 7 days). The wet cake of form P (air for approximately 5 min) can be dried in two ways: (a) overnight in air and at room temperature, and (b) for 3 hours under vacuum and at 40°C. Both dried cakes can be analyzed by XRPD, 1H-NMR, and TGA. The air-dried cake of form P yields an XRPD pattern consistent with form P, approximately 1% weight loss by TGA at a maximum of approximately 50°C, and an EtOAc peak by 1H NMR. On the other hand, after oven drying, the sample of form P can exhibit an XRPD pattern consistent with form A, show no weight loss by TGA at ≤100°C, and show no EtOAc peak by 1H-NMR. Therefore, form P can be converted to form A after drying. In another embodiment, the present invention provides a method for converting a solid form of compound 1 or a mixture of solid forms of compound 1 into different anhydrous forms of compound 1. In one embodiment, form A, a mixture of form A or form K, or a mixture of form A, form C, and form K can be converted to form C via slurry conversion in ethyl acetate, n-butanol, or methyl tributyl ether at room temperature or elevated temperatures (e.g., 50°C or 65°C). In these three-solvent systems, form C is the only form remaining after slurry conversion, revealing that this solid form is thermodynamically more stable than forms A and K at room temperature to 50°C. In another embodiment, form C can be obtained by soluble compound 1 (original form A) being crystallized in ethyl acetate at elevated temperature (e.g., 65°C) in the presence of a small amount (e.g., 0.2%-1.0%) of seed crystals of form C, followed by cooling the batch to a temperature not lower than 25°C to 30°C. Pharmaceutical Composition

[0080] In another embodiment, the present invention provides a pharmaceutical composition comprising a solid form of the compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0081] The pharmaceutical compositions provided herein can be administered via a variety of routes, including but not limited to oral (enteral), non-enteral (by injection), rectal, local, transdermal, intradermal, intrathecal, subcutaneous (SC), intramuscular (IM), sublingual / buccal, ocular, ocular, vaginal, intranasal, or inhalation.

[0082] Typically, the solid form of Compound 1 provided herein is administered in an effective amount. The actual amount of Compound 1 in solid form administered will usually be determined by the physician based on factors including: the condition to be treated, the route of administration, the actual compound administered, the individual patient's age, weight and response, the severity of the patient's symptoms, and so on.

[0083] When used for the prevention of CNS symptoms, the solid form of compound 1 described herein will generally be administered, under the supervision of a physician, to individuals at risk of developing the condition at the aforementioned dosage values. Individuals at risk of developing a particular condition generally include those with a family history of the condition, or those who have been identified by genetic testing or screening as particularly susceptible to the condition.

[0084] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administration of the solid form of Compound 1 or a pharmaceutical composition thereof over an extended period of time (e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.), or indefinitely, for example, throughout an individual’s remaining life. In some embodiments, long-term administration is intended, for example, to provide a consistent level of Compound 1 in the blood within a therapeutic window of the extended period of time.

[0085] The pharmaceutical compositions of the present invention can be further delivered using a variety of administration methods. For example, in some embodiments, the pharmaceutical composition can be administered in a concentrated dose to, for instance, increase the concentration of compound 1 in the blood to an effective level. The site of administration of the concentrated dose depends on the desired systemic concentration of the active ingredient throughout the body; for example, intramuscular or subcutaneous concentrated doses allow for a slow release of the active ingredient. Furthermore, in other embodiments, the pharmaceutical composition can be administered first in a concentrated dose, followed by continuous infusion.

[0086] Compositions intended for oral administration may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, compositions are present in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable for a single dose for use in human individuals and other mammals, each unit containing a calculated combination of a predetermined amount of active ingredient and suitable pharmaceutical excipients to produce the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, or the like. In such compositions, the solid form of compound 1 is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various mediators or excipients and processing aids that contribute to the formation of the desired dosing form.

[0087] For oral administration, a typical regimen is 1 to 5 times daily, particularly 2 to 4 times, and usually 3 times daily. Using these administration methods, each dose provides about 0.01 to about 20 mg / kg of compound 1 provided herein in solid form, and preferred doses each provide about 0.1 to about 10 mg / kg, particularly about 0.2 to about 5 mg / kg.

[0088] The selection of transdermal dosage is generally to provide a similar or lower blood content compared to that achieved by using injectable dosage, and the amount is generally in the range of about 0.01 to about 20% by weight, for example, in a transdermal patch drug reservoir or drug-adhesive reservoir, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0089] Solid compositions may include, for example, any of the following components or compounds with similar properties in solid form: binders, surfactants, diluents or fillers, buffers, anti-adhesion agents, flow aids, hydrophilic or hydrophobic polymers, retardants, stabilizers or stabilizers, disintegrants or hyperdistegrants, dispersants, antioxidants, defoamers, fillers, flavoring agents, colorants, lubricants, adsorbents, preservatives, plasticizers, coatings or sweeteners or mixtures thereof. For example, one or more excipients may be binders, such as microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, low-viscosity hydroxypropyl methylcellulose, tragacanth gum, or gelatin; diluents, such as mannitol, microcrystalline cellulose, maltodextrin, starch, or lactose; disintegrants, such as alginate, Primogel, sodium starch glycolate, croscarmellose sodium, crospovidone, or corn starch; lubricants, such as magnesium stearate, sodium stearyl fumarate, or glyceryl betaine; flow aids, such as colloidal silica; preservatives, such as potassium sorbate or methylparaben; surfactants, such as sodium lauryl sulfate, sodium docusate, polysorbate 20, polysorbate 80, hexadecyl triethylammonium bromide, polyethylene oxide-polypropylene oxide copolymer, or Cremophor EL. EL); antioxidants, such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, tocopherol or tocopheryl acetate, sodium sulfite or sodium metabisulfite; coatings, comprising one or more of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, methacrylate copolymers, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, shellac, and others; sweeteners, such as sucrose, sucralose, acesulfame K, aspartame sodium, or saccharin sodium; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. Any well-known pharmaceutical excipient may be included in the dosage form, and see the FDA's Inactive Ingredients Guide; Remington: The Science and Practice of Pharmacy (21st edition, Pharmaceutical Press, 2005); Handbook of Pharmaceutical Excipients (6th edition, Pharmacrutical Press, 2009), all of which are incorporated herein by reference.

[0090] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is usually combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with, for example, an oil-in-water cream base. These transdermal formulations are well known in the art and often include other ingredients to enhance the dermal 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 substances in the form of suspensions or emulsions intended for external application, including spray lotions) and aqueous solutions; semi-solid formulations, such as gels (colloids in which the dispersed phase has been combined with a dispersion medium to produce a semi-solid substance, such as a jelly), creams (soft solids or thick liquids) and ointments (soft oily preparations); and solid formulations, such as topical patches. Therefore, the delivery media components of interest include (but are not limited to): oil-in-water (O / W) and water-in-oil (W / O) emulsions, emulsions, lotions, creams, ointments, gels, serums, powders, masks, packs, sprays, aerosols, sticks, and patches.

[0091] The solid form of Compound 1 provided herein can also be administered via a transdermal device. Therefore, transdermal administration can be accomplished using reservoir-type or film-type patches, adhesive-based patches, or patches of other matrix types. The delivery compositions of interest include liquid formulations, such as lotions (liquids containing insoluble materials, in suspension or emulsion form, intended for external application, including spray lotions) and aqueous solutions; semi-solid formulations, such as gels (colloids, where the dispersed phase has been combined with a dispersion medium to produce a semi-solid substance, such as a jelly), creams (soft solids or thick liquids), and ointments (soft oily preparations); and solid formulations, such as topical patches. Therefore, the delivery media components of interest include (but are not limited to): oil-in-water (O / W) and water-in-oil (W / O) emulsions, emulsions, lotions, creams, ointments, gels, serums, powders, masks, packs, sprays, aerosols, sticks, and patches. For transdermal patches, the active agent layer includes one or more active agents, one of which is compound I. In some embodiments, the matrix is ​​an adhesive matrix. The matrix may include polymeric materials. Suitable polymers for adhesive matrices include (but are not limited to): polyurethanes, acrylates, styrene block copolymers, polysiloxanes, and the like. For example, adhesive matrices may include, but are not limited to, acrylate polymers, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrene block polymers, combinations thereof, and the like. Other examples of adhesives are described in the following literature: Satas, "Acrylic Adhesives", Handbook of Pressure-Sensitive Adhesive Technology, 2nd edition, pp. 396-456 (edited by D. Satas), Van Nostrand Reinhold, New York (1989), the disclosure of which is incorporated herein by reference.

[0092] In some embodiments, the surfactant layer includes a penetration enhancer. The penetration enhancer may include, but is not limited to, the following: aliphatic 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; alkanolamines, such as, but not limited to, triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; and polyol alkyl ethers, such as, but not limited to, alkyl ethers of the following polyols: for example, glycerol, ethylene glycol, propylene glycol, 1,3-butanediol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, and dipropylene glycol. The composition includes polypropylene glycol, dehydrated sorbitol, sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reducing oligosaccharides, wherein the alkyl portion of the polyol alkyl ether preferably has 6 to 20 carbon atoms; polyoxyethylene alkyl ethers, such as, but not limited to, polyoxyethylene alkyl ethers in which the alkyl portion has 6 to 20 carbon atoms and the number of repeating units (e.g., -OCH2CH2-) in the polyoxyethylene chain is 1 to 9, such as, but not limited to, polyoxyethylene lauryl ether, polyoxyethylene hexadecyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oil ether; glycerides (i.e., fatty acid esters of glycerol), such as, but not limited to, glycerides of fatty acids having 6 to 18 carbon atoms, diglycerides, triglycerides, or combinations thereof. In some embodiments, the polymer matrix includes polyvinylpyrrolidone. The composition may further include one or more fillers or one or more antioxidants. In some embodiments, the transdermal formulation may have a multilayer structure. For example, the transdermal formulation may have an adhesive matrix and a backing.

[0093] The above-described components of the oral, injectable, or topical administration compositions are representative only. Other materials, processing techniques, and similar statements are described in Chapter 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which are incorporated herein by reference.

[0094] The solid form of compound 1 of this invention can also be delivered in a sustained-release form or via a sustained-release drug delivery system. For a description of representative sustained-release materials, please refer to Remington's Pharmaceutical Sciences. How to use

[0095] This document provides a method for treating a condition (e.g., a CNS-related condition) in an individual in need, comprising administering to the individual an effective amount of compound 1 (e.g., compound 1 in solid form as described herein) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In some embodiments, the condition is a CNS-related condition selected from the group consisting of: sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, and tinnitus. In some embodiments, the condition is a comorbid condition (e.g., depression comorbid with personality disorders or sleep disorders comorbid with personality disorders). [Neurotic disorder] [] [Neurodegenerative or neurodevelopmental disorders and symptoms] []

[0096] The solid form of compound 1 or a pharmaceutically acceptable composition thereof may be used in the methods described herein, for example for the treatment of the conditions described herein, such as neurodevelopmental disorders or conditions or neurodegenerative disorders or conditions.

[0097] The term "neurodegenerative disease" includes diseases and conditions associated with progressive loss of neuronal structure or function or neuronal death. Neurodegenerative diseases and conditions include (but are not limited to) Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic and ischemic injury; ataxia and spasticity (including treatment and prevention of seizures induced by affective schizophrenia or by medications used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod's neuroacanthocytosis syndrome (MLS); intracranial injury; coma; contusions (e.g., spinal cord injury and head injury); dementia, including multiple infarct dementia and Alzheimer's disease; altered consciousness; Down syndrome; drug-induced or drug-induced Parkinsonism. (For example, acute akathisia induced by antipsychotic drugs, acute dystonia, Parkinson's disease or tardive dyskinesia, antipsychotic malignant syndrome or postural tremor induced by drug treatment); epilepsy; X-chromosome splitting syndrome; Gilles de la Tourette's syndrome; head trauma; hearing loss; Huntington's disease; Lennox syndrome. Levodopa-induced motor difficulties; intellectual disability; motor disorders, including dyskinesia and dyskinesia (rigidity) syndrome (including basal ganglia calcification, corticobasal ganglia degeneration, multiple system atrophy, Parkinson's disease-ALS dementia syndrome, Parkinson's disease, post-encephalitis Parkinson's disease, and progressive supranuclear palsy); muscle spasms based on muscle spasm or weakness-related conditions, including chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiparesis, Huntington's disease, neuroacanthocytosis, Sydenham's chorea). Chorea and symptomatic chorea), motor difficulties (including convulsions, such as complex convulsions, simple convulsions, and symptomatic convulsions), myoclonus (including generalized myoclonus and focal myoclonus), tremors (such as resting tremor, spontaneous tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic finger spasm, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia (such as blepharospasm), oromandibular dystonia, spasmodic dysarthria, and torticollis); neuronal damage, including eye injury, retinopathy, or macular degeneration; stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, perinatal asphyxia, and neurotoxic damage after cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus;Neurodegeneration induced by arteriosclerosis and viral infections (e.g., by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include (but are not limited to) stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, perinatal asphyxia, and neurotoxic damage following cardiac arrest. Treatment or prevention of neurodegenerative diseases also includes treating or preventing the neuronal function loss specific to neurodegenerative conditions. [Neuroendocrine disorders and dysfunctions] []

[0098] This article provides methods for treating neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to a variety of conditions caused by imbalances in the production of hormones directly related to the brain. Neuroendocrine disorders involve the interaction between the nervous and endocrine systems. Because the hypothalamus and pituitary gland are two regions in the brain that regulate hormone production, damage to the hypothalamus or pituitary gland due to traumatic brain injury can affect hormone production and other neuroendocrine functions. In some embodiments, neuroendocrine disorders or dysfunctions are associated with women's health disorders or conditions (e.g., the women's health disorders or conditions described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a woman's health disorder or condition is polycystic ovary syndrome (PCOS).

[0099] Symptoms of neuroendocrine disorders include (but are not limited to) behavioral, mood and sleep-related symptoms, reproductive function-related symptoms and physical symptoms; including (but are not limited to) fatigue, poor memory, anxiety, depression, weight gain or loss, mood instability, lack of concentration, difficulty concentrating, lack of libido, infertility, amenorrhea, muscle loss, increased abdominal fat, low blood pressure, low heart rate, hair loss, anemia, constipation, poor cold tolerance and dry skin. [Mental Abnormality] [Mood Disorders] []

[0100] This article also provides methods for treating mood disorders such as clinical depression, postnatal or birth depression, perinatal depression, atypical depression, depressive depression, psychotic major depressive disorder, rigid depression, seasonal affective disorder, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or bipolar disorder, depression caused by a chronic medical condition, comorbid depression, treatment-resistant depression, refractory depression, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide therapeutic effects for individuals suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or conditions described herein (e.g., neuroendocrine disorders and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0101] Clinical depression, also known as major depressive disorder, severe depression (MDD), unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a deep and persistent low mood accompanied by low self-esteem and a lack of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience difficulty falling asleep, weight loss, and often feel irritable and easily angered. Clinical depression affects how an individual feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may find it difficult to perform daily activities and may feel as if life is meaningless.

[0102] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, feeling anxious, difficulty falling asleep, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, disconnection from the baby and / or fetus, and loss of interest in activities that were previously enjoyable.

[0103] Postnatal depression (PND), also known as postpartum depression (PPD), refers to a group of clinical depressions affecting women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., as described herein). In some embodiments, PND is intractable depression (e.g., as described herein).

[0104] In some embodiments, individuals with perinatal depression (PND) also experience depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In these embodiments, individuals experiencing perinatal depression have an increased risk of developing PND.

[0105] Atypical depression (AD) is characterized by mood responsiveness (e.g., bizarre alexia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or hypersomnia (excessive sleep), heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived social rejection.

[0106] Depressive depression is characterized by loss of pleasure in most or all activities (amortia), unresponsiveness to interesting stimuli, depressive mood that is more severe than sadness or loss, excessive weight loss, or excessive guilt.

[0107] Major psychotic depression (PMD) or psychotic depression refers to severe depressive episodes, particularly melancholic ones, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0108] Kititary-associated depression refers to major depressive disorder involving motor and behavioral disturbances as well as other symptoms. Individuals may become mute and catatonic, and remain motionless or exhibit aimless or bizarre movements.

[0109] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which individuals have a seasonal pattern of depressive episodes that begin in the fall or winter.

[0110] Dysphoric mood refers to a condition involving unipolar depression, in which the same physical and cognitive problems are prominent. It is less severe than unipolar depression and often lasts longer (e.g., at least 2 years).

[0111] Double depression refers to extremely depressive mood (dysphoric mood) that lasts for at least 2 years and worsens during the major depressive phase.

[0112] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0113] Recurrent transient depression (RBD) refers to a condition in which an individual experiences approximately one depressive episode per month, each lasting two weeks or less and usually less than two to three days.

[0114] Mild depressive disorder or mild depression refers to depression in which at least two of the symptoms are present for two weeks.

[0115] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer, chronic pain, chemotherapy, and chronic stress.

[0116] Treatment-resistant depression refers to a condition in which an individual has received treatment for depression, but whose symptoms have not improved. For example, antidepressants or psychotherapy cannot alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, an individual with treatment-resistant depression may experience symptom improvement, but then relapse. Intractable depression occurs in patients with depression who resist standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics) as well as nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0117] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., due to the inevitable death of someone). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and normally enjoyed activities, or persistent feelings of worthlessness or hopelessness.

[0118] Mood disorders related to women’s health conditions or illnesses refer to mood disorders (e.g., depression) that are related to (e.g., caused by) women’s health conditions or illnesses (e.g., as described herein).

[0119] Suicidal ideation, suicidal thought, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation refers to thoughts about suicide or, unusually, intense focus on suicide. The range of suicidal ideation varies considerably, from brief thoughts to broad ideas, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, acquiring suicide tools, avoiding social contact, contemplating death, feeling trapped or hopeless about the situation, increased alcohol or drug use, engaging in dangerous or self-destructive activities, and saying goodbye as if never to see someone again.

[0120] Depression or personality disorders can also co-occur with another condition. For example, depression can co-occur with personality disorders. In another instance, personality disorders can co-occur with sleep disorders.

[0121] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, lethargy, agitation, difficulty sleeping, insomnia, irritability, fatigue, physical challenge, loss of interest in activities or hobbies, difficulty concentrating, weakness, poor self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. The symptoms of depression and their remission can be determined by a physician or psychologist (e.g., through a mental status examination). [Anxiety disorder] []

[0122] This article provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorder is a general term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria identify numerous anxiety disorders.

[0123] Generalized anxiety disorder (GAD) is a common chronic condition characterized by persistent anxiety that is not focused on any particular object or situation. Those suffering from GAD experience nonspecific, persistent fear and distress and become excessively worried about everyday matters. GAD is the most common anxiety disorder affecting older adults.

[0124] In panic disorder, an individual experiences brief onslaughts of intense fright and anxiety, typically marked by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. Panic attacks, defined by the APA as a sudden increase in fear or discomfort that peaks within less than 10 minutes, can last for hours and can be triggered by stress, fear, or even movement; however, the specific cause is not always obvious. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that these attacks have chronic consequences: distress over the potential impact of the attack, persistent fear of future attacks, or significant changes in behavior associated with the attack. Therefore, individuals with panic disorder experience symptoms even outside of specific panic attacks. Typically, panic victims notice normal changes in their heart rate, leading them to wonder if there is a problem with their heart or if another panic attack is imminent. In some cases, an heightened perception of bodily functions (hypervigilance) occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0125] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by recurring obsessive thoughts (troubling, persistent, and intrusive thoughts or influences) and compulsive behaviors (impulses to perform specific actions or rituals). In terms of its design, which believes in causal relationships that do not actually exist, OCD thought patterns can resemble superstition. Often, the process is completely illogical; for example, compulsive behaviors such as walking in a certain pattern may be used to alleviate obsessive thoughts of impending harm. In many cases, the compulsive behaviors are completely inexplicable, merely an impulse to complete a neuroticly triggered ritual. In rare cases, OCD sufferers may experience only obsessive thoughts without obvious compulsive behaviors; significantly fewer sufferers experience only compulsive behaviors.

[0126] The single largest category of anxiety disorders is phobias, which includes all situations in which fear and anxiety are triggered by specific stimuli or circumstances. Victims typically anticipate frightening consequences upon encountering the object of their fear, which can be anything from animals to places to bodily fluids.

[0127] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. PTSD can stem from extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to severe stressors, such as a soldier who can tolerate individual combat but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behaviors, and depression. [Mental Illness] []

[0128] Compound 1 in solid form or in pharmaceutically acceptable compositions thereof may be used in the methods described herein, for example, for treating the conditions described herein, such as mental disorders. In some embodiments, the impulse control disorder is schizophrenia or bipolar disorder. In some embodiments, the mental disorder is schizophrenia. In some embodiments, the mental disorder is bipolar disorder.

[0129] Bipolar disorder or bipolar disorder causes extreme mood swings, including euphoria (mania or hypomania) and depression (depression). [Impulse control disorder] []

[0130] Compound 1 in solid form or in pharmaceutically acceptable compositions thereof may be used in the methods described herein, for example, for treating the conditions described herein, such as impulse control disorders. In some embodiments, impulse control disorders are anorexia nervosa or alcohol withdrawal. In some embodiments, impulse control disorders are anorexia nervosa. In some embodiments, impulse control disorders are anorexia nervosa. [Example] []

[0131] To provide a more comprehensive understanding of the invention described herein, the following examples are set forth. These examples, set forth in this application, are intended to illustrate the crystalline solid form provided herein and are not intended to be construed as limiting its scope in any way. [Example] [1.] [Solid form] [A] [Preparation] []

[0132] Form A is prepared by stirring crude compound 1 in ethyl acetate at below 10°C to form a slurry, followed by filtration and drying under vacuum. It is also formed by dissolving crude compound 1 in dichloromethane, followed by concentrating the solution twice under vacuum with ethyl acetate until dry. [Example] [2.] [Various wet methods for obtaining other solid forms of the present invention through crystallization] []

[0133] To identify new crystal forms, form A was used as the starting material to evaluate different crystallization methods. In addition to form A, these methods were used to identify 13 crystal forms (B, C, D, E, F, H, I, J, K, L, M, N, and O). [] Slow evaporation

[0134] Slow evaporation crystallization experiments were conducted across eight different solvent systems. In each experiment, approximately 10 mg of Form A was dissolved in 0.4 to 1.0 mL of solvent in a 1.5 mL glass vial. Parafilm® sealed glass vials with 3 to 5 punctures were used to allow solvent evaporation. Slurry conversion

[0135] In each experiment, approximately 10 to 20 mg of form A was suspended in 0.5 mL of solvent or a mixture of solvents. After stirring at RT or 50°C for 48 hours, the solid was separated by centrifugation for analysis (wet sample). If the suspension became a clear solution, the clear solution was allowed to evaporate slowly under ambient conditions. Antisolvent addition

[0136] In each experiment, approximately 10 mg of form A was dissolved in 0.1 to 1 mL of each solvent to obtain a clear solution. Antisolvent was added in increments of 50 µL until precipitation was observed, or until the total volume of antisolvent reached 20 times the volume of the solvent. The precipitate was then separated by centrifugation for analysis (wet sample). A slow evaporation experiment was performed if a clear solution was observed. Slow cooling

[0137] In each experiment, approximately 10 mg of form A was suspended in 0.8 to 1.0 mL of each solvent mixture at 50 °C. The resulting suspension was immediately filtered through a 0.2 µm filter, and the filtrate was collected and cooled from 50 °C to 5 °C at a rate of 0.1 °C / min. The precipitate was then separated for analysis by centrifugation at 10,000 rpm for 3 to 5 minutes (wet sample). Solution vapor diffusion

[0138] In each experiment, approximately 10 mg of form A was dissolved in a suitable solvent in a 3 mL glass vial to obtain a clear solution. The vial was then placed in a 20 mL glass vial containing 3 mL of antisolvent and sealed. The system was kept at RT for 7 days to allow sufficient time for the solid to precipitate. The solid was separated and analyzed by centrifugation at 10,000 rpm for 3 to 5 minutes (wet sample). In cases where no precipitation was observed, the sample was kept at ambient conditions for slow evaporation. Solid vapor diffusion

[0139] In each experiment, approximately 10 mg of form A was placed in a 3 mL glass vial, which was then sealed into a 20 mL glass vial containing 3 mL of the specified solvent. The system was kept at RT for 7 days to allow sufficient time for the organic vapor to interact with the solid. The solid (wet sample) was then analyzed. rapid evaporation

[0140] In each experiment, approximately 10 mg of Form A was dissolved in 0.5 to 1.0 mL of solvent in a 1.5 mL glass vial. The visually clear solution was kept under ambient conditions, and the cap was removed for rapid evaporation. The solids obtained via evaporation (dry sample) were then analyzed. Reverse solvent addition

[0141] In each experiment, approximately 20 mg of form A was dissolved in 0.2 to 0.6 mL of each solvent to obtain a clear solution. The solution was added to a glass vial containing 2.0 mL of each antisolvent under RT conditions. The resulting precipitate was centrifuged at 10,000 rpm for 3 to 5 minutes for analysis (wet sample). If no precipitation was observed, a slow evaporation experiment was performed on the remaining solution. Water activity experiment

[0142] Water activity assays were performed using H₂O and acetonitrile in the range of 0 to 1 water activity (aw) at 0.2 intervals. Approximately 10 mg of form A was weighed into a 1.5 mL vial and 0.5 mL of solvent mixture was added. The suspension was stirred at 1000 rpm at room temperature. Residual solvent was removed from the sample by centrifugation (10000 rpm, 3 min). [Example] [3.] [solid] [form] [B] [Preparation] []

[0143] Form B is prepared by slow evaporation, slurry conversion in a dichloromethane (DCM) / n-heptane solvent system, antisolvent addition, solid vapor diffusion, and slow cooling crystallization in various solvent systems. The isomorphic system of Form B characterized in this invention is obtained by slurry conversion in dichloromethane (DCM) / n-heptane and by antisolvent addition in tetrahydrofuran (THF) / n-heptane or chloroform (CHCl3) / methyl tributyl ether (MBTE). [Example] [4.] [solid] [form] [C] [Preparation] []

[0144] Form C was prepared from form A by slurry conversion crystallization in isopropanol (IPA) and isopropyl acetate (IPAc) at 50°C. [Example] [5.] [Solid form] [D] [Preparation] []

[0145] Form D was prepared from form A by antisolvent addition crystallization in tetrahydrofuran (THF) / water (H2O) at room temperature (RT). [Example] [6.] [Solid form] [E] [Preparation] []

[0146] Form E was prepared from Form A by antisolvent addition crystallization in 1,4-dioxane / n-heptane at ambient room temperature (RT). [] [Example] [7.] [Solid form] [F] [Preparation] []

[0147] Form F was prepared from form A by reverse antisolvent addition crystallization in 1,4-dioxane / n-heptane at ambient room temperature (RT). [Example] [8.] [Solid form] [H] [Preparation] []

[0148] Form H was prepared in n-heptane at room temperature (RT) via solution vapor diffusion crystallization. [Example] [9.] [Solid form] [I] [Preparation] []

[0149] Form I is prepared in methanol (MeOH) at room temperature (RT) via a slow cooling crystallization technique. [Example] [10.] [Solid form] [J] [Preparation] []

[0150] Form J was prepared in MeOH at room temperature (RT) via solid vapor diffusion crystallization. [Example] [11.] [Solid form] [K] [Preparation] []

[0151] Form K is prepared by heating forms A, B, C, E, or F to an elevated temperature. The sample of form K analyzed was prepared by heating form F to 100°C. [Example] [12.] [Solid form] [L] [Preparation] []

[0152] Form L was prepared by storing Form B in a sealed vial for one month under ambient conditions. [Example] [13.] [Solid form] [M] [Preparation] []

[0153] Form M is prepared by storing form B in a sealed vial for one month under ambient conditions. [Example] [14.] [Solid form] [N] [Preparation] []

[0154] Form N is prepared by a self-reverse antisolvent addition crystallization technique in 1,4-dioxane / n-heptane in an attempt to replicate the formation of form F. [Example] [15.] [Solid form] [O] [Preparation] []

[0155] Form O was prepared by aqueous active crystallization in H2O / acetonitrile (ACN) (0.041:0.959 v / v; aw=0.6). Acetonitrile plays a crucial role in the formation of form O, and this solvent may be required to produce this form. [。] [] [Example] [16.] [By] [XRPD] [Characterizing solid form] [AO]

[0156] Throughout this study, a PANalytical Empyrean X-ray powder diffractometer with a 12-well automated sampler platform was used for analysis. The XRPD parameters used are listed in Table 8. Instrument resolution calibration was performed every 6 months, and sensitivity measurements were conducted after changing the sample platform. Silicon (Si) powder tablets were used as reference standards. [surface] [8.] [] [XRPD] [Parameters] [] [] [Parameters of Reflection Mode] X-ray wavelength Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2 / Kα1 strength ratio: 0.50 X-ray tube setup 45 kV, 40 mA Diverging slit automatic Scanning mode continued Scan range (2θ degrees) 3º to 40º Step size (2θ degrees) 0.017° Scanning speed (degrees / min) Approximately 10

[0157] Form A: Form A crystals were observed by XRPD, as shown in the figure. As shown in [1A].

[0158] Form B: Diagram [2A] shows the XRPD pattern as a B-1 series crystal. [2B] shows XRPD patterns in B-1, B-2 and B-3 series crystals.

[0159] Form C: Diagram [3A] shows the XRPD pattern as a C-series crystal.

[0160] Form D: As shown in the figure As shown in the XRPD pattern provided in [4A], form D is crystalline. XRPD analysis also indicates that after drying under ambient conditions, form D transforms into form A, as shown in the figure. [4B] is illustrated in the diagram.

[0161] Form E: Graph-based [5] The XRPD pattern obtained from the wet sample showed E-type crystallization.

[0162] Form F: Diagram [6A] shows the XRPD pattern obtained from the sample dried under vacuum, which is in the form of F-series crystals.

[0163] Form H: Diagram [7A] The XRPD pattern obtained from the wet sample shows form H-type crystals. XRPD analysis indicates that after drying under ambient conditions for 3 days, form H transforms into form A, as shown in the figure. [7B] is illustrated in the diagram.

[0164] Form I: Diagram The XRPD pattern obtained from the wet sample in [8A] shows that Form I is a crystalline form. XRPD analysis indicates that after drying under ambient conditions for 3 days, Form I transforms into Form A, as shown in the figure. [8B] is illustrated in the diagram.

[0165] Form J: Diagram [9A] The XRPD pattern obtained from the wet sample shows that form J is a crystal. XRPD analysis indicates that after drying under ambient conditions for 3 days, form J transforms into form A, as shown in the figure. [9B] illustrates this.

[0166] Form K: Diagram The XRPD pattern obtained in [10A] shows the K-series crystals.

[0167] Form L: Diagram The XRPD pattern obtained in [11A] shows form L as a crystal. After 3 days under ambient conditions, form L transforms into a mixture of forms B and M, as shown in the figure. As shown in the XRPD pattern presented in [11B].

[0168] Form M: Diagram

[12] The XRPD pattern obtained shows that the M-series has poor crystallization.

[0169] Form N: Diagram [13A] shows the XRPD pattern of the dried sample under environmental conditions, revealing N-system crystals. The XRPD pattern in [13B] shows that after overnight exposure to ambient conditions, form N transforms into form A.

[0170] Form O: Diagram The XRPD pattern obtained in [14A] shows the O-type crystal structure. [Example] [17.] [Generation Form] [A] [and format] [C] [Methods for Single Crystal Formation] []

[0171] Form A: A single crystal system suitable for structure determination is obtained by slowly cooling it from 50°C to 5°C in isopropanol.

[0172] Form C: The single crystal system suitable for structure determination was obtained by slowly cooling from 25°C to 5°C at a rate of 0.01°C / min in a cosolvent of isopropyl acetate / acetone (6:1, v / v) containing Form C seed crystals. [Example] [18.] [form] [A] [and format] [C] [Single Crystal] [X-] [Radiation data] []

[0173] X-ray intensity data for prismatic crystals of forms A (Table 9) and C (Table 10) were collected at 290(2) K using a Bruker D8 Venture diffractometer (Mo Kα radiation, λ = 0.71073 Å). The crystal structures of forms A and C were determined from the obtained data. [surface] [9.] [form] [A] [Detailed information on the crystal structure and composition of single crystals:] [] [Empirical] C25H35N3O2 [Formula] 409.56 [temperature] 100(2) K [wavelength] 0.71073 Å [Crystal system, space group] Monoclinic P21 [Unit cell size] a = 9.379(3) Å b = 9.922(3) Å c = 12.092(4) Å α = 90° β = 101.606(9)° γ = 90° [volume] 1102.2(6) Å3 [, Z , ] [Calculate density] 2, 1.234Mg / m3 [Absorption Coefficient] 0.079 mm-1 [, F , ] [(000)] 444 [Crystal Size] 0.30 × 0.20 × 0.10 mm3 [Data Collection] [θ] [scope] 2.22 - 27.56° [Restriction Index] -12 ≤ h ≤ 12 -12 ≤ k ≤ 12 -15 ≤ l ≤ 15 [Collected Reflections] [ / ] [unique] 23466 / 5060 [R(int) = 0.0670] [Completeness] 99.9% [Detailed Methods] Least square of the entire matrix for F2 [material] [ / ] [constraint] [ / ] [parameter] 5060 / 1 / 274 [right] [, F , ] [, 2 , ] [Goodness of fit] 1.071 [final] [R] [index] [[I>2σ(I)]] R1 = 0.0425 wR2 = 0.0989 [Peaks and troughs of the greatest difference] 0.309 and -0.368 e∙Å⁻³ [Absolute structural parameters] 1.5(11) [surface] [10.] [form] [C] [Detailed information on the crystal structure and composition of single crystals:] [] [Empirical] C25H35N3O2 [Formula] 409.56 [temperature] 290(2) K [wavelength] 0.71073 Å [Crystal system, space group] Rhombus P212121 [Unit cell size] a = 9.6642(8)Å b = 9.8676(8) Å c = 23.9408(19) Å α = 90º β = 90º γ=90º [volume] 2283.1(3)Å3 [, Z , ] [,] [Calculate density] 4, 1.192 mg / m3 [Absorption Coefficient] 0.076 mm-1 [, F , ] [(000)] 888 [Crystal Size] 0.28 × 0.05 × 0.03 mm3 [Data Collection] [θ] [scope] 2.71 - 27.61º [Restriction Index] -12 ≤ h ≤ 12 -12 ≤ k ≤ 12 -31 ≤ l ≤ 31 [Collected Reflections] [ / ] [unique] 33905 / 5265 [R(int) = 0.0823] [Completeness] 99.3% [Detailed Methods] Least square of the entire matrix for F2 [material] [ / ] [constraint] [ / ] [parameter] 5265 / 7 / 272 [right] [, F , ] [, 2 , ] [Goodness of fit] 1.042 [final] [R] [index] [[I>2σ(I)]] R1 = 0.0647 wR2 = 0.1128 [Peaks and troughs of the greatest difference] 0.248 and -0.335 e∙Å⁻³ [Absolute structural parameters] 0.0(19) [Example] [19.] [form] [A] [and format] [C] [The unit cell of a single-crystal structure] []

[0174] Form A is shown in the figure along the b-axis as a unit cell. [1B] In the figure. Form C is drawn along the b-axis in unit cell. [3B] in. [Example] [20.] [Using temperature-dependent instrumental methods] (TGA) [、] [DSC] [and] [VT-XRPD] [Characterizing solid form] [AO]

[0175] Thermogravimetric analysis (TGA) data were collected using a TA Q500 / Q5000 TGA from TA Instruments, and differential scanning calorimetry (DSC) was performed using a TA Q200 / Q2000 DSC from TA Instruments. Instrument parameters are provided in Table 11. [surface] [11. TGA] [and] [DSC] [Test Parameters] [parameter] [TGA] [DSC] method slope slope Sample tray Platinum, Open Aluminum, rolled edge temperature RT to 350℃ RT to 300℃ heating rate 10℃ / min 10℃ / min purge gas N2 N2

[0176] To supplement the temperature-dependent study and confirm the dissolution state in solid form, solution NMR was collected using dimethyl sulfoxide (DMSO-d6) as a solvent on a Bruker 400 MHz NMR spectrometer.

[0177] Form A: Thermogravimetric analysis (TGA) and DSC were performed, and details are provided in Figure 1C. Thermogravimetric analysis of Form A resulted in a 1.0% weight loss at a maximum temperature of 200°C. The endothermic reaction observed on the DSC curve at 157.2°C (starting temperature) represents the transformation of Form A to Form K, followed by a sharp melting peak for Form K at 203.8°C (starting temperature). Verification of the transformation to Form K was performed using VT-XRPD, as shown in Figure 1C. As shown in [1D].

[0178] Form B-1: Implement TGA and DSC, and their respective curves are provided in the figure. [2C] In the figure. The TGA curve shows a two-stage weight loss, with a 5.7% loss of residual solvent at a maximum of 76°C, followed by an 8.5% loss (desolventization) at a maximum of 200°C. The DSC curve shows two endothermic peaks at 87.2°C and 211.7°C (starting temperature), corresponding to solvent loss (conversion to form K) and the melting point of form K, respectively. XPRD analysis indicates that form B-1 is converted to form K upon heating to 100°C, as shown in the figure. As shown in [2D]. Based on the graph. The 1H NMR data shown in [2G] indicates that form B is a n-heptane solvate, and the molar ratio of compound 1 to n-heptane (approximately 8.9 wt% n-heptane) is 1:0.4, which is in excellent agreement with the TGA results. Residual DCM was also observed in the 1H NMR data, with a molar ratio of compound 1 to DCM (1.2 wt%) of 1:0.06.

[0179] Form B-2: The TGA curve of this isomorphic shape is displayed together with the TGA curves of the other two isomorphic shapes in the figure. In [2E], the DSC curve of this homomorphic object is plotted together with the superposition of two other homomorphic objects in the figure. In [2F], it exhibits two endothermic events, one starting at T 85.4℃ and the other starting at T 212.2℃. (Figure) The 1H NMR spectrum of [2H] shows that form B is a solvate of n-heptane, the molar ratio of compound 1 to n-heptane is 1:0.3, and no THF was observed.

[0180] Form B-3: The TGA curve of this isomorphic shape is displayed together with the TGA curves of the other two isomorphic shapes in the figure. In [2E], the DSC curve of this homomorphic object is plotted together with the superposition of two other homomorphic objects in the figure. In [2F], it exhibits two endothermic events, one starting at T 69.2℃ and the other at T 211.6℃. (Figure) The 1H NMR spectrum in [2I] shows that form B is a chloroform solvate, the molar ratio of compound 1 to chloroform is 1:0.5, and residual methyl tributyl ether was detected.

[0181] Form C: Implementing TGA and DSC, with their respective curves provided in the figure. [3C] The TGA curve shows a 4.3% weight loss below 50°C, indicating possible loose solvent or amorphous solvent remaining due to insufficient drying. The DSC curve shows two endothermic peaks at 183.8°C and 211.0°C (starting temperature). Further investigation was conducted on the endothermic reaction at 183.8°C by heating form C to 185°C, which resulted in a transformation of form C to form K, as shown in the figure. As shown in [3D]. Form C was analyzed by VT-XRPD in the presence and absence of nitrogen (N2) flow to investigate possible air rehydration. (Figure) As shown in [3E], no difference was observed in the presence or absence of N2, indicating that form C is anhydrous.

[0182] Form F: Implementing TGA and DSC, with their respective curves provided in the figure. [6B] The TGA curve shows a total weight loss of 19.7% at a maximum temperature of 200°C. The DSC curve shows two endothermic peaks at 63.1°C and 210.7°C (starting temperature), corresponding to solvent loss (conversion to form K) and the melting point of form K, respectively. This is further confirmed by the conversion of form F to form K after heating to 100°C, as shown in the figure. As shown in [6C]. Based on the diagram. The 1H NMR spectrum shown in [6D] is in the form of an F-series 1,4-dioxane solvate with a molar ratio of 1:0.9 (16.2 wt% 1,4-dioxane), which is in excellent agreement with the TGA results. Residual n-heptane was also observed in the 1H NMR data with a molar ratio of 1:0.03 (0.7 wt% n-heptane).

[0183] Form K: Implements TGA and DSC, and their respective curves are provided in the figure. [10B] In this study, the TGA curve shows a weight loss of 1.6% at a maximum temperature of 200°C, and the DSC curve shows an endothermic peak at 211.6°C (starting temperature), corresponding to the melting endothermic reaction of form K. Based on its low volatile contents, form K is an unsolvated material.

[0184] Form L: shown in the figure The DSC curve for form L in [11C] shows two endothermic peaks at 81.7 °C and 210.6 °C (starting temperature). The first endothermic peak is attributed to possible solvent loss or form transformation. The second endothermic peak in the DSC curve matches the melting endothermic effect of form K.

[0185] Form N: Diagram The TGA curve in [13C] shows a two-step weight loss: 2.5% at a maximum of 60°C, followed by 7.1% at a maximum of 200°C. The DSC curve shows two endothermic peaks at 75.4°C and 210.4°C (starting temperature), attributed to solvent loss (based on 1H NMR) and the melting point of form K, respectively. Based on the figure... [13D] 1H NMR results, in the form of N-series 1,4-dioxane solvate, the molar ratio of compound 1:1,4-dioxane (6.1 wt% 1,4-dioxane) is 1:0.3, which is consistent with the second step weight loss in TGA analysis.

[0186] Form O: In the diagram A two-step weight loss was observed in the TGA curve presented in [14B]: 5.3% at a maximum of 55.1°C, followed by 5.9% at a maximum of 200°C. The DSC curve showed three endothermic peaks at 65.0°C, 168.5°C, and 210.8°C (starting temperature), corresponding to solvent loss to form C, the conversion of form C to form K, and the melting point of form K, respectively. To investigate the endothermic effect observed in the DSC analysis, form O was heated to 120°C, resulting in its conversion to form C, as shown in the figure. As shown in [14C]. ¹H NMR spectroscopy reveals that after heating to 50 °C to remove residual solvent, the molar ratio of form O:ACN (1.9 wt%) is 1:0.2, as shown in Figure [14C]. [14D] is illustrated in the diagram. [Example] [twenty one.] [As a means] [DVS] [The form measured] [A] [、] [C] [and] [K] [Hygroscopicity] []

[0187] Dynamic vapor adsorption (DVS) was measured using the SMS (Surface Measurement System) and DVS intrinsic system. Relative humidity at 25°C was calibrated for the deliquescence points of LiCl, Mg(NO3)2, and KCl. The instrument parameters of the DVS system used throughout this study are listed in Table 12. [surface] [13. DVS] [Test Parameters] [] [parameter] [DVS] [temperature] 25℃ [Sample size] 10 to 20 mg [Gas and Flow Rate] N2, 200 mL / min [dm / dt] 0.002% / min [Minimum] [dm / dt] [Stability Duration] 10 min [Maximum Equilibrium Time] 180 min [RH] [scope] 0%RH to 95%RH [RH] [Step length] [(] [Adsorption] [)] 10%RH from 0%RH to 90%RH 5%RH from 90%RH to 95%RH [RH] [Step length] [(] [Detoxification] [)] 10%RH from 90%RH to 0%RH 5%RH from 95%RH to 90%RH

[0188] The hygroscopicity of forms A, C, and K was investigated using DVS at 25°C. XRPD patterns of each sample before and after DVS were compared to investigate changes in any potential form.

[0189] picture The DVS isotherm plot of form A shown in [1E] shows a water uptake of 0.06% by weight at 80% RH and less than 0.12% by weight at 95% RH, revealing that form A is non-hygroscopic. The XRPD pattern in [1F] indicates that form A has no form change before and after DVS.

[0190] Similarly, the diagram The DVS isotherm plot of form C shown in [3F] shows 0.12% wt% water uptake at 80% RH and less than 0.30% wt% water uptake at 95% RH, indicating that form C is non-hygroscopic. The XRPD pattern in [3G] shows no change in form C before and after DVS.

[0191] picture The DVS isotherm plot of form K shown in [10C] shows a water uptake of 0.18 wt% at 80% RH and less than 0.35 wt% at 95% RH, revealing that form K is non-hygroscopic. The XRPD pattern in [10D] shows no change in form K before and after DVS. [Example] [twenty two.] [form] [A] [、] [C] [and] [K] [Through slurry transformation and interconversion] []

[0192] In one embodiment, the interconversion between forms A, C, and K was investigated in a series of slurry conversion experiments conducted in ethyl acetate, n-butanol, and methyl tributyl ether (MBTE) at both room temperature (RT) and 50°C. Compound 1 exhibited moderate solubility and produced a solvated form during these screening experiments. The results of the slurry conversion experiments are summarized in Table 14. The transition temperature between forms A and C was estimated to be about 17°C, and the transition temperature between forms K and C was above 100°C. [surface] [14.] [] [Overview of the slurry conversion experiment] [] [solvent] [condition] [Initial Form] [Final Form] Ethyl acetate RT Forms A and K (containing form C seed crystals) Form C 50℃ Forms A and K Form C n-Butanol RT Forms A, C, and K Form C 50℃ Forms A, C, and K Form C MBTE RT Forms A, C, and K Form C 50℃ Forms A, C, and K Form C [Example] [twenty three.] [form] [A] [Using form] [C] [Seed crystal transforms into form] [C]

[0193] Compound 1 (initial form A) was soluble in ethyl acetate at a concentration of about 200 g / L to 225 g / L in the presence of 0.2%–1.0% seed crystals of form C. The solution was then heated to 65°C and held for 1–3 hours. The batch was then slowly cooled to a temperature between 25°C and 30°C over a period of less than 3 hours to obtain form C. Seed crystals of form C can be obtained using the procedure described in Example 4.

[0194] XRPD was performed using a Rigaku MiniFlex 600 (Cu Kα radiation at 40 kV tube voltage and 15 mA tube current) with a 2θ scan range of 2° to 40°, a step size of 0.01°, and a scan rate of 1° or 2° / min. The conversion of seed crystals of form A to form C from 225 g / L in ethyl acetate at 65°C using 1.0% form C seed crystals over time was monitored using XRPD, as shown in the figure. As indicated in

[15] . [Example] [twenty four.] [form] [P] [Preparation and Characterization] []

[0195] During solubility measurements, XRPD patterns were detected in the following substances: (a) a slurry of form A in EtOAc at 5 °C (after 1 h) and 20 °C (after 2 days), and (b) a slurry of form C in EtOAc at 5 °C (after 1 h) and 20 °C (after 7 days). The XRPD pattern of this solid form did not directly match other crystal forms of compound 1. The results indicate that, at least at ≤ 20 °C, this solid form of compound 1 in EtOAc (referred to as form P) is more stable than both forms A and C in EtOAc.

[0196] The wet cake of form P was dried in two ways (approximately 5 min in air): (a) overnight in air and at room temperature, and (b) for 3 hours under vacuum and at 40°C. The two dried cakes were analyzed by XRPD, 1H-NMR, and TGA. XRPD data are presented in the figure.

[16] NMR data are presented in Figure 16. [17A] [and] diagram [17B] In. TGA data is presented in the figure. [18A] Figure and [18B] In this study, the XRPD pattern of the air-dried cake conformed to form P, with approximately 1% weight loss by TGA at a maximum of about 50°C, and an EtOAc peak by 1H NMR. This indicates that form P is an EtOAc solvate of compound 1. On the other hand, the XRPD pattern of the sample of form P after oven drying conformed to form A, with no weight loss by TGA at ≤100°C, and no EtOAc peak by 1H-NMR. Therefore, the data indicate that form P is a solvate of form A and is converted to form A after drying. [Example] [25.] [form] [A] [、] [C] [and] [P] [Solubility and relative stability] []

[0197] The solubility profiles of forms A, C, and P across the temperature range indicate the relative stability of different forms within different temperature ranges. Sufficient equilibrium solubility data were collected from experiments covering 5–70 °C. The results are presented in Table 12 and Figure 12.

[19]

[0198] The data indicate that (1) form C is more stable than form A across the entire processing temperature range; (2) at ≤20°C, form P becomes more stable than form C; (3) at approximately 25 to 30°C, there is very little interconversion between the three forms due to slow conversion kinetics; (4) form P becomes unstable in EtOAc at ≥35°C and converts to form A; and (5) after drying in air or N2, form P converts to form A.

[0199] The phase relationships of forms A, C, and P in EtOAc are illustrated in the figure.

[20] In EtOAc and at low temperatures, forms A and C can be converted to form P. Form A can also be generated from form C at very low temperatures (e.g., for better separation yield). [surface] [12.] [form] [A] [、] [C] [and] [P] [Solubility data] [.] [Other Embodiments] []

[0200] In the claims, unless the context clearly indicates the opposite meaning or otherwise, the articles such as "a," "an," and "the" may refer to one or more. Unless the context clearly indicates the opposite meaning or otherwise, claims or descriptions including "or" among one or more members of a group are considered to satisfy the condition that one, more than one, or all group members are present, used in, or otherwise associated with the given product or method. This invention includes embodiments in which exactly one member of the group is present, used in, or otherwise associated with the given product or method. This invention also includes embodiments in which more than one or all group members are present, used in, or otherwise associated with the given product or method.

[0201] Furthermore, this invention covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim belonging to another claim may be modified to include one or more limitations found in any other claim belonging to the same basic claim. If elements are presented in a list format, such as in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, generally, if an invention or a form of invention is referred to as comprising certain elements and / or features, then certain embodiments of the invention or a form of invention consist of or substantially consist of such elements and / or features. For simplicity, such embodiments are not explicitly stated herein by reference. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of other elements or steps. Where a scope is given, the endpoint is included. Furthermore, unless the context and understanding of a person skilled in the art indicate otherwise or have other explicit meaning, values ​​expressed as ranges in different embodiments of the invention may be assumed to be any specific value or subrange within the stated range, up to one-tenth of the unit of the lower limit of the range, unless the context explicitly indicates otherwise.

[0202] This application relates to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of the invention falling within the prior art may be expressly excluded from any one or more claims. Such embodiments are considered to be known to those skilled in the art, and therefore may be excluded even if such exclusion is not expressly stated herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0203] Those skilled in the art will recognize or be able to identify various equivalent forms of the specific embodiments described herein using only conventional experiments. The scope of the embodiments described herein is not intended to be limited to the foregoing description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A crystalline solid form of compound 1, wherein the solid form is characterized by substantially having an XRPD pattern as shown in FIG3A.

2. The crystalline solid form of claim 1, wherein the solid form is further characterized by having an endothermic start temperature of about 183.8°C and an endothermic start temperature of about 211.0°C, as determined by differential scanning calorimetry.

3. The crystalline solid form as claimed in claim 2, wherein the solid form is further characterized by being substantially a differential scanning calorimeter as shown in FIG3C.

4. The crystalline solid form of claim 1, wherein the solid form is further characterized by a weight gain of 0.12% by water uptake at 80% relative humidity and a weight gain of less than 0.30% by water uptake at 95% relative humidity, as determined by dynamic vapor adsorption at 25°C.

5. The crystalline solid form as claimed in claim 4, wherein the solid form is further characterized by a dynamic vapor adsorption diagram substantially as shown in Figure 3F at 25°C.

6. The crystalline solid form of claim 1, wherein the solid form is further characterized by an orthorhombic space group P212121, a unit cell volume of about 2283.1(3) Å3 and the following unit cell dimensions as determined by single-crystal X-ray diffraction: .

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