MGLUR5 modulating compounds, compositions and methods of use

Abstract

The present disclosure provides compositions of (4R, 5R)-5-(2-chlorphenyl)-4-(5-(phenylethynyl) pyridin-3-yl) oxazolidin-2-one (Compound 1). Crystalline forms and solvate forms of the compounds and formulations comprising the compounds are also provided. Methods of using the compounds and methods of administering the formulations to subjects in need thereof are provided to treat or prevent CNS disorders, such as Alzheimer's disease.

Description

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant U01 AG058608 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0003] Glutamate is the main excitatory neurotransmitter in the brain and is involved in various mental and medical conditions. Glutamate regulates central nervous system function through the action of ion channel receptors and metabotropic receptors. Three groups of metabotropic (mGlu) receptors change neuronal activity through G-protein coupled signaling. In particular, the first group of receptors, mGluR5 receptors, play an important role in mental health and various central nervous system (CNS) disorders. Several mGluR5 antagonists have been designed, such as 3-[2-methyl-1,3-thiazol-4-yl]ethynyl]pyridine (MTEP), acamprosate, memantine, AFQ056 and fenobam. The allosteric modulators of mGluR5 can be divided into positive allosteric modulators (PAM), negative allosteric modulators (NAM) and silent allosteric modulators (SAM).

[0004] There remains a need for compounds and compositions that modulate mGluR5 to improve mental health and treat CNS disorders. Summary of the invention

[0005] In one aspect of the present disclosure, a pharmaceutical composition is provided, comprising (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one In some embodiments, the pharmaceutical composition comprises Compound 1, lactose monohydrate, croscarmellose sodium, and / or magnesium stearate.

[0006] Another aspect of the present disclosure provides a method of treating a CNS disorder by administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the CNS disorder is Alzheimer's disease. In some embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is used to prevent epileptic seizures, reverse synaptic loss, or reduce Tau accumulation in a subject in need thereof.

[0007] The present disclosure also provides a crystalline form of Compound 1, such as an anhydrous crystalline form. The present disclosure also provides a solvate of Compound 1, such as an isopropyl solvate.

[0008] In one aspect, the invention features an anhydrous (AH) crystalline form of Compound 1 (Form A) having an XRPD pattern comprising 2θ angular peaks at 9.02, 11.65, and 11.86 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern also includes 2θ angular peaks at 12.15, 14.99, 28.99, and 44.03 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern also includes three 2θ angular peaks at 21.09, 21.49, and 21.88 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern further comprises 2θ angular peaks at 9.02, 11.65, 11.86, 12.15, 14.99, 21.09, 21.49, 21.88, 28.99, and 44.03 degrees 2θ as measured by X-ray diffraction by irradiation with Cu Ka X-rays. In some embodiments, the XRPD pattern is substantially as follows Figure 3 as shown in .

[0009] In some embodiments, Form AH has a melting endotherm peak at about 134°C-138°C in a differential scanning calorimetry (DSC) thermogram. In some embodiments, Form AH has substantially Figure 4 In some embodiments, Form AH has a thermogravimetric analysis (TGA) weight loss of about 0.02% (w / w) between ambient temperature and about 250° C. In some embodiments, Form AH has substantially Figure 4 TGA of the TGA pattern shown in . In some embodiments, Form AH is substantially purified.

[0010] In one aspect, the invention features a method for preparing an anhydrous (AH) crystalline form (Form A) of compound 1, comprising precipitating an anhydrous crystalline form from a solution comprising compound 1 and a solvent selected from ethyl acetate (EtOAc), heptane, and a mixture thereof. In some embodiments, the solvent is a mixture of EtOAc and heptane. In some embodiments, the ratio of EtOAc to heptane is 90: 10, 80: 20, 70: 30, 60: 40, 50: 50, 40: 60, 30: 70, 20: 80, or 10: 90. In some embodiments, the method further comprises cooling the solution. In some embodiments, the method further comprises isolating the AH crystalline form by filtration.

[0011] In one aspect, the invention features a solvate form of Compound 1 (Form B) having an XRPD pattern comprising at least three of the following 2θ angular peaks at 16.07, 16.27, 16.58, and 16.77 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern also includes three or more of the following 2θ angular peaks at 13.18, 13.4, 13.54, 13.54, and 13.70 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern also includes 2θ angular peaks at 37.31 and 39.92 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Kα X-rays. In some embodiments, the XRPD pattern includes 2θ angular peaks at 13.18, 13.4, 13.54, 13.54, 13.70, 16.07, 16.27, 16.58, 16.77, 37.31, and 39.92 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays. In some embodiments, the solvate Form B has substantially Figure 5 The XRPD pattern shown in .

[0012] In some embodiments, the solvate Form B has a melting endotherm peak at about 134°C-138°C in a differential scanning calorimetry (DSC) thermogram. In some embodiments, the solvate Form B has substantially Figure 6 In some embodiments, the solvate Form B has a thermogravimetric analysis (TGA) weight loss of about 6.7% (w / w) between ambient temperature and about 200° C. In some embodiments, the solvate Form B has substantially Figure 6 In some embodiments, the solvate form B is an isopropanol solvate. In some embodiments, the solvate form B is substantially purified.

[0013] In one aspect, the invention features a method for preparing a solvate Form B of Compound 1, comprising evaporating a mixture of Compound 1 and isopropanol in a drying oven under an inert atmosphere. In some embodiments, the evaporation is performed over a period of 1-2 weeks. In some embodiments, the method further comprises drying the solvate Form B under vacuum.

[0014] In one aspect, the invention features a solvate form of Compound 1 (Form C) having an XRPD pattern comprising only two peaks between 13.32 and 13.82 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Ka X-rays. In some embodiments, the XRPD pattern also includes only three peaks between 2θ angles at 32.22 and 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ), or includes 2θ angle peaks at 3.4, 8.33, 10.94, 16.32, and 16.66 degrees 2θ (each ± ​​0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Ka X-rays. In some embodiments, the XRPD pattern comprises 2θ angular peaks at 3.4, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 32.22, 32.59, 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays. In some embodiments, the solvate Form C has substantially Figure 7 In some embodiments, the solvate form C has an XRPD pattern substantially as shown in Fig. 9 The XRPD pattern shown in .

[0015] In some embodiments, the solvate Form C has a melting endotherm peak at about 129-133° C. in a differential scanning calorimetry (DSC) thermogram. In some embodiments, the solvate Form C has substantially Figure 8 In some embodiments, the solvate Form C has a thermogravimetric analysis (TGA) weight loss of about 3.4% (w / w) between ambient temperature and about 200° C. In some embodiments, the solvate Form C has substantially Figure 8 In some embodiments, Form C is an isopropanol solvate. In some embodiments, Form C is substantially purified.

[0016] In one aspect, the invention features a method of preparing a solvate Form C of Compound 1 using a long-term slurry. In some embodiments, the method further comprises precipitating the solvate form from a solution comprising Compound 1 and isopropanol. In some embodiments, the method further comprises stirring the solution at 20° C. for two weeks. In some embodiments, the method further comprises isolating the solvate Form C by filtration.

[0017] In some embodiments, the solvate Form C has endothermic peaks at about 89.4° C. and at about 134.2° C. in a differential scanning calorimetry (DSC) thermogram. In some embodiments, the solvate Form C has substantially Fig.10 In some embodiments, the solvate Form C has a thermogravimetric analysis (TGA) weight loss of about 3.2% (w / w) between ambient temperature and about 200° C. In some embodiments, the solvate Form C has substantially Fig.10 TGA of the TGA graph shown in .

[0018] In one aspect, the invention features a method of preparing a solvate Form C of Compound 1 using vapor diffusion. In some embodiments, the method further comprises:

[0019] (i) dissolving compound 1 in isopropanol to form a saturated solution;

[0020] (ii) filtering the mixture of step (i) into a vial, which is placed in an outer vial containing an anti-solvent;

[0021] (iii) stirring the inner vial mixture of step (ii) to precipitate solids; and

[0022] (iv) filtering the solid from step (iii) and drying the solid under vacuum at room temperature.

[0023] In some embodiments, the anti-solvent is pentane.

[0024] In some embodiments, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a crystalline form or solvate form of the present invention. In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 30% (w / w) of the crystalline form or solvate form of the present invention. In some embodiments, the pharmaceutical composition comprises about 5% (w / w), 10% (w / w), 24% (w / w) or about 25% (w / w) of the crystalline form or solvate form of the present invention. In some embodiments, the pharmaceutical composition of the present invention is a nanosuspension or a spray-dried nanosuspension. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable plasticizer, a binder, an extender, a carrier, an excipient, a lubricant, a disintegrant and / or a surfactant. In some embodiments, the pharmaceutical composition further comprises at least one of hydroxypropyl methylcellulose, sodium lauryl sulfate and lactose monohydrate. In some embodiments, the pharmaceutical composition further comprises at least one of cross-linked carboxymethyl cellulose and magnesium stearate. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the capsule is selected from a hard hydroxypropyl methylcellulose capsule, a hard gelatin capsule or a soft gelatin capsule. In some embodiments, the pharmaceutical compositions of the present invention comprise the components in the following table:

[0025]

[0026]

[0027] Provided that the amounts of binder, surfactant, carrier, disintegrant and lubricant are not all 0%. In some embodiments, the binder is hydroxypropyl methylcellulose, the surfactant is sodium lauryl sulfate, the carrier and binder are lactose monohydrate, the disintegrant is cross-linked carboxymethyl cellulose, and the lubricant is magnesium stearate.

[0028] In some embodiments, the pharmaceutical composition comprises a nanosuspension of Compound 1 (e.g., Form A, Form B, or Form C) having an x90 < 400 μm (as measured by PSD), e.g., an x90 of about 300, an x50 of about 135, and / or an x10 of 70. In some embodiments, the pharmaceutical composition comprises particles comprising a carrier (e.g., lactose) onto which a nanosuspension of Compound 1 (e.g., Form A, Form B, or Form C) is sprayed, e.g., in combination with a bulking agent (e.g., lactose).

[0029] In one aspect, the invention features a method of treating Alzheimer's disease, preventing seizures, reversing synaptic loss, or reducing Tau accumulation in a subject in need thereof, comprising treating the subject with a therapeutically effective amount of Form A, Form B, or Form C of compound 1. In some embodiments, about 10 mg, 40 mg, 70 mg, 100 mg, 150 mg, or 200 mg of compound 1 is administered. In some embodiments, compound 1 is administered orally. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The foregoing and other objects, features and advantages will become apparent from the following description of specific embodiments of the present disclosure, as illustrated in the accompanying drawings, in which like reference numerals refer to the same parts throughout the different views. The drawings are not necessarily drawn to scale, emphasis instead being placed upon illustrating the principles of the various embodiments of the present disclosure.

[0031] Figure 1 Compound 1 is shown to replace [ 18 F]Dose response of FPEB.

[0032] Figure 2 Compound 1 treatment is shown to prevent PAM-induced seizures.

[0033] Figure 3 XRPD data for Compound 1AH Form A is shown.

[0034] Figure 4 Shown are TGA / DSC data for Compound 1AH Form A. The TGA showed a decomposition event occurring above 250° C. The DSC trace showed a single endothermic event starting at 135.1° C. with a peak at 136.5° C. due to melting of the crystalline material.

[0035] Figure 5 XRPD data for Compound 1 Form B is shown.

[0036] Figure 6 TGA / DSC data for Compound 1 Form B are shown. The TGA shows a desolvation event occurring up to about 200° C. The DSC trace shows an endothermic event, the first onset at about 83.4° C. with a peak at 90.3° C. due to desolvation, and the second onset at 133.8° C. with a peak at 136.0° C. due to melting of the crystalline material.

[0037] Figure 7 Shown are XRPD data for Compound 1 Form C prepared from a long-term slurry using isopropanol.

[0038] Figure 8TGA / DSC data for Compound 1 Form C prepared from a long-term slurry using isopropanol are shown. The TGA shows a desolvation event occurring up to about 200° C. The DSC trace shows a first endothermic event starting at 86.1° C. with a peak at 89.1° C. due to desolvation and a second endothermic event starting at 129.1° C. with a peak at 131.7° C. due to melting of the crystalline material.

[0039] Fig. 9 Shown are XRPD data for Compound 1 Form C prepared from vapor diffusion using isopropanol.

[0040] Fig.10 TGA / DSC data for Compound 1 Form C prepared from vapor diffusion using isopropanol are shown. The TGA shows a desolvation event occurring up to about 200° C. The DSC trace shows a first endothermic event starting at 78.7.1° C. with a peak at 89.4° C. and a second endothermic event starting at 132.7° C. with a peak at 134.2° C. DETAILED DESCRIPTION

[0041] The present disclosure provides compounds and compositions and methods for using the compounds and compositions to regulate mGluR5 receptors. The mGluR5 receptor is widely expressed throughout the CNS, primarily localized postsynaptically, but also presynaptically expressed. It is a Gαq-coupled receptor that activates phospholipase C and increases intracellular calcium levels, thereby activating downstream signaling molecules. Many studies have confirmed the role of this receptor in regulating N-methyl-D-aspartate (NMDA) receptor activity and synaptic plasticity, indicating that this receptor plays a key role in glutamatergic signal transduction.

[0042] The compounds disclosed herein are combined with mGluR5 and are allosteric modulators of mGluR5. In some embodiments, the compounds are mGluR5 silent allosteric modulators. Therefore, the compounds and compositions described herein can be used to regulate mGluR5 and treat individual subjects suffering from diseases, disorders and / or conditions (such as but not limited to CNS disorders) associated with mGluR5.

[0043] I. Compounds of the Disclosure

[0044] The compound disclosed herein is (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one or a pharmaceutically acceptable salt thereof, as described in U.S. Patent No. 8,691,821, hereby incorporated by reference.

[0045] The compounds of the present disclosure can be prepared using any convenient method known to those skilled in the art, such as the method disclosed in US Pat. No. 8,691,821.

[0046] Solid form of compound 1

[0047] Solids exist in amorphous or crystalline forms. Polymorphism refers to the various crystalline forms of a chemical substance. These solid forms and crystalline forms have different characteristics in structure and physical properties such as XRPD spectra, IR spectra and melting points. A specific solid form or polymorph form may have advantages over other forms and may be more suitable for the manufacture and use of a drug substance.

[0048] An anhydrous (AH) form (Form A), two solvated forms (solvates S1 and S2, interchangeably referred to as Form B and Form C, respectively), and multiple amorphous forms of Compound 1 have been found. The amorphous forms produce gels upon evaporation in various solvent systems. Anhydrous Form A is the most stable form, for example, as determined by DSC and TGA analysis.

[0049] AH Form A can be identified by single crystal X-ray powder diffraction (XRPD) irradiated with Cu Kα X-rays. The major peaks of Form A were identified and their relative intensities are listed in Table 1. As will be appreciated by those skilled in the art, the relative intensities of the peaks in Table 1 may vary due to various factors, such as the purity of the material being analyzed, the orientation effects of the crystal in the X-ray beam, the crystallinity of the sample, etc. The peak positions may also shift due to changes in sample height, but the peak positions will remain essentially as defined in Table 1. It will also be appreciated by those skilled in the art that, according to the Bragg equation (nλ=2d sinθ), measurements using different wavelengths will result in different shifts. Such other XRPD patterns generated using alternative wavelengths are alternative representations of the XRPD patterns of crystalline materials.

[0050] Table 1. XRPD peak list of Form A

[0051]

[0052]

[0053]

[0054] Form A can be characterized by any of the peaks in Table 1. For example, Form A can be characterized by any of the following peaks, including: 6.75, 6.88, 9.02, 11.65, 11.86, 12.15, 13.55, 14.99, 15.59, 17.55, 17.97, 18.45, 18.93, 19.46, 20.34, 21.09, 21.49, 21.88, 22.29, 22.75, 23.59, 24.24, 24.54, 25.08, 25.63, 26.14, 26.44, 26. 40.99, 41.68, 42.32, or 43.03 degrees 2θ, each with ±0.2 degrees 2θ. Form A may also be characterized by any of the following d-spacings, including: 13.08, 12.84, 9.80, 7.59, 7.46, 7.28, 6.53, 5.90, 5.68, 5.05, 4.93, 4.81, 4.69, 4.56, 4.36, 4.21, 4.13, 4.06, 3.99, 3.91, 3.77, 3.67, 3.63, 3.55, 3.47 , 3.41, 3.37, 3.32, 3.29, 3.24, 3.19, 3.14, 3.08, 3.03, 2.99, 2.95, 2.92, 2.89, 2.87, 2.82, 2.77, 2.73, 2.70, 2.69, 2.62, 2.57, 2.51, 2.45, 2.37, 2.33, 2.31, 2.23, 2.20, 2.17, 2.13, each Form A can also be prepared by substantially Figure 3 The XRPD patterns shown in .

[0055] In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has a molecular weight comprising 6.75, 6.88, 9.02, 11.65, 11.86, 12.15, 13.55, 14.99, 15.59, 17.55, 17.97, 18.45, 18.93, 19.46, 20.34, 21.09, 21.49, 21.88, 22.29, 22.75, 23.59, 24.24, 24.54, 25.08, 25.63, 26.14, 26.44, 26.81, 27.12, 2Θ (±0.2 degrees 2Θ for each).

[0056] In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has a molecular weight comprising 6.75, 6.88, 9.02, 11.65, 11.86, 12.15, 13.55, 14.99, 15.59, 17.55, 17.97, 18.45, 18.93, 19.46, 20.34, 21.09, 21.49, 21.88, 22.29, 22.75, 23.59, 24.24, 24.54, 25.08, 25.63, 26.14, 26.44, 26.81, 27.1 2Θ (± 0.2 degrees 2Θ each).

[0057] In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has an X-ray powder diffraction (XRPD) pattern comprising 9.02, 11.65, and 11.86 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has an X-ray powder diffraction (XRPD) pattern comprising 12.15, 14.99, 28.99, and 44.03 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has an X-ray powder diffraction (XRPD) pattern comprising 21.09, 21.49, and 21.88 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the anhydrous crystalline form of Compound 1 is Form A and has an X-ray powder diffraction (XRPD) pattern comprising 9.02, 11.65, 11.86, 12.15, 14.99, 21.09, 21.49, 21.88, 28.99, and 44.03 degrees 2θ (each ± ​​0.2 degrees 2θ).

[0058] In some embodiments, Form A exhibits a melting endotherm at about 134° C. to 138° C. as analyzed by differential scanning calorimetry (DSC) thermogram, such as Figure 4 as shown in .

[0059] In some embodiments, Form A exhibits dehydration from ambient temperature to about 250° C. with a weight loss of about 0.02% (w / w) as analyzed by thermogravimetric analysis (TGA), such as Figure 4 as shown in .

[0060] Some embodiments provide a method for preparing an anhydrous (AH) crystalline form of compound 1, comprising precipitating an anhydrous crystalline form from a solution comprising compound 1 and a solvent selected from ethyl acetate (EtOAc), heptane, and a mixture thereof. In some embodiments, the solvent may be a mixture of EtOAc and heptane. The ratio of EtOAc to heptane is 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, or 10:90. The method may also include cooling the solution and / or isolating the AH crystalline form by filtration.

[0061] Form B can be identified by single crystal X-ray powder diffraction (XRPD) irradiated with Cu Kα X-rays. The major peaks of Form B are identified and their relative intensities are listed in Table 2. As will be appreciated by those skilled in the art, the relative intensities of the peaks in Table 2 may vary due to various factors, such as the purity of the material being analyzed, the orientation effects of the crystal in the X-ray beam, the crystallinity of the sample, etc. The peak positions may also shift due to changes in sample height, but the peak positions will remain essentially as defined in Table 2. It will also be appreciated by those skilled in the art that, according to the Bragg equation (nλ=2d sinθ), measurements using different wavelengths will result in different shifts. Such other XRPD patterns generated using alternative wavelengths are alternative representations of the XRPD patterns of crystalline materials.

[0062] Table 2. XRPD Peak Listing of Form B

[0063]

[0064]

[0065]

[0066]

[0067] Form B can be characterized by any of the peaks in Table 2. For example, Form B can be characterized by any of the following peaks, including: 3.36, 6.75, 6.85, 8.19, 10.14, 10.84, 13.18, 13.4, 13.54, 13.7, 15.65, 16.07, 16.27, 16.58, 16.77, 17.15, 17.74, 18.63, 18.73, 19.16, 19.44, 19.63, 19.95, 20.21, 20.36, 20.6, 21.56, 21.78, 22.42, 22.88, 23.06, 23.22, 23.43, 23.75, 23.99, 24.53, 24.88, 43.79, 44.67, 45.23, 45.43, 46.03, 46.63, 47.27, 48.83, 49.92, 50.26, 50.58, 51.37, 52.56, 53.38, 54.71, 55.11, 56.13, 57.70, 58.43, 59.81, 61.11, 62.13, 63.71, 64.11, 65.87, 66.91, 67.91, 68.61, 69.83, 70.91, 71.11, 72.13, 73.73, 74.91 Form B may also be characterized by any of the following d-spacings, including: 26.31, 13.09, 12.9, 10.79, 8.72, 8.15, 6.71, 6.6, 6.54, 6.46, 5.66, 5.51, 5.45, 5.34, 5.28, 5.17, 4.99, 4.76, 4.73, 4.63, 4.56, 4.52, 4.45, 4.39, 4.36, 4.31, 4.12, 4.08, 3.96, 3.88, 3.85, 3.83, 3.79, 3.74, 3.71 , 3.63, 3.58, 3.53, 3.5, 3.42, 3.34, 3.31, 3.27, 3.22, 3.16, 3.03, 2.98, 2.95, 2.93, 2.91, 2.87, 2.82, 2.79, 2.77, 2.75, 2.72, 2.67, 2.66, 2.62, 2.59, 2.55, 2.5, 2.48, 2.45, 2.41, 2.38, 2.35, 2.32, 2.26, 2.24, 2.22, 2.18, 2.12, 2.08 or 2.03, each Form B may also be prepared by substantially Figure 5 The XRPD patterns shown in .

[0068] In some embodiments, the solvate form of Compound 1 is Form B and has a molecular weight comprising 3.36, 6.75, 6.85, 8.19, 10.14, 10.84, 13.18, 13.4, 13.54, 13.7, 15.65, 16.07, 16.27, 16.58, 16.77, 17.15, 17.74, 18.63, 18.73, 19.16, 19.44, 19.63, 19.95, 20.21, 20.36, 20.6, 21.56, 21.78, 22.42, 22.88, 23.06, 23.22, 23.43, 23.75, 23.99, 24.53, 24.88, 25.23, 25.4 3, 26.03, 26.63, 26.89, 27.27, 27.7, 28.22, 29.44, 29.95, 30.24, 30.51, 30.71, 31.14, 31.72, 32.01, 32.27, 32.47, 32.85, 33.48, 33.62, 34.15, 34.63, 3 or 44.67 degrees 2Θ (each ± ​​0.2 degrees 2Θ).

[0069] In some embodiments, the solvate form of Compound 1 is Form B and has a molecular weight comprising 3.36, 6.75, 6.85, 8.19, 10.14, 10.84, 13.18, 13.4, 13.54, 13.7, 15.65, 16.07, 16.27, 16.58, 16.77, 17.15, 17.74, 18.63, 18.73, 19.16, 19.44, 19.63, 19.95, 20.21, 20.36, 20.6, 21.56, 21.78, 22.42, 22.88, 23.06, 23.22, 23.43, 23.75, 23.99, 24.53, 24.88, 25.23, 25. .43, 26.03, 26.63, 26.89, 27.27, 27.7, 28.22, 29.44, 29.95, 30.24, 30.51, 30.71, 31.14, 31.72, 32.01, 32.27, 32.47, 32.85, 33.48, 33.62, 34.15, 34. X-ray powder diffraction (XRPD) pattern of all peaks at 63, 35.23, 35.91, 36.16, 36.71, 37.31, 37.79, 38.2, 38.83, 39.92, 40.26, 40.58, 41.37, 42.56, 43.38 and 44.67 degrees 2Θ (each ± ​​0.2 degrees 2Θ).

[0070] In some embodiments, the solvate form of compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern including at least three of the following 2θ angle peaks at 16.07, 16.27, 16.58, and 16.77 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern including three or more of the following 2θ angle peaks at 13.18, 13.4, 13.54, 13.54, and 13.70 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern including 2θ angle peaks at 37.31 and 39.92 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of Compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern comprising 2θ angle peaks at 13.18, 13.4, 13.54, 13.54, 13.70, 16.07, 16.27, 16.58, 16.77, 37.31, and 39.92 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of Compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, six, seven, eight, or all of the following 2θ angle peaks at 15.65, 17.74, 27.7, 31.14, 37.79, 38.83, 40.23, 40.58, 41.37 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of Compound 1 is Form B and has an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, or all of the following 2θ angle peaks at 3.36, 8.19, 10.84, 43.38, and 44.67 degrees 2θ (each ±0.2 degrees 2θ).

[0071] In some embodiments, Form B exhibits a melting endotherm at about 134-138° C. as analyzed by differential scanning calorimetry (DSC) thermogram, such as Figure 6 as shown in .

[0072] In some embodiments, Form B exhibits desolvation from ambient temperature to about 200° C. with a weight loss of about 6.7% (w / w) as analyzed by thermogravimetric analysis (TGA), such as Figure 6 as shown in .

[0073] Some embodiments provide a method for preparing Form B of Compound 1, comprising evaporating a mixture of Compound 1 and isopropanol in a drying oven under an inert atmosphere, such as nitrogen. In some embodiments, the evaporation may be performed over a period of 1-2 weeks. In some embodiments, the method may further comprise drying the crystalline Form B under vacuum.

[0074] Form C prepared from a long-term slurry using isopropanol can be identified by single crystal XRPD irradiation with Cu Kα X-rays. The major peaks of Form C were identified and their relative intensities are listed in Table 3. As will be appreciated by those skilled in the art, the relative intensities of the peaks in Table 3 may vary due to various factors, such as the purity of the material being analyzed, the orientation effects of the crystals in the X-ray beam, the crystallinity of the sample, etc. The peak positions may also shift due to changes in sample height, but the peak positions will remain essentially as defined in Table 3. It will also be appreciated by those skilled in the art that, according to the Bragg equation (nλ=2d sinθ), measurements using different wavelengths will result in different shifts. Such other XRPD patterns generated using alternative wavelengths are alternative representations of the XRPD patterns of crystalline materials.

[0075] Table 3. XRPD peak list for Form C prepared from long term slurry using isopropanol

[0076]

[0077]

[0078]

[0079] Form C prepared from a long-term slurry using isopropanol can be characterized by any of its peaks in Table 3. For example, Form C can be characterized by any of the following peaks, including: 3.40, 6.83, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 16.95, 17.24, 18.76, 19.27, 19.6, 20.13, 20.31, 20.81, 21.86, 22.72, 23.15, 23.38, 23.57, 23.86 , 24.30, 24.89, 25.61, 26.24, 26.92, 27.28, 28.53, 29.51, 30.63, 31.64, 32.22, 32.59, 32.96, 33.72, 34.34, 34.8, 35.36, 36.25, 36.91, 38.24, 42.75, 43.52 or 44.99 degrees 2θ, each ±0.2 degrees 2θ. Form C prepared from a long-term slurry in isopropanol may also be characterized by any of the following d-spacings, including: 25.93, 12.92, 10.61, 8.08, 6.64, 6.4, 5.43, 5.32, 5.23, 5.14, 4.73, 4.6, 4.53, 4.41, 4.37, 4.26, 4.06, 3.91, 3.84 , 3.8, 3.77, 3.73, 3.66, 3.57, 3.48, 3.39, 3.31, 3.27, 3.13, 3.02, 2.92, 2.83, 2.78, 2.75, 2.72, 2.66, 2.61, 2.58, 2.54, 2.48, 2.43, 2.35, 2.11, 2.08 or 2.01, each Form C prepared from a long-term slurry using isopropanol can also be prepared by essentially Figure 7 The XRPD patterns shown in .

[0080] In some embodiments, the solvate form of Compound 1 is Form C prepared from a long-term slurry using isopropanol and has a 3.40, 6.83, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 16.95, 17.24, 18.76, 19.27, 19.6, 20.13, 20.31, 20.81, 21.86, 22.72, 23.15, 23.38, 23.57, 23.86, 24. 2Θ (±0.2 degrees 2Θ for each).

[0081] In some embodiments, the solvate form of Compound 1 is Form C prepared from a long-term slurry using isopropanol and has a molecular weight comprising 3.40, 6.83, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 16.95, 17.24, 18.76, 19.27, 19.6, 20.13, 20.31, 20.81, 21.86, 22.72, 23.15, 23.38, 23.57, 23.86, X-ray powder diffraction (XRPD) pattern with all peaks at 24.30, 24.89, 25.61, 26.24, 26.92, 27.28, 28.53, 29.51, 30.63, 31.64, 32.22, 32.59, 32.96, 33.72, 34.34, 34.8, 35.36, 36.25, 36.91, 38.24, 42.75, 43.52, and 44.99 degrees 2Θ (each ± ​​0.2 degrees 2Θ).

[0082] In some embodiments, the solvate form of compound 1 is Form C prepared from a long-term slurry using isopropanol and has an X-ray powder diffraction (XRPD) pattern comprising only two peaks between 13.32 and 13.82 degrees 2θ (each ± ​​0.2 degrees 2θ), for example, at 13.32 and 13.82 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of compound 1 is Form C prepared from a long-term slurry using isopropanol and has an X-ray powder diffraction (XRPD) pattern comprising only three peaks between 32.22 and 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ), for example, at 32.22, 32.59, and 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of compound 1 is Form C prepared from a long-term slurry using isopropanol and has an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.4, 8.33, 10.94, 16.32, and 16.66 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of compound 1 is Form C prepared from a long-term slurry using isopropanol and has an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.4, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 32.22, 32.59, 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ). In some embodiments, the solvate form of Compound 1 is Form C prepared from a long-term slurry using isopropanol and has an X-ray powder diffraction (XRPD) pattern comprising peaks at 16.95, 36.25, 42.75, 43.52, and 44.99 degrees 2θ (each ±0.2 degrees 2θ).

[0083] In some embodiments, Form C prepared from a long-term slurry using isopropanol exhibits a melting endotherm at about 129-133° C. as analyzed by differential scanning calorimetry (DSC) thermogram, such as Figure 8 as shown in .

[0084] In some embodiments, Form C prepared from a long-term slurry using isopropanol exhibits dehydration from ambient temperature to about 200° C. with a weight loss of about 3.4% (w / w) as analyzed by thermogravimetric analysis (TGA), such as Figure 8 as shown in .

[0085] Some embodiments provide a method for preparing Form C of Compound 1, comprising precipitating a solvate form from a solution comprising Compound 1 and isopropanol. In some embodiments, the solution may be stirred at 10-30° C. (e.g., 20° C.) for two weeks. The method may further comprise isolating the solvate by filtration.

[0086] Form C prepared from vapor diffusion using isopropanol can be identified by single crystal XRPD irradiation with Cu Kα X-rays. The major peaks of Form C were identified and their relative intensities are listed in Table 4. As will be appreciated by those skilled in the art, the relative intensities of the peaks in Table 4 may vary due to various factors, such as the purity of the material being analyzed, the orientation effects of the crystal in the X-ray beam, the crystallinity of the sample, etc. The peak positions may also shift due to changes in sample height, but the peak positions will remain essentially as defined in Table 4. It will also be appreciated by those skilled in the art that, according to the Bragg equation (nλ=2d sinθ), measurements using different wavelengths will result in different shifts. Such other XRPD patterns generated using alternative wavelengths are alternative representations of the XRPD patterns of crystalline materials.

[0087] Table 4. XRPD Peak Listing for Form C Prepared from Vapor Diffusion Using Isopropanol

[0088]

[0089]

[0090] Form C prepared using isopropanol from vapor diffusion can be characterized by any of its peaks in Table 4. For example, Form C can be characterized by any of the following peaks, including: 3.38, 6.85, 8.35, 10.95, 13.31, 13.84, 16.31, 16.65, 16.99, 17.23, 18.76, 19.33, 19.6, 20.13, 20.30, 20.80, 21.05, 21.86, 22.68, 23.13, 23. .6, 23.88, 24.3, 24.9, 25.64, 26.24, 26.88, 27.26, 28, 28.53, 29.53, 30.66, 31.64, 32.59, 32.95, 33.74, 34.78, 36.21, 36.94, 38.24, 40.17, 40.80, or 43.55 degrees 2θ, each ± ​​0.2 degrees 2θ. Form C prepared using isopropanol from vapor diffusion may also be characterized by any of the following d-spacings, including: 26.12, 12.9, 10.58, 8.07, 6.65, 6.39, 5.43, 5.32, 5.21, 5.14, 4.73, 4.59, 4.53, 4.41, 4.37, 4.27, 4.22, 4.06, 3.92, 3.84, 3.77, 3.72, 3.66, 3.57, 3.47, 3.39, 3.31, 3.27, 3.18, 3.13, 3.02, 2.91, 2.83, 2.75, 2.72, 2.65, 2.58, 2.48, 2.43, 2.35, 2.24, 2.21, or 2.08, each Form C prepared by vapor diffusion using isopropanol can also be prepared by essentially Fig. 9 The XRPD patterns shown in .

[0091] In some embodiments, the solvate form of Compound 1 is Form C prepared from vapor diffusion using isopropanol and has a % to % ratio of 3.38, 6.85, 8.35, 10.95, 13.31, 13.84, 16.31, 16.65, 16.99, 17.23, 18.76, 19.33, 19.6, 20.13, 20.30, 20.80, 21.05, 21.86, 22.68, 23.13, 23.6, 2 or 43.55 degrees 2Θ (each ± ​​0.2 degrees 2Θ).

[0092] In some embodiments, the solvate form of Compound 1 is Form C prepared from vapor diffusion using isopropanol and has a % to % ratio including 3.38, 6.85, 8.35, 10.95, 13.31, 13.84, 16.31, 16.65, 16.99, 17.23, 18.76, 19.33, 19.6, 20.13, 20.30, 20.80, 21.05, 21.86, 22.68, 23.13, 23. 6, 23.88, 24.3, 24.9, 25.64, 26.24, 26.88, 27.26, 28, 28.53, 29.53, 30.66, 31.64, 32.59, 32.95, 33.74, 34.78, 36.21, 36.94, 38.24, 40.17, 40.80, and 43.55 degrees 2Θ (each ± ​​0.2 degrees 2Θ).

[0093] In some embodiments, Form C prepared from vapor diffusion using isopropanol exhibits an endothermic peak at about 89.4° C. and a smaller endothermic peak at about 134.2° C. as analyzed by differential scanning calorimetry (DSC) thermogram, such as Fig.10 as shown in .

[0094] In some embodiments, Form C prepared from vapor diffusion using isopropanol as analyzed by thermogravimetric analysis (TGA) exhibits dehydration from ambient temperature to about 200° C. with a weight loss of about 3.2% (w / w), such as Fig.10as shown in .

[0095] Some embodiments provide a method for preparing Form C of Compound 1, comprising: (i) dissolving Compound 1 in isopropanol to form a saturated solution; (ii) filtering the mixture of step (i) into a new vial, which is placed in an outer vial containing an anti-solvent; (iii) stirring the inner vial mixture of step (ii) to precipitate a solid; and (iv) filtering the solid of step (iii) and drying the solid under vacuum at room temperature.

[0096] II. Pharmaceutical Compositions

[0097] In some embodiments, the compounds and compositions of the present disclosure are administered to humans, human patients or subjects. For the purposes of the present disclosure, the expression "active ingredient" generally refers to a compound as described herein. One aspect of the present disclosure provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of the present disclosure.

[0098] Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any other animal, for example, to non-human animals, such as non-human mammals. It is well known that pharmaceutical compositions suitable for administration to humans are modified to make the compositions suitable for administration to various animals, and veterinary pharmacologists of ordinary skill can design and / or perform such modifications using only ordinary experiments (if any). Subjects to which the pharmaceutical compositions are contemplated for administration include, but are not limited to, humans and / or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and / or rats; and / or poultry, including commercially relevant poultry such as poultry, chickens, ducks, geese, and / or turkeys.

[0099] The formulations of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparation methods include the steps of bringing the active ingredient into association with an excipient and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, dividing, shaping and / or packaging the product into the desired single or multiple dose units.

[0100] Pharmaceutical compositions according to the present disclosure can be prepared, packaged and / or sold in batches in a single unit dosage form and / or in a plurality of single unit dosage forms. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to the subject, and / or a suitable fraction of such a dose, for example, such as half or one-third of such a dose.

[0101] The relative amounts of active ingredient, pharmaceutically acceptable excipient and / or any additional ingredients in a pharmaceutical composition according to the present disclosure will vary with the identity, size and / or condition of the subject being treated and also with the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 100%, such as between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w / w) of active ingredient.

[0102] The compounds of the present disclosure may be formulated using one or more excipients to: (1) increase stability; (2) allow for sustained or delayed release; (3) alter biodistribution; (4) alter the release profile of the compound in vivo. Non-limiting examples of excipients include any and all solvents, dispersion media, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, and preservatives. Thus, the formulations of the present disclosure may include one or more excipients, each in an amount that together increases the stability of the compound.

[0103] excipient

[0104] The pharmaceutical preparation may contain pharmaceutically acceptable excipients such as those suitable for the particular dosage form desired, as used herein, including any and all solvents, dispersion media, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. Remington's "The Science and Practice of Pharmacy", 21st edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety) discloses various excipients used in the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition, its use is expected to be within the scope of the present disclosure.

[0105] In some embodiments, the purity of a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%. In some embodiments, the excipient is approved for human and veterinary use. In some embodiments, the excipient is approved by the U.S. Food and Drug Administration. In some embodiments, the excipient is pharmaceutical grade. In some embodiments, the excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia and / or the International Pharmacopoeia.

[0106] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Such excipients may optionally be included in the pharmaceutical composition.

[0107] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and / or combinations thereof.

[0108] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate Sodium lauryl sulfate, quaternary ammonium compounds and / or combinations thereof.

[0109] Exemplary surfactants and / or emulsifiers include, but are not limited to, natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate Polyoxyethylene sorbitan Polyoxyethylene sorbitan monooleate Sorbitan monopalmitate Sorbitan monostearate Sorbitan tristearate Glyceryl monooleate, Sorbitan monooleate ), polyoxyethylene esters (e.g., polyoxyethylene monostearate Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., ), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether ), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, 68. 188. Cetrimide bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, Kolliphor SLS and / or combinations thereof.

[0110] Exemplary binders include, but are not limited to, starches (e.g., corn starch and starch paste); gelatin; sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g., gum arabic, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate and larch arabogalactan); alginate; polyethylene oxide; polyethylene glycol; inorganic calcium salt; silicic acid; polymethacrylate; wax; water; alcohol; and combinations thereof.

[0111] Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives and / or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium pyrosulfite and / or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid and / or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetyltrimethylammonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexetidine, imidurea, phenol, phenoxyethanol, phenylethanol, phenylmercuric nitrate, propylene glycol and / or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate and / or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate and / or phenylethanol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and / or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetyltrimethylammonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT Methylparaben, 115. II. NEOLONE TM , KATHON TM and / or

[0112] Exemplary buffers include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glucuronate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and / or combinations thereof.

[0113] Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0114] Exemplary oils include, but are not limited to, almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, black currant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geranium oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavender oil, lavender oil, lemon oil, litsea cubeba oil, macademia oil, nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, atlantic bream oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasanqua oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, tsubaki oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and / or combinations thereof.

[0115] Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and / or perfuming agents can be present in the composition, according to the judgment of the formulator.

[0116] In some embodiments, the compositions of the present disclosure comprise compound 1 (such as AH crystalline form of compound 1 (e.g., Form A), a solvate form of compound 1 (e.g., Form B and Form C), or a mixture thereof), optionally at least one carrier (such as, but not limited to, lactose monohydrate), optionally at least one disintegrant (such as, but not limited to, cross-linked carboxymethylcellulose sodium), and / or optionally at least one lubricant (such as, but not limited to, magnesium stearate). In some embodiments, the composition comprising compound 1 is a nanomilled suspension or a spray-dried nanosuspension. The composition optionally comprises hydroxypropyl methylcellulose (HPMC; such as HPMC 63), sodium lauryl sulfate (SLS; such as Kolliphor SLS), lactose monohydrate, cross-linked carboxymethylcellulose, magnesium stearate, or a mixture thereof. The amount of Compound 1 in these compositions is between about 5% (w / w) to about 30% (w / w), such as about 5% (w / w), about 10% (w / w), about 15% (w / w), about 20% (w / w), about 25% (w / w), or about 30% (w / w). Non-limiting examples of nanosuspension and active particle compositions are shown in Table 2 below. Non-limiting examples of active capsule compositions are shown in Table 3 below. DL = drug loading.

[0117] Table 2. Nanosuspension and active particle compositions

[0118]

[0119] Table 3. Active Capsule Composition

[0120]

[0121]

[0122] Some embodiments of the present application provide a pharmaceutical composition comprising an effective amount of compound 1, such as the AH crystalline form of compound 1 (e.g., Form A), a solvate form of compound 1 (e.g., Form B and Form C), or a mixture thereof. In some embodiments, about 5% (w / w) to about 30% (w / w) of compound 1 (such as Form A, Form B, or Form C) may be in the pharmaceutical composition. In some embodiments, about 5% (w / w), 10% (w / w), 24% (w / w), or about 25% (w / w) of compound 1 (such as Form A, Form B, or Form C) may be in the pharmaceutical composition. The pharmaceutical composition may also include at least one of hydroxypropyl methylcellulose (such as HPMC 603), sodium lauryl sulfate (such as Kolliphor SLS), or lactose monohydrate (such as 11SD), and optionally at least one of cross-linked carboxymethyl cellulose (such as Ac-di-Sol) or magnesium stearate (such as Ligamed MF-2-V). Examples of weight percentages of each component are shown in Table 4. In some embodiments, the pharmaceutical composition may be in the form of a capsule, such as a capsule containing 5 mg, 50 mg, or 100 mg of Compound 1 (eg, Form A, Form B, or Form C).

[0123] Table 4. Weight percentage of components

[0124]

[0125]

[0126] III. How to use

[0127] The mGluR5 receptor has become a target with potential therapeutic utility in many disease states. Based on the expression pattern and functional effects of mGluR5, this receptor is an important target for drug discovery in multiple therapeutic indications. Evaluations of transgenic mice lacking mGluR5 and compounds that regulate receptor function show that ligands that regulate mGluR5 receptor function have therapeutic utility in CNS and peripheral disease states, including but not limited to schizophrenia, cognitive impairment, Alzheimer's disease, Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia, addiction, anxiety, depression, psychosis, epilepsy, fragile X, gastroesophageal reflux disease, migraine, pain, infectious or genetically acquired prion diseases (such as but not limited to Creutzfeldt-Jakob disease, tzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia), tauopathies (such as, but not limited to, frontotemporal dementia, corticobasal syndrome, Richardson syndrome, Parkinson's disease, pure akinesia with freezing of gait, and rare motor neuron symptoms or cerebellar ataxia), rare neurodegenerative diseases similar to Parkinson's disease, etc.

[0128] In some embodiments, a therapeutically effective amount of a compound or composition of the present disclosure may be used to treat CNS disorders and neurological or psychiatric disorders such as, but not limited to, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia, addiction, anxiety, depression, psychosis, epilepsy, fragile X, gastroesophageal reflux disease, migraine, pain, borderline personality disorder, bipolar disorder, or other neurological and / or psychiatric disorders associated with glutamate dysfunction.

[0129] In one embodiment, a method for treating Alzheimer's disease is provided, comprising administering a therapeutically effective amount of a compound or composition of the present disclosure to a patient in need thereof. The compound may be compound 1. In some embodiments, a therapeutically effective amount of a compound or composition of the present disclosure is used to reverse a decrease in synaptic density or synaptic loss in a subject in need thereof, such as a decrease in cortical and hippocampal synaptic density. In some embodiments, a therapeutically effective amount of a compound or composition of the present disclosure is used to reduce Tau accumulation in a subject in need thereof.

[0130] In some embodiments, a method of preventing epileptic seizures is provided, comprising administering a therapeutically effective amount of a compound or composition of the present disclosure to a patient in need thereof. The compound may be Compound 1.

[0131] In some embodiments, the compounds and compositions of the present disclosure are used in the manufacture of a medicament for the treatment of CNS disorders and neurological or psychiatric disorders such as, but not limited to, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's disease, Parkinson's disease levodopa-induced dyskinesia, addiction, anxiety, depression, psychosis, epilepsy, fragile X, gastroesophageal reflux disease, migraine, pain, borderline personality disorder, bipolar disorder, or other neurological and / or psychiatric disorders associated with glutamate dysfunction.

[0132] In one embodiment, the compounds or compositions of the present disclosure are used to manufacture a medicament for treating Alzheimer's disease. The compound may be Compound 1.

[0133] Alzheimer's disease

[0134] Despite the millions of people suffering from it, there is currently no disease-modifying therapy for Alzheimer's disease (AD). Without being bound by theory, AD diagnosis requires evidence of Aβ peptide accumulation. Key accompaniments are misfolded Tau (MAPT) accumulation, phosphorylation and proliferation, plus microglial and astrocyte reactivity. Genetic evidence from dominant early-onset AD mutations in APP and presenilin, Down syndrome, and protective APP alleles are consistent with a pathogenic role for Aβ. Biomarker studies have documented Aβ accumulation two decades before the onset of symptoms, consistent with a triggering role for Aβ. However, the temporal disconnect between Aβ accumulation and symptoms, and the clinical failure of multiple Aβ-lowering therapies have expanded the focus of AD pathophysiology. Genetic studies have shown that microglia are associated with AD risk and progression, so the role of brain innate immunity in symptomatic AD has attracted increasing attention. For example, TREM2 signaling has multiple effects on Aβ-driven pathology. Additionally, components of the classical complement cascade have been directly implicated in phagocytic synapse removal in AD, but the basis for synaptic selectivity remains unclear.

[0135] Synaptic loss is critical for the progression of clinical AD from presymptomatic to mild cognitive impairment (MCI) to dementia. Synaptic loss was initially documented ultrastructurally at autopsy but can now be tracked indirectly with FDG-PET or directly with SV2A PET. PET tracers targeting synaptic vesicle glycoprotein 2A (SV2A), which is ubiquitously expressed in synaptic vesicles, allow quantification of synaptic density via noninvasive scans, facilitating tracking of neurodegenerative disease progression and drug development. Using [ 11 C] PET imaging of UCB-J has previously demonstrated that hippocampal synaptic density is significantly reduced in patients with Alzheimer's disease MCI relative to undamaged controls and has also been able to detect pharmacological rescue of synaptic loss in a mouse model of AD (APPswe / PS1ΔE9; hereafter referred to as APP / PS1).18 F]SynVesT-1 has a longer half-life and higher resolution, has greater potential for clinical translation, and is able to discern differences in synaptic density between APP / PS1 mice and control littermates.

[0136] The only reported unbiased genome-wide expression clonal screen for the biochemical events of AD synaptic failure identified cellular prion protein (PrP C ) was identified as a high-affinity receptor for Aβ oligomers (Aβo). C It exhibits unique selectivity for oligomeric Aβ. In AD models, Aβo and PrP C The binding of Aβo and PrP plays a role in impaired synaptic plasticity, learning and memory deficits, and synaptic loss. C Screening for postsynaptic transmembrane proteins associated with intraneuronal signaling identified neuronal metabotropic glutamate receptor 5 (mGluR5) as a key link to Fyn and Pyk2 (PTK2B). Importantly, these kinases are associated with Tau and implicated in AD risk. Genetic deletion and pharmacological inhibition studies have demonstrated that reducing mGluR5 activity alleviates synaptic and memory deficits in a variety of AD models. However, the molecular and cellular basis of the role of mGluR5 in AD synaptic loss, including neuroglia interactions and complement-driven synaptic phagocytosis, remains unclear.

[0137] Allosteric mGluR5 modulators have been subdivided into positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), and silent allosteric modulators (SAMs). PAMs enhance, while NAMs inhibit, glutamate-induced G-protein-mediated Ca 2+ Mobilize and / or alter glutamate efficacy. Multiple NAMs reduce physiological glutamate signaling and Aβo-PrP C -dependent synaptic defects. As a dose-limiting side effect, blocking glutamate at mGluR5 with NAM impairs learning and memory independently of AD. Surprisingly, compound 1 does not alter basal signaling or glutamate signaling, but does inhibit PrP C Compound 1 significantly expands the potential therapeutic window of mGluR5 as a disease-modifying target for AD.

[0138] In some embodiments, Compound 1 is used to modulate the expression of neuronal and glial genes, regulate neuro-immune interactions in AD synapse loss, restore synaptic density, and prevent synaptic localization of C1q without altering total C1q levels or overall gliosis.

[0139] In some embodiments, Compound 1 is used to increase synaptic density, slow the loss of synaptic density, reduce the loss of synaptic density, increase the levels of presynaptic and postsynaptic markers (SV2A and PSD-95), restore the loss of synaptic markers (SV2A and PSD-95), prevent epileptic seizures, inhibit human transporter P-glycoprotein (P-gp), organic ion transporting polypeptide (OATP) 1B1 and OATP1B3. In some embodiments, Compound 1 is used to regulate cerebrospinal fluid (CSF) or plasma biomarkers, such as but not limited to total Tau protein levels, phosphorylated Tau protein levels, SNAP-24, neurofilament light chain, GAP-43, synaptotagmin-1, alpha-synuclein (including phosphorylated versions) and neurogranulin. In some embodiments, Compound 1 is used to regulate complement activation biomarkers.

[0140] In some embodiments, patients receiving Compound 1 have changes in fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, synaptic vesicle glycoprotein 2A (SV2A)-PET imaging, metabotropic glutamate receptor subtype 5 (mGluR5)-PET imaging, Tau PET imaging, amyloid β PET imaging, electroencephalogram (EEG) activity, functional magnetic resonance imaging, and / or volumetric magnetic resonance imaging.

[0141] In some embodiments, the patient is diagnosed with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD, e.g., based on:

[0142]

[0143]

[0144] Combination therapy

[0145] In some embodiments, the present invention provides a method for treating a disease or condition described herein, comprising administering a compound or composition of the present invention in combination with one or more additional active agents or therapies. Suitable agents or therapies that can be used in combination with the compounds of the present invention include, but are not limited to, anti-amyloid immunotherapy, anti-tau immunotherapy, an active agent intended to reduce amyloid beta levels in any form, an active agent specifically intended to block amyloid-beta oligomer toxicity, microglial inflammation targeted therapy, acetylcholinesterase inhibitors, and NMDA receptor antagonists (such as, but not limited to, donepezil and memantine).

[0146] The compounds or compositions of the present disclosure and the additional active agent may be administered simultaneously, sequentially or in any order. The compounds or compositions of the present disclosure and the additional active agent may be administered at different doses, at different dosing frequencies or via different routes, whichever is appropriate.

[0147] IV. Dosing and Administration

[0148] The present disclosure contemplates delivery of the disclosed compounds or compositions by any appropriate route for any therapeutic, prophylactic, pharmaceutical, diagnostic, or imaging use, taking into account possible advances in drug delivery science.

[0149] The compounds or compositions disclosed herein can be administered by any approach that produces a therapeutically effective outcome. These approaches include, but are not limited to, oral, intravenous (into the vein), intrathecal (into the spinal canal or into the subarachnoid space to reach CSF), intracerebral parenchyma (into the brain parenchyma), ear drops, nasal aerosols or inhalation. In a specific embodiment, the compound or composition can be administered in a manner that allows it to pass through the blood-brain barrier, vascular barrier or other epithelial barriers.

[0150] In some embodiments, the compounds or compositions of the present disclosure can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When an aqueous suspension is administered orally, the active ingredient can be combined with an emulsifier and a suspending agent. If necessary, certain sweeteners and / or flavoring agents and / or coloring agents can be added.

[0151] In some embodiments, the compounds or compositions of the present disclosure may be formulated for administration to the CNS by routes known in the art, such as, but not limited to, direct intraparenchymal administration, intrathecal delivery, and intraventricular infusion.

[0152] Dosage form

[0153] The pharmaceutical compositions described herein can be formulated into dosage forms described herein, such as capsules, tablets, aqueous suspensions or solutions, topicals, intranasals, intratracheals, or injections (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, subcutaneous). It should be understood that the total daily dosage of the compositions of the present disclosure can be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level, prophylactic effective dosage level, or appropriate imaging dosage level for any particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound being employed; the specific composition being employed; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound being employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound being employed; and similar factors well known in the medical field.

[0154] In some embodiments, the compositions according to the present disclosure may be sufficient to deliver about 0.0001 mg / kg to about 100 mg / kg, about 0.001 mg / kg to about 0.05 mg / kg, about 0.005 mg / kg to about 0.05 mg / kg, about 0.001 mg / kg to about 0.005 mg / kg, about 0.05 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg. , about 0.1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 25 mg / kg, about 25 mg / kg to about 50 mg / kg, about 50 mg / kg to about 100 mg / kg, about 100 mg / kg to about 125 mg / kg, about 125 mg / kg to about 150 mg / kg, about 150 mg / kg to about 175 mg / kg, about 175 mg / kg to about 200 mg / kg, about 200 mg / kg to about 250 mg / kg of subject weight / day dosage level once or multiple times a day to obtain the desired treatment, diagnosis, prevention or imaging effect. The desired dosage can be delivered three times a day, twice a day, once a day, every other day, every three days, every week, every two weeks, every three weeks or every four weeks. In some embodiments, the desired dosage can be delivered using multiple administrations (e.g., twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times or more administrations). When multiple administrations are employed, a split dosing regimen, such as those described herein, may be used. In some embodiments, the compounds or compositions of the present disclosure are administered by continuous infusion.

[0155] As used herein, "fractionated dose" is a single unit dose or total daily dose divided into two or more doses, e.g., two or more administrations of a single unit dose. As used herein, a "single unit dose" is a dose of any therapeutic agent administered in one dose / once / single route / single contact point (i.e., a single administration event). As used herein, a "total daily dose" is the amount given or prescribed within a 24-hour period. It can be administered in a single unit dose.

[0156] Administration of the compounds or compositions disclosed herein can be used as chronic or acute therapy. The amount of drug that can be combined with a carrier to produce a single dosage form will vary with the host being treated and the specific mode of administration. A typical formulation will contain from about 5% to about 95% active compound (w / w).

[0157] After the patient's condition improves, if necessary, a maintenance dose of the compounds, compositions or combinations of the present disclosure may be administered. Subsequently, the dosage or frequency of administration or both may be reduced according to the symptoms until the improved condition is maintained, and treatment should be stopped when the symptoms have been alleviated to the desired level. However, patients may require long-term intermittent treatment upon any recurrence of disease symptoms.

[0158] As will be appreciated by those skilled in the art, lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, co-administration, severity and course of infection, the patient's management of the infection, and the judgment of the treating physician.

[0159] In some embodiments, the subject is treated with about 10 mg, about 40 mg, about 70 mg, about 100 mg, about 150 mg, or about 200 mg of Compound 1. In some embodiments, the subject is treated once or twice a day. In one non-limiting example, the subject is treated with between about 75 mg and about 125 mg of Compound 1 twice a day. In another non-limiting example, the subject is treated with at least 200 mg of Compound 1 once a day.

[0160] In some embodiments, the compounds or compositions of the present disclosure are administered via oral route in capsules. In some embodiments, the capsule contains about 5 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg of the compound. In some embodiments, the capsule also includes lactose monohydrate, cross-linked sodium carboxymethyl cellulose, and / or magnesium stearate. Lactose monohydrate can be spray-dried. Cross-linked sodium carboxymethyl cellulose and magnesium stearate are in extra-granular form. In some embodiments, the concentration of the compound in the capsule is between about 1% (w / w) and about 50% (w / w), such as between about 1% (w / w) and about 5% (w / w), between about 6% (w / w) and about 10% (w / w), between about 11% (w / w) and about 20% (w / w), between about 21% (w / w) and about 30% (w / w), between about 31% (w / w) and about 40% (w / w), or between about 41% (w / w) and about 50% (w / w). In one embodiment, the capsule has about 5 mg of compound 1, and the concentration of compound 1 in the capsule is about 5% (w / w). In another embodiment, the capsule has about 50 mg or 100 mg of compound 1, and the concentration of compound 1 in the capsule is about 25% (w / w).

[0161] In some embodiments, the capsules are stored at 25°C / 60% relative humidity (RH).The compound in the capsules is stable for at least 30 months under accelerated and long term stability conditions, and the capsules are stable for at least 1 month.

[0162] V. Kits and Devices

[0163] The present disclosure also provides a variety of kits and devices for conveniently and / or effectively implementing the methods of the present disclosure. Typically, the kit will include sufficient amounts and / or numbers of components to allow the user to perform multiple treatments on a subject and / or conduct multiple experiments.

[0164] In one embodiment, the disclosure provides a kit for treating a CNS disorder, comprising a compound or composition of the disclosure, optionally in combination with any other active agent.

[0165] The kit may also include packaging and instructions and / or a delivery agent that forms the formulation composition. The delivery agent may include saline, a buffer solution, or any delivery agent disclosed herein. The amount of each component may be varied to enable a consistent, reproducible, higher concentration saline or simple buffer formulation to be obtained. The components may also be varied to increase the stability of the compound in the buffer solution over a period of time and / or under various conditions.

[0166] The present disclosure provides devices that can incorporate compounds or compositions of the present disclosure. These devices contain stable formulations that can be used for immediate delivery to subjects (such as human patients) in need thereof. In some embodiments, the subject suffers from a CNS disorder.

[0167] Non-limiting examples of the device include pumps, catheters, needles, transdermal patches, pressurized suction and olfactory delivery devices, iontophoresis devices, multilayer microfluidic devices. The device can be used to deliver the compounds or compositions of the present disclosure according to a single, multiple or divided dosing regimen. The device can be used to deliver the compounds or compositions of the present disclosure across biological tissues, intradermally, subcutaneously or intramuscularly.

[0168] VI. Definitions

[0169] For convenience, the meanings of certain terms and expressions used in this specification, examples, and appended claims are provided below. If there is an apparent discrepancy between the use of a term in other parts of this specification and the definition provided in this section, the definition in this section shall prevail.

[0170] Abbreviations used herein have their conventional meanings in the scientific field. Chemical elements are identified according to the periodic table of the elements, 75th edition, Handbook of Chemistry and Physics (CAS version). In addition, the general principles of organic chemistry are described in M. Loudon, Organic Chemistry, 5th edition, Roberts and Company, Greenwood Village, Colo.: 2009; and MB Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 7th edition, John Wiley & Sons, Hoboken: 2013, the entire contents of which are hereby incorporated by reference.

[0171] As used herein, the term "about" means + / - 10% of the recited value.

[0172] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the drawn structure.

[0173] The term "substantially purified" refers to a state free from other heterogeneous compounds and impurities with which the crystalline form of the invention is normally associated in its native state, such that a "substantially purified" crystalline form is at least 95% by weight of a given sample material.

[0174] As used herein, the term "subject" or "patient" refers to any organism to which particles can be administered, for example, for experimental, therapeutic, diagnostic and / or preventive purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, guinea pigs, cows, pigs, sheep, horses, dogs, cats, hamsters, llamas, non-human primates, and humans).

[0175] As used herein, the terms "treating" or "preventing" may include preventing a disease, disorder, or condition from occurring in an animal that may be susceptible to the disease, disorder, and / or condition but has not yet been diagnosed as having the disease, disorder, or condition; inhibiting the disease, disorder, or condition, e.g., hindering its progression; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease, disorder, or condition may include ameliorating at least one symptom of a particular disease, disorder, or condition, even without affecting the underlying pathophysiology, such as treating pain in a subject by administering an analgesic, even if such an agent does not treat the cause of the pain.

[0176] As used herein, the terms "manage" or "maintain" may refer to alleviating the symptoms of a disease, reducing the severity of symptoms of a disease, or preventing symptoms of a disease from worsening.

[0177] The term "therapeutic effect" is well known in the art and refers to a local or systemic effect caused by a pharmacologically active substance in an animal, particularly a mammal, more particularly a human. Thus, the term means any substance intended for use in diagnosing, curing, alleviating, treating or preventing a disease, disorder or condition, or enhancing desired physical or psychological development and conditions in an animal (e.g., a human).

[0178] The term "modulate" is art-recognized and refers to upregulation (i.e., activation or stimulation), downregulation (i.e., inhibition or suppression), or both in combination or separately, of a response. Modulation is typically compared to a baseline or reference that can be internal or external to the therapeutic entity.

[0179] The terms "sufficient" and "effective" as used interchangeably herein refer to the amount (e.g., mass, volume, dosage, concentration, and / or time period) required to achieve one or more desired results. A "therapeutically effective amount" is at least the minimum concentration required to achieve a measurable improvement or prevention of at least one symptom or a specific condition or illness, to achieve a measurable increase in life expectancy, or to improve the quality of life of a patient in general. Therefore, the therapeutically effective amount depends on the specific biologically active molecule and the specific condition or illness to be treated. The therapeutically effective amount of many active agents (such as antibodies) is known in the art. The therapeutically effective amount of the compounds and compositions described herein, for example, for treating a specific illness, can be determined by techniques that are completely within the skill of a person skilled in the art, such as a physician.

[0180] The terms "biologically active agent" and "active agent" as used interchangeably herein include, but are not limited to, physiologically or pharmacologically active substances that act locally or systemically in the body. Bioactive agents are substances used to treat (e.g., therapeutic agents), prevent (e.g., prophylactic agents), diagnose (e.g., diagnostic agents), cure, or alleviate a disease or disorder; substances that affect the structure or function of the body; or prodrugs that become biologically active or more active after they have been placed in a predetermined physiological environment.

[0181] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of reasonable medical judgment, commensurate with a reasonable benefit / risk ratio, according to the guidelines of agencies such as the U.S. Food and Drug Administration. As used herein, "pharmaceutically acceptable carrier" refers to all components of a pharmaceutical formulation that promote the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrants, expanders, fillers, stabilizers and combinations thereof.

[0182] The term "pharmaceutically acceptable salt" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention.

[0183] The term "substantially purified" means that the compound is at least 90% pure relative to other forms of the compound, such as about 90%, about 95%, or about 99%.

[0184] The details of one or more embodiments of the present disclosure are set forth in the description attached below. Preferred materials and methods will now be described, but any materials and methods similar or equivalent to those described herein may be used in the practice or testing of the present disclosure. Other features, objects and advantages of the present disclosure will be apparent from this description. In this description, unless the context clearly provides otherwise, singular referent forms also include plural referents. Unless otherwise defined, all technical and scientific terms used herein will have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. In the event of a conflict, this description shall prevail.

[0185] The present disclosure is further illustrated by the following non-limiting examples.

[0186] Example

[0187] Example 1. Polymorph Screening and Characterization

[0188] Crystallization occurs

[0189] The polymorph study protocol involved the use of a range of solvents, initially evaluating the solubility of Compound 1. Four types of experiments were then set up: temperature cycling, evaporation, long-term slurry, and vapor diffusion. The number of solvents, solvent volumes, and amounts of material used in each experiment were based on the solubility values ​​and the type of experiment.

[0190] The approximate solubility of Compound 1 was assessed (visually) in a list of solvents selected based on class diversity (including solvent / water mixtures) (Table 5). Compound 1 (5.0 ± 0.2 mg) was weighed into a vial and a known aliquot of solvent was added stepwise at 20°C until a clear solution was visually observed; magnetic stirring was applied. The final solution was stirred at room temperature overnight to evaluate any recrystallization.

[0191] Table 5. Approximate solubility of compound 1

[0192]

[0193]

[0194] Overall, the compound showed moderate / high solubility in most of the solvents screened. Only heptane and water acted as antisolvents. Due to the high solubility, the solvents used in the following experiments were selected based on solvent properties (e.g., boiling point, miscibility) and solubility.

[0195] A total of 38 samples were prepared. The experiments involved in the plan were temperature cycling, evaporation, long-term slurry and vapor diffusion experiments.

[0196] Temperature Cycle

[0197] The slurry of compound 1 was prepared in eight solvent systems with solubility <30 mg / mL. In the Integrity workstation, the slurry was subjected to six temperature cycles under magnetic stirring (650 rpm). Each cycle included a heating / cooling ramp at a rate of 2 ° C / min, and the step duration at 20 ° C and 40 ° C was 110 minutes. The presence of solids under hot conditions was ensured by visual inspection. Solid samples were separated by filtration on a 20 μm PTFE filter syringe and vacuum dried at 20 ° C for about 2 hours, and then XRPD analysis was performed.

[0198] Evaporation experiment

[0199] Twelve organic solvents with boiling points below 110°C and solubility greater than 15 mg / mL were selected for evaporation experiments.

[0200] An almost saturated solution of compound 1 was prepared in the selected solvent system and stirred at room temperature for about 1 hour to maximize the dissolution equilibrium. The mixture was filtered through a 0.45 μm PTFE filter into a new vial. The resulting clear solution was evaporated in a drying oven under an inert atmosphere (e.g., nitrogen) (open vial, no stirring).

[0201] Long-term slurry

[0202] Slurries of Compound 1 were prepared in eight solvent systems selected based on solubility < 30 mg / mL. The slurries were placed in a thermostatic block at 20°C and stirred for two weeks.

[0203] Solvate Form B (i.e., solvate S1) was prepared using an evaporation experiment. An almost saturated solution of compound 1 was prepared in isopropanol and stirred at room temperature for about 1 hour to maximize dissolution equilibrium. The mixture was filtered into a new vial (open vial without stirring) through a 0.45 p.m PTFE filter. Within a week, almost all isopropanol was evaporated. The residue was dried in a vacuum oven at 20 ° C for 1 hour.

[0204] Solvate Form C (ie, Solvate S2) was prepared using a long term slurry in isopropanol. The slurry was placed in a thermostatic block at 20°C and stirred for two weeks. A solid sample was isolated by filtration on a 20 pm PTFE filter syringe and dried under vacuum for approximately 2 hours.

[0205] Also use vapor diffusion to prepare solvate form C (that is, solvate S2) with isopropanol and pentane as antisolvent.Prepare a concentrated solution of compound 1 in isopropanol, and stir at room temperature for about 1 hour to maximize dissolution equilibrium.The mixture is filtered into a new vial by a 0.45 pm PTFE filter, and is placed in an outer vial equipped with pentane without a cap.The system is sealed, stored at room temperature, stirred and regularly checked for solid formation.Only when the mixture is stirred, the solid of form C is formed.Solid is isolated by removing the supernatant, and dried at room temperature for at least 30 minutes in a vacuum oven.

[0206] A summary of the results is shown in the table below.

[0207] Table 6. Results using various solvents and different processes

[0208]

[0209]

[0210] Further studies were performed and Form A was found to be anhydrous (AH) form and isolated using a mixture of EtOAc and heptanes, providing crystalline material in significant yield and high purity grade.

[0211] The following scheme was used to generate solubility data: a slurry of compound 1 was prepared and allowed to balance at 20 ° C for about 18 hours under stirring. In order to determine the concentration in the supernatant, about 0.1 mL of slurry was sampled with a syringe, filtered, weighed, diluted with MeCN, and injected into HPLC. The slurry was heated at 45 ° C for about 3 hours, and then repeated sampling was performed to obtain solubility data under thermal conditions. The sample was cooled to 20 ° C, and the solid residue was separated by filtering on a 20-μm PTFE filter, vacuum dried at 40 ° C, and XRPD analysis was performed. The compound 1 peak area of ​​each sample was recorded, and the solubility data (245nm, 1460mAU*sec / mg / mL, Table 7) was calculated using the previously determined response factor. The data was merged and visualized on a chart, which shows the change of solubility with the volume percentage of heptane. Compound 1 exhibits high solubility in pure EtOAc and in the presence of a relatively high percentage of heptane (10-20). As the amount of heptane increases, the solubility decreases steadily. All solid residues exhibited a physical form consistent with Form A.

[0212] Table 7. Solubility data of compound 1

[0213]

[0214] Based on the solubility data, the width of the metastable zone was tested in EtOAc / heptane ratios of 80:20, 70:30, and 60:40 in order to determine appropriate operating conditions / seeding points.

[0215] The metastable zone width was generated using an Electrothermal Integrity instrument coupled to an IR turbidity probe. Samples with different amounts of material were weighed in vials and diluted with 1 mL of the appropriate solvent mixture. The concentrations screened were in the range of 115-215 mg / mL, taking into account the contribution estimated to correspond to about 1 volume of solids. A step / plateau temperature program was set up: heating rate of 0.1°C / min, step of 1°C, and plateau duration of 1 minute. Step heating was set at 78°C (the highest temperature allowed by the solvent component with the lowest boiling point); step cooling was performed with the same parameters. The vials were monitored by the turbidity probe to obtain the dissolution temperature (during the heating ramp) and the self-crystallization temperature (during the cooling ramp) for each concentration.

[0216] All solvent compositions provided regular dissolution curves with good fit to previously collected solubility data. Selected samples were isolated by filtration and analyzed by XRPD: consistency with Form A was confirmed. Overall, the 80:20 ratio of EtOAc / heptane appeared to be a good choice for dissolution, while the 70:30 composition was preferred as a seeding point. In fact, the latter provided a practical concentration range in which the initial solution could be easily pushed towards the supersaturated region. On the other hand, the 60:40 solvent ratio of MSZW was considered too narrow and risky from an operational point of view.

[0217] Characterization

[0218] XRPD

[0219] XRPD spectra were collected in transmission mode on a Panalytical X'Pert Pro or Empyrean instrument with an X'Celerator detector using standard methods. The samples were irradiated with Cu Kα X-rays. The data were evaluated using Panalytical Data Viewer software. Details of the standard screening data collection method are listed below. A representative XRPD pattern of AH Form A is shown in Figure 3 A representative XRPD pattern of Form B is shown in Figure 5 A representative XRPD pattern of Form C is shown in Figure 7 and 9 Shown in.

[0220]

[0221]

[0222] TGA

[0223] TGA analysis was performed on a TA Q5000 instrument. TGA method details are listed below. A representative graph of AH Form A is shown in Figure 4 A representative image of Form B is shown in Figure 6 A representative diagram of Form C is shown in Figure 8 and 10 Shown in.

[0224]

[0225]

[0226] DSC

[0227] DSC analysis was performed on a TA Q5000 instrument. The DSC method details are listed below. A representative graph of AH Form A is shown in Figure 4 A representative image of Form B is shown in Figure 6 A representative diagram of Form C is shown in Figure 8 and 10 Shown in.

[0228]

[0229] Example 2. Crossover pharmacokinetic study of intravenous and oral investigations in male CD rats

[0230] This study evaluated the PK of Compound 1AH Form A in male Sprague Dawley rats (3 / group) after a single IV (intravenous) administration at 1 mg / kg as a solution in 2.5% N-methyl-2-pyrrolidone (NMP) + 1% Solutol HS15 in water or PO (oral) administration of 3 formulations at 5 and 50 mg / kg, crossed over to the same animals with a 7-day recovery period. For PO administration, the compound was formulated as a nanomilled suspension (Formulation A) or 2 different solutions (Formulation B or C).

[0231] Serial plasma samples were collected at regular time intervals up to 24 hours after administration, and the level of compound 1 in each plasma sample was determined by LC-MS / MS. The pharmacokinetic parameters were determined and are shown in Table 8.

[0232] Table 8. Plasma pharmacokinetic parameters of Compound 1 after single intravenous and oral administration to male rats

[0233]

[0234] NA - Not Applicable

[0235] 1 -AUC reported for this IV dose inf And used to determine F%.

[0236] A - Nanomilled suspension (10% (w / w) of Compound 1) in a MilliQ water solution of 2% (w / w) HPMC 603 and 0.5% (w / w) SLS.

[0237] B-40% PEG 400, 20% Transcutol, 10% Vit E TPGS, 0.5% Poloxamer 407 in water

[0238] C-5% DMSO, 0.5% HPMC aqueous solution

[0239] Following each PO dose, there is an initial plasma peak at 0.5 to 2 hours post-dose, followed by a decline in levels and a second, higher peak at 6 to 8 hours post-dose. inf and AUC of PO doses 最后 The calculated F% was high for all formulations.

[0240] At 5 and 50 mg / kg, Formulation A showed PO exposures (as AUC 最后 ).

[0241] At 5 and 50 mg / kg, Formulation B showed PO exposures (as AUC 最后 ).

[0242] At 50 mg / kg, the highest systemic exposure (AUC last ,168000ng.h / mL), and C max The highest (8847 ng / mL), so this formulation was used in a 28-day toxicology study in rats and monkeys.

[0243] T after IV administration 1 / 2 4.49 hours, V dss was 2.23 L / kg, and CL was 5.98 mL / min / kg.

[0244] Example 3. Methods for preparing formulations of compounds

[0245] 1. Nanosuspension composition

[0246] Studies were conducted to select suitable nanosuspension compositions for AH Form A of Compound 1. Three qualitatively different vehicles were prepared, each at a 200 g scale, to verify the feasibility and stability of nanomilled suspensions in these media.

[0247] By dissolving appropriate amounts of polymer and surfactant in purified water The vehicle was pre-prepared with 1% paraformaldehyde. Complete dissolution of the material was achieved by magnetic stirring. Compound 1 Form A was then added to the prepared vehicle and suspended (all compositions were uniformly suspended within approximately 15 minutes).

[0248] The materials list is shown in Table 9. The qualitative and quantitative formulation compositions are reported in Table 10.

[0249] Table 9. Materials list

[0250]

[0251]

[0252] Table 10. Qualitative components studied

[0253]

[0254] To investigate the feasibility of the nano-milling process, a small-scale Dynomill (Dynomill RL) was used at this stage. After assembly, 65% of the total volume of the milling chamber (50 mL) was filled with milling media beads (equivalent to 32.5 mL of 0.4 mm YTZ milling beads, corresponding to approximately 120 g). The manufactured nanosuspensions were characterized: particle size distribution (PSD) by Malvern Mastersizer (LLS); particle size distribution by Malvern Zeta sizer (Z-sizer); Z-potential; X-ray diffraction (XRPD); content / impurities by HPLC; and homogeneity by HPLC.

[0255] Based on the physical and chemical characterization of the nanoabrasive compositions, it can be concluded that:

[0256] - Compositions 2 and 3 showed similar PSD characteristics (unimodal distribution) and reached the target size after 60 minutes of milling, while composition 1 showed a bimodal distribution with the presence of particles > 1 μm

[0257] - Compositions 2 and 3 showed better zeta potential values, consistent with typical stable nanosuspension products (values ​​below -25 mV)

[0258] -XRPD data showed that the nanomilling process did not affect the crystalline form of all 3 compositions

[0259] Stability studies were performed on all three nanosuspension compositions (under refrigerated conditions only). The 7-day stability results focused primarily on the appearance of the formulations, the stirring method, and the sampling points.

[0260] Informal stability: 7-day time point

[0261] The three manufactured nanosuspensions were characterized after 7 days of storage under refrigerated conditions. The analyses performed were: particle size distribution by laser light scattering using a Malvern Mastersizer; zeta potential measurements by a Malvern Zetasizer; X-ray pattern diffraction; and homogeneity and impurities by HPLC.

[0262] Based on the results from physical and chemical characterization, it was confirmed that Composition 1 was more unstable and inhomogeneous.

[0263] Informal stability: 14 days

[0264] The stability of compositions 2 and 3 was evaluated by storage under refrigeration for 14 days. The following tests were performed: particle size distribution analysis by laser light scattering with a Malvern Mastersizer; zeta potential measurement by a Malvern Zetasizer; X-ray pattern diffraction; and homogeneity and impurities analysis by HPLC.

[0265] Based on the results from the physical and chemical characterization, both compositions 2 and 3 can be considered stable for 14 days under refrigerated conditions. However, composition 3 exhibits a more desirable zeta potential value.

[0266] With this in mind, use the following composition for the following activities:

[0267] Table 11. Compositions to be used

[0268] Material %(w / w) Compound 1AH Form A 10.0 HPMC 603–Hydroxypropyl methylcellulose 603 2.0 SLS – Kolliphor SLS fine 0.5 Purified water 87.5 total 100.0

[0269] Oral dosage form development

[0270] Table 12. Materials list

[0271]

[0272]

[0273] The prepared nanosuspension was divided into small batches (four aliquots) and used to study top spray granulation. Two water soluble bulking agents / carriers were tested:

[0274] -Lactose monohydrate, Supertab 11SD (spray dried grade)

[0275] -Mannitol, Pearlitol 200SD (spray dried grade)

[0276] To obtain a compound-carrier matrix that inhibits crystal growth, a small amount of the above materials was dissolved in an aliquot of the nanomilled suspension to be sprayed (1:1 ratio to the concentration of Compound 1). Four top-spray granulation trials (2 carriers, 2 drug loadings) were performed as follows:

[0277] - 330 g of nanomilled material (+ lactose 11 SD or mannitol 200 SD as bulking agent) was sprayed on 550 g of the selected carrier to obtain a suitable drug loading of approximately 5% granule DL to prepare 5 mg capsule strength.

[0278] - 550 g of nanomilled material (+ lactose 11 SD or mannitol 200 SD as bulking agent) was sprayed on 100 g of the selected carrier to obtain a suitable drug loading of approximately 20% granule DL to prepare 50 mg and 100 mg capsule strengths.

[0279] Table 13 below shows the composition of the nanosuspension after dilution with the bulking agent:

[0280] Table 13. Diluted nanosuspension composition

[0281]

[0282]

[0283] After adding and dissolving the bulking agent to an aliquot of the nanosuspension, the carrier was loaded into the granulator bowl and warmed before starting top spray granulation. The following Tables 14 and 15 show the composition of the four granules prepared:

[0284] Table 14. Theoretical granule composition with mannitol

[0285]

[0286] Table 15. Theoretical granule composition with lactose

[0287]

[0288] Four top spray granulations were performed to investigate process feasibility and generate sufficient material for subsequent capsule preparation. The resulting granules (5% and 20% DL) looked visually different: both lactose and mannitol based granules at 20% DL showed coarse agglomerates, while the 5% granules DL showed very fine agglomerates.

[0289] As a general observation for the following manufacturing batches, these feasibility tests were conducted at a suboptimal batch size, especially for 20% DL (due to low amount of carrier), while slight adhesion of fines to the granulator wall was observed for both drug loadings. Batch size and feed rate adjustments were then made for the following batches.

[0290] Four types of prepared particles were characterized for: loss on drying (LOD) (IPC); particle size distribution (PSD); X-ray diffraction pattern (XRPD); particle size upon reconstitution; XRPD of reconstitution; bulk and tap density; particle uniformity; and impurity profile.

[0291] From a processability perspective, the lactose composition had better properties compared to mannitol (movement of the powder blend in the granulator chamber). Furthermore, the granules with lactose at 21% DL were the only composition that could be reconstituted to the input nanosuspension PSD.

[0292] Based on these considerations, lactose is advantageous as a carrier.

[0293] The extragranular excipients were added to the four granulation batches prior to manual capsule filling. At this stage, 4% (w / w) of disintegrant (croscarmellose Ac-di-Sol) and 1% (w / w) of lubricant (magnesium stearate) were added to each granulation batch.

[0294] The equipment used to blend the granules with the extragranular materials was a low shear blender (Pharmatec) equipped with appropriate bowl sizes (1 L bowl for 20% (w / w) granules; 2 L bowl for 5% (w / w) granules).

[0295] Disintegrants and lubricants were sieved through a 500 micron screen directly into the bowl containing the granules and blended at 17 rpm for 10 minutes and 17 rpm for 3 minutes respectively.

[0296] Two drug loadings were prepared for each carrier used, as follows:

[0297] - 4.62% of the final blend was then used to prepare 5 mg capsule strength.

[0298] - 20.00% of the final blend was then used to prepare two capsule strengths, 50 mg and 100 mg.

[0299] The final blend composition given in % (w / w) is reported in Table 16:

[0300] Table 16. Final blend composition

[0301]

[0302]

[0303] Research bulking agents

[0304] 1,800 g of nano-grinding material (without extender) was sprayed on 500 g of lactose 11SD (carrier) to obtain a granule DL of approximately 24%. Table 17 below shows the composition of the prepared granules:

[0305] Table 17. Granule composition without bulking agent

[0306]

[0307] From a processability point of view, a larger amount of carrier (500 g) fits into the granulator bowl capacity, allowing for adequate movement of the carrier during heating and granulation: after preheating the granulator and carrier, spraying was started at a very low feed rate (approximately 2 g / min), then increased during the process until it reached approximately 12 g / min, maintaining a product temperature of 28-35° C. The resulting granules appeared fine, but visually granular, with a final yield of 92.14% (669 g of granules).

[0308] Particle size distribution (by LLS and sieving analysis)

[0309] In terms of PSD, this batch showed a tight unimodal size distribution as in the previous example, but a smaller x90 was observed (340 microns versus 500 microns from the feasibility experiment). The values ​​detected by laser light scattering were consistent with the sieve analysis results.

[0310] Exemplary PSDs of the nanosuspensions are shown in Table 18.

[0311] Table 18. PSD characterization of particle compositions. The values ​​reported are the average of three analytical runs.

[0312]

[0313] X-ray diffraction pattern (XRPD)

[0314] XRPD of the 20% DL particles (light green trace) showed the presence of Compound 1.

[0315] Reconstructed particle size distribution

[0316] The reconstitution of the manufactured particles was tested to the nanometer range. The reconstitution kinetics were lower compared to the lactose composition manufactured in the previous example: the faster kinetics observed previously could be attributed to the presence of the bulking agent, which acts as a "stabilizer" and "steric inhibitor" between the compound-compound particles, preventing the formation of agglomerates. Nevertheless, a portion of the compound particles freely reconstituted in the input nanosuspension in the same nanometer range.

[0317] Bulk and tap densities after reconstruction.

[0318] This composition exhibits an improvement in flowability compared to the previous examples, as evidenced by the "Hausner Ratio" index.

[0319] Particle uniformity

[0320] The homogeneity of the granules was checked. Six samples were taken from the bulk. As reported in the table below, the granules achieved good potency, with an average of 100.76% of the theoretical drug loading, compared to the lower average detected during the feasibility trial (87% (w / w)), confirming the impact of inappropriate batch size at this stage. The observed RSD was slightly higher, but within acceptable limits (RSD < 5%).

[0321] No impurities were detected (less than 0.05%).

[0322] Capsule filling for dissolution evaluation

[0323] Six hand-filled capsules prepared with the granules at a strength of 100 mg were subjected to dissolution testing to understand whether the absence of bulking agent had an effect on the release of the compound. The dissolution testing confirmed that the absence of bulking agent improved the release of the compound. Although there was still a fairly high variability between the individual capsules (as observed previously), all samples achieved more than 90% release at 60 minutes.

[0324] Example 4. In vitro studies

[0325] In vitro inhibition of human transporters P-gp, OATP1B1, OATP1B3, and BSEP

[0326] The in vitro potential of Compound 1 Form A as an inhibitor of the human transporters P-glycoprotein (P-gp), organic ion transporting polypeptide (OATP) 1B1, and OATP1B3 was evaluated in various in vitro cellular test systems, and as an inhibitor of BSEP in membrane vesicles.

[0327] The reduction in transporter-mediated activity of the probe substrate in the presence of a positive control inhibitor, as determined from incubations with the test compound, demonstrates that the in vitro test system is capable of identifying transporter inhibitors.

[0328] Under the current assay conditions, Compound 1 Form A is an inhibitor of probe substrate transport mediated via P-gp, OATP1B1, OATP1B3, and BSEP with IC50s of 27.7, 6.74, 32.0, and 13.9 μM, respectively.

[0329] Supersomes overexpressing human CYP enzymes TM In vitro CYP450 reaction phenotype study in

[0330] The CYPP450 enzymes involved in the phase I metabolism of compound 1 form A were studied in vitro. Compound 1 form A was metabolized by CYP1A2, CYP2D6, and CYP3A4 with T1 / 2 values ​​of 64, 14, and 176 minutes, respectively, and CLints of 0.261, 0.984, and 0.0786 μL / min / pmol CYP, respectively. No evidence of compound 1 being metabolized by CYP2B6, CYP2C8, CYP2C9, and CYP2C19 was observed.

[0331] The predicted contribution of each CYP to the metabolism of Compound 1 Form A was assessed using the relative activity method of factors. These calculations indicated that CYP1A2, CYP3A4, and CYP2D6 accounted for 43.1%, 38.9%, and 18% of the total metabolism, respectively.

[0332] In vitro CYP inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes

[0333] This study evaluated the potential inhibitory effects of Compound 1 Form A on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Known inhibitors of each CYP were used as positive controls.

[0334] The results showed that Compound 1 Form A inhibited several CYP enzymes with IC50s of 1.95, 6.17, 12.4, 52.1 and 55.7 μM for CYP1A2, CYP2C19, CYP2C9, CYP2C8 and CYP3A4 (atorvastatin only), respectively.

[0335] CYP2D6 or CYP3A4 were not inhibited using midazolam or nifedipine as substrates.

[0336] In vitro metabolism-dependent inhibition studies of CYP2D6 and CYP3A4 in human liver microsomes

[0337] This study evaluated the metabolism-dependent inhibitory potential of Compound 1 Form A against CYP3A4 and CYP2D6 in human liver microsomes. Troleandomycin and paroxetine, known metabolism-dependent inhibitors of CYP3A4 and CYP2D6, respectively, were used as positive controls.

[0338] The overall results indicate that Compound 1 Form A is not a metabolism-dependent inhibitor of CYP3A4 and CYP2D6.

[0339] Activation of PXR and AhR receptors by Compound 1 Form A

[0340] The purpose of this study was to determine the activation potential of Compound 1 Form A at human and rat pregnane X receptor (PXR) and human and rat aryl hydrocarbon receptor (AhR) receptors. Activation of PXR is a marker for induction of CYP3A4 / 5 and CYP2C6, while activation of AhR is a marker for induction of CYP1A.

[0341] Compound 1 activated PXR receptors with an average maximum activation fold of 4.58 in humans (29.6% of the positive control) and a calculated F2 value of 5.05 μM. At 30 μM, the average activation in rats was 4.70-fold.

[0342] Compound 1 activated AhR receptors with an average maximum activation fold of 1.78 in humans (1.11% of the positive control) and an average maximum activation fold of 1.42 in rats (0.946% of the positive control) at 30 μM. This suggests that compound 1 is a potential inducer of CYP3A4 and CYP2C6.

[0343] Example 5. In vivo studies

[0344] Compound 1 (eg, Form A) prevents abnormal synaptic signaling triggered by Alzheimer's disease while maintaining physiological Glu activation. Studies have shown that oral administration of Compound 1 effectively occupies the [ 18 F]FPEB PET visualization of brain mGluR5 sites at doses 250-fold below the adverse effect level. In aged transgenic and double knock-in mouse models of Alzheimer's disease, [ 18 F] SV2A PET imaging performed by SynVesT-1 revealed reduced synaptic density in the cortex and hippocampus, and these reductions were fully restored by treatment with compound 1. The disease-modifying benefit persisted after drug washout. Tau accumulation in double knock-in mice was also reduced by compound 1 treatment. Single-nucleus transcriptomics showed that compound 1 treatment normalized expression patterns in neurons to a much greater extent than in glia. Compound 1 did not alter production of the microglial mediator C1q, but Alzheimer's gene-dependent C1q localization to synapses and synaptic phagocytosis were prevented. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators.

[0345] [ 18 F]FPEB replacement study

[0346] In mice, mGluR5 PET ligands [ 18F]FPEB was used to assess receptor occupancy. Mice were orally administered different doses of compound 1 twice daily. Available mGluR5 sites in the brain were assessed in anesthetized mice, with peak values ​​at 1 hour after a single dose and trough values ​​after 7 days of oral administration twice daily (bid). The 3.75 mg / kg bid dose maintained >90% receptor occupancy throughout the dosing period. This is consistent with a free trough drug level of 15 nM and displacement of compound 1 from mGluR5 of 0.6 nM. 3 The inhibitor constant (K i ). The 3.75 mg / kg bid dosing regimen keeps free drug above K i 25 times. Figure 1 As shown in 18 [F]FPEB is taken up into the brain of mice. Displacement studies were performed at expected trough levels and at three dose levels: 0.42, 1.25 and 3.75 mg / kg. The 3.75 mg / kg dose was able to achieve >90% receptor occupancy at the trough.

[0347] PET imaging and immunohistochemistry studies in the APP / PS1 mouse model with washout period

[0348] The aim of this study was to assess synaptic density in control and APP / PS1 mice before and after treatment with Compound 1 and to evaluate the reversibility of any observed effects after a drug washout period.

[0349] Control and APP / PS1 mice were given vehicle (95% polyethylene glycol (PEG) 400 / 5% solutol) or 7.5 mg / kg / day (3.75 mg / kg q12) of compound 1 by oral administration for at least 28 days. A subgroup of mice stopped treatment after four weeks, followed by a four-week washout period.

[0350] To further maximize translational relevance, in other studies, mice were aged to the point where synaptic loss could be detected using SV2A PET. 18 F]SDM-8SUVR-1, synaptic density was reduced in APP / PS1 mice relative to wild-type. Crucially, rescanning of the same mice after a one-month course of treatment with compound 1 revealed a highly significant increase in synaptic density to levels matching those of wild-type mice.

[0351] The reduction in synaptic density in APP / PS1 samples relative to controls was confirmed by immunohistochemical staining of presynaptic and postsynaptic markers (SV2A and PSD-95) in hippocampal and cortical sections. APP / PS1 samples treated with compound 1 showed a significant increase in both markers in both regions (relative to vehicle-treated samples); after a one-month washout period, the observed synaptic density recovery was retained.

[0352] APP NLGF SV2A PET imaging and immunohistochemistry in the / MAPT mouse model

[0353] The aim of this study was to evaluate the effects of compound 1 on the expression of amyloid precursor protein / microtubule-associated protein tau (APP) in controls and cells carrying the NL-GF mutation before and after treatment. NLGF / MAPT) (dKI-double knock-in) mice. Control and dKI mice were given vehicle (95% PEG-400 / 5% solutol) or 7.5 mg / kg / day (3.75 mg / kgq12) of Compound 1 by oral administration for at least 28 days.

[0354] To further maximize translational relevance, in other studies, mice were aged to the point where synaptic loss could be detected using SV2A PET. 18 F]SDM-8SUVR-1, synaptic density was reduced in dKI mice relative to wild-type. Crucially, rescanning of the same mice after a one-month course of treatment with compound 1 revealed a highly significant increase in synaptic density.

[0355] The reduction in synaptic density in dKI samples relative to controls was confirmed by immunohistochemical staining for presynaptic and postsynaptic markers (SV2A and PSD-95) in hippocampal and cortical sections. dKI samples treated with Compound 1 showed a significant increase in SV2A in the hippocampus and both markers in the cerebral cortex relative to vehicle-treated samples.

[0356] Prevention of seizures induced by positive allosteric modulators

[0357] The aim of this study was to evaluate the enantioselectivity of compound 1 for the mGluR5 receptor in preventing epileptic seizures. It has been previously reported that PAMs of mGluR5 are able to induce seizures in C57 / Bl6J mice. It has also been previously shown that a single 7.5 mg / kg dose of compound 1 can prevent seizures induced by (4R,5R)-5-(4-fluorophenyl)-4-(5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)oxazolidin-2-one (PAM).

[0358] Compound 1 (0.12, 0.24, 0.47, 0.94, 1.88, 3.75 or 7.5 mg / kg), enantiomers of compound 1 (7.5, 15 or 30 mg / kg) or vehicle was administered to C57 / Bl6J mice aged 3-11 months by oral gavage. Two hours later, 20 mg / kg of PAM compound was administered via intraperitoneal injection. The animals were then placed in acrylic cages with a diameter of 10 inches for observation and video recording within 2 hours after dosing, and seizures were scored using the Racine seizure scoring criteria and standardized based on a scale of 0-1.

[0359] Compound 1 exhibited a dose-dependent prevention of mGluR5 PAM-induced seizure activity in C57 / Bl6J mice. Figure 2 SAM in ) inhibited PAM-induced epileptic seizures with an IC50 of 1.09 mg / kg ( Figure 2 ). High doses of compound 1 enantiomer ( Figure 2 eSAM in ) showed no seizure prevention activity.

[0360] The seizure prevention activity of Compound 1 demonstrated dose-dependent occupancy of mGluR5 receptors in the brains of C57 / Bl6J mice. High doses of the Compound 1 enantiomer did not show a reduction in seizure activity, indicating that receptor binding is stereoselective.

[0361] Example 6. Phase I clinical study

[0362] Overview of Study Design

[0363] This was an open-label, single ascending dose (SAD) study conducted in healthy male and female participants aged 50 to 80 years (inclusive) with no history of cognitive impairment to evaluate the safety of a single oral dose of Compound 1.

[0364] Six cohorts of 6 participants each received a single oral dose of Compound 1 in the fasting state at the following dose levels: 10, 40, 70, 100, 150 and 200 mg, followed by 7 days; the starting dose of 10 mg was less than 10% of the 140 mg human equivalent dose (HED) of the rat NOAEL in the 28-day rat study of GLP at 15 mg / kg.

[0365] The study drug was a capsule containing 5, 50, or 100 mg of the nanomilled active pharmaceutical ingredient; dosing for each cohort was achieved using a combination of these capsules. Doses were administered in an inpatient setting, and all participants were closely monitored until discharge on day 3, with face-to-face follow-up visits on days 4 and 7 and a telephone call on day 5 to inquire about general health.

[0366] Administration of Compound 1 is carefully monitored within and between cohorts to ensure patient safety, and the decision to initiate the next dose cohort is made once all participants in a given cohort have completed the study and the investigators, medical monitors, DSMB, and IND sponsors have reviewed all available clinical and safety data.

[0367] After study drug administration, vital signs were monitored every 1 hour for the first 8 hours, then every 3 hours until discharge on day 3, and ECGs were performed at approximately 6, 24, and 48 hours after drug administration. To monitor changes in consciousness, a Glasgow Coma Scale (GCS) test was performed before dosing, then every 2 hours for the first 8 hours, and then every 3 hours until discharge on day 3. To monitor cognitive or psychiatric side effects, MOCA, GDS, and NPIQ were performed before oral dosing, again at approximately 6 hours after dosing (approximate peak concentration), and approximately 24 hours after dosing. Adverse events were monitored continuously. Blood was collected for laboratory studies of safety before drug dosing and on days 2 and 3.

[0368] Participant Distribution, Demographics, and Baseline Characteristics

[0369] A total of 36 participants (6 in each dose cohort) enrolled and completed the trial. Across all cohorts, the mean age and body mass index (BMI) at baseline ranged from 68.3 to 72.8 years and 24.8 to 27.8, respectively.

[0370] The majority of participants were white (97%) and female (58.3%), and mean scores on cognitive and depression scales at baseline did not indicate cognitive impairment or clinically significant depressive symptoms (Table 20).

[0371] Table 20. Participant demographics and baseline characteristics

[0372]

[0373]

[0374] Abbreviations: BMI=body mass index; CDR=Clinical Dementia Rating Scale; GCS=Glasgow Coma Scale; GDS=Geriatric Depression Scale; MMSE=Mini-Mental State Examination; MoCA=Montreal Cognitive Assessment; SD=standard deviation.

[0375] 1 Scores above 0 indicate progressive decline due to cognitive disorders.

[0376] 2 Scores range from 1 to 19; higher scores indicate better delayed verbal recall.

[0377] 3 Scores range from 1 to 30; higher scores indicate better cognitive ability

[0378] 4 Scores range from 3 to 15; lower scores indicate impaired consciousness.

[0379] 5 Scores range from 0 to 15; higher scores indicate a greater likelihood of depression.

[0380] 6 Scores range from 0 to 30; higher scores indicate better cognitive ability

[0381] Safety Results

[0382] The single oral dose of Compound 1 was well tolerated, with no deaths, SAEs, or serious TEAEs observed in any participant. There was also no evidence of clinically significant changes in consciousness (as measured by GCS) or cognitive or psychiatric side effects (as measured by MOCA, GDS, and NPIQ) in any participant. All TEAEs were mild or moderate in intensity, and 8 TEAEs were considered possibly related to treatment; all other TEAEs were assessed as unlikely to be related. These potentially related TEAEs included 3 transient oral sensation reports (abnormal taste, tingling tongue, oral pain), 1 transient dizziness episode, 2 transient headache reports (one treated with a single dose of 500 mg acetaminophen), 1 transient hypertension episode, and 1 laboratory measurement showing an increase in triglycerides on day 7 in a participant with a history of hypertriglyceridemia.

[0383] Equivalents and scope

[0384] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the disclosure described herein.The scope of the present disclosure is not intended to be limited to the above "specific embodiments", but rather is set forth in the appended claims.

[0385] In the claims, unless otherwise indicated or otherwise obvious from the context, articles such as "a", "an", and "the" may mean one or more than one. Unless otherwise indicated or otherwise obvious from the context, a claim item or description including "or" between one or more members in the group is deemed to be satisfied if one, more than one, or all of the group members are present, employed, or otherwise related to a given product or method, if one, more than one, or all of the group members are present, employed, or otherwise related to a given product or method, the present disclosure includes embodiments in which exactly one group member is present, employed, or exactly one group member is otherwise related to a given product or method. The present disclosure includes embodiments in which more than one or all of the group members are present, employed, or more than one or all of the group members are otherwise related to a given product or method, if one, more than one, or all of the group members are present, employed, or ... more than one, or all of the group members are otherwise related to a given product or method, if one, more than one, or all of the group members are present, employed, or more than one, or all of the group members are otherwise related to a given product or method, if one, more than one, or all of the group members are

[0386] It should also be noted that the term "comprising" is intended to be open ended and allows but does not require the inclusion of additional elements or steps. When the term "comprising" is used herein, the term "consisting of" is also thereby encompassed and disclosed.

[0387] When a range is given, the endpoints are also included. In addition, it should be understood that unless otherwise stated or otherwise obvious from the context and the understanding of a person of ordinary skill in the art, the values ​​expressed in the form of a range can take any specific value or sub-range within the specified range in different embodiments of the present disclosure, unless the context clearly dictates otherwise, up to one-tenth of the lower limit of the range.

[0388] In addition, it should be understood that any specific embodiment of the present disclosure that falls within the scope of the prior art may be explicitly excluded from any one or more claims. Since such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if they are not explicitly stated to be excluded herein. Any specific embodiment of the composition of the present disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) may be excluded from any one or more claims for any reason, whether or not related to the existence of prior art.

[0389] It is understood that the words used are words of description rather than limitation and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects.

[0390] Although the present disclosure has been described in some detail and with some particularity with respect to several described embodiments, it is not intended that it should be limited to any such details or embodiments or to any particular embodiment, but rather should be interpreted with reference to the appended claims so as to provide the broadest possible interpretation of such claims in light of the prior art, thereby effectively covering the intended scope of the present disclosure.

Claims

1. (4R, 5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one An anhydrous (AH) crystalline form (Form A) of the invention has an XRPD pattern including 2θ angular peaks at 9.02, 11.65, and 11.86 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

2. The AH crystalline Form according to claim 1, wherein the XRPD pattern further comprises 2θ angular peaks at 12.15, 14.99, 28.99 and 44.03 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

3. The AH crystalline form according to claim 1 or 2, wherein the XRPD pattern further comprises three 2θ angular peaks at 21.09, 21.49 and 21.88 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

4. The AH crystalline form according to any one of claims 1-3, wherein the XRPD pattern comprises 2θ angular peaks at 9.02, 11.65, 11.86, 12.15, 14.99, 21.09, 21.49, 21.88, 28.99 and 44.03 degrees 2θ as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

5. The AH Form according to any one of claims 1 to 4, which has an XRPD pattern substantially as shown in Figure 3.

6. The AH form according to any one of claims 1 to 5, which has a melting endothermic peak at about 134°C-138°C in a differential scanning calorimetry (DSC) thermogram.

7. The AH form according to any one of claims 1-6, which has a DSC thermogram substantially as shown in Figure 4.

8. The AH Form of any one of claims 1-7, having a thermogravimetric analysis (TGA) weight loss of about 0.02% (w / w) between ambient temperature and about 250°C.

9. The AH form according to any one of claims 1 to 8, which has a TGA having a TGA graph substantially as shown in Figure 4.

10. The AH form according to any one of claims 1-9, which is substantially purified.

11. A method for preparing an anhydrous (AH) crystalline form of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), the method comprising precipitating the anhydrous crystalline form from a solution comprising Compound 1 and a solvent selected from ethyl acetate (EtOAc), heptane, and mixtures thereof.

12. The process of claim 11, wherein the solvent is a mixture of EtOAc and heptane.

13. The method of claim 12, wherein the ratio of EtOAc to heptane is 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 or 10:

90.

14. The method of any one of claims 11-13, further comprising cooling the solution.

15. The method of claim 14, further comprising isolating the AH crystalline form by filtration.

16. An anhydrous (AH) crystalline form of Compound 1 prepared by the method according to any one of claims 11-15.

17. A solvate form (Form B) of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), wherein the solvate Form B has an XRPD pattern comprising at least three of the following 2θ angular peaks at 16.07, 16.27, 16.58 and 16.77 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Kα X-rays.

18. The solvate Form B of claim 17, wherein the XRPD pattern further comprises three or more of the following 2θ angular peaks at 13.18, 13.4, 13.54, 13.54 and 13.70 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with CuKα X-rays.

19. The solvate Form B according to claim 17 or 18, wherein the XRPD pattern further comprises 2θ angular peaks at 37.31 and 39.92 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

20. The solvate Form B of any one of claims 17-19, wherein the XRPD pattern further comprises 2θ angular peaks at 13.18, 13.4, 13.54, 13.54, 13.70, 16.07, 16.27, 16.58, 16.77, 37.31 and 39.92 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

21. The solvate Form B of any one of claims 17-20, having an XRPD pattern substantially as shown in Figure 5.

22. The solvate Form B according to any one of claims 17 to 21, which has a melting endothermic peak at about 134°C-138°C in a differential scanning calorimetry (DSC) thermogram.

23. The solvate Form B according to any one of claims 17 to 22, having a DSC thermogram substantially as shown in Figure 6.

24. The solvate Form B of any one of claims 17-23, having a thermogravimetric analysis (TGA) weight loss of about 6.7% (w / w) between ambient temperature and about 200°C.

25. The solvate Form B according to any one of claims 17-24, having a TGA having a TGA pattern substantially as shown in Figure 6.

26. The solvate Form B according to any one of claims 17-25, wherein the solvate is an isopropanol solvate.

27. The solvate Form B according to any one of claims 17-26, which is substantially purified.

28. A method for preparing solvate Form B of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), the method comprising evaporating a mixture of Compound 1 and isopropanol in a dry box under an inert atmosphere.

29. The method of claim 28, wherein the evaporation is performed over a period of 1-2 weeks.

30. The method of claim 28 or 29, further comprising drying the crystalline Form B under vacuum.

31. A crystalline Form B of Compound 1 prepared by the method according to any one of claims 28-30.

32. A solvate form (Form C) of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), wherein the solvate Form C has an XRPD pattern comprising only two peaks between 13.32 and 13.82 degrees 2θ (each ±0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Kα X-rays.

33. The solvate Form C of claim 32, wherein the XRPD pattern further comprises only three peaks between 32.22 and 32.96 degrees 2θ (each ±0.2 degrees 2θ), or comprises 2θ angle peaks at 3.4, 8.33, 10.94, 16.32, and 16.66 degrees 2θ (each ±0.2 degrees 2θ), as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

34. The solvate Form C of claim 32 or 33, wherein the XRPD pattern comprises 2θ angular peaks at 3.4, 8.33, 10.94, 13.32, 13.82, 16.32, 16.66, 32.22, 32.59, 32.96 degrees 2θ (each ± ​​0.2 degrees 2θ) as measured by X-ray diffraction by irradiation with Cu Ka X-rays.

35. The solvate Form C of any one of claims 32-34, having an XRPD pattern substantially as shown in Figure 7.

36. The solvate Form C of any one of claims 32-35, having an XRPD pattern substantially as shown in Figure 9.

37. The solvate Form C according to any one of claims 32 to 36, which has a melting endotherm peak at about 129-133°C in a differential scanning calorimetry (DSC) thermogram.

38. The solvate Form C of any one of claims 32-37, having a DSC thermogram substantially as shown in Figure 8.

39. The solvate Form C of any one of claims 32-38, having a thermogravimetric analysis (TGA) weight loss of about 3.4% (w / w) between ambient temperature and about 200°C.

40. The solvate Form C of any one of claims 32-39, having a TGA having a TGA pattern substantially as shown in Figure 8.

41. The solvate Form C according to any one of claims 32-40, wherein the solvate is an isopropanol solvate.

42. The solvate Form C according to any one of claims 32-41, which is substantially purified.

43. A method for preparing solvate Form C of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), the method comprising precipitating the solvate form from a solution comprising Compound 1 and isopropanol.

44. The method of claim 43, wherein the solution is stirred at 20°C for two weeks.

45. The method of claim 43 or 44, further comprising isolating the crystalline Form C by filtration.

46. ​​Crystalline Form C of Compound 1, prepared by the method according to any one of claims 43-45.

47. The solvate Form C according to any one of claims 32-36, which has endothermic peaks at about 89.4°C and at about 134.2°C in a differential scanning calorimetry (DSC) thermogram.

48. The solvate Form C of any one of claims 32-36 or 47, having a DSC thermogram substantially as shown in Figure 10.

49. The solvate Form C of any one of claims 32-36, 47 or 48, having a thermogravimetric analysis (TGA) weight loss of about 3.2% (w / w) between ambient temperature and about 200°C.

50. The solvate Form C of any one of claims 32-36 or 47-49, having a TGA having a TGA pattern substantially as shown in Figure 10.

51. A method for preparing Solvate Form C of (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1), the method comprising: (i) dissolving compound 1 in isopropanol to form a saturated solution; (ii) filtering the mixture of step (i) into a new vial, which is placed in an outer vial containing an anti-solvent; (iii) stirring the inner vial mixture of step (ii) to precipitate solids; and (iv) filtering the solid from step (iii) and drying the solid under vacuum at room temperature.

52. The method of claim 51, wherein the anti-solvent is pentane.

53. Solvate Form C of Compound 1, prepared by the method according to claim 51 or 52.

54. A pharmaceutical composition comprising an effective amount of a crystalline form or a solvate form according to any one of claims 1-10, 16-27, 31-42, 46-51 or 53.

55. The pharmaceutical composition of claim 54, comprising about 5% (w / w) to about 30% (w / w) of the crystalline form or solvate form.

56. The pharmaceutical composition of claim 55, comprising about 5% (w / w), 10% (w / w), 24% (w / w) or about 25% (w / w) of the crystalline form or solvate form.

57. A pharmaceutical composition according to any one of claims 54-56, wherein the composition is a nanomilled suspension or a spray-dried nanosuspension.

58. A pharmaceutical composition according to any one of claims 54-57, further comprising a pharmaceutically acceptable plasticizer, binder, extender, carrier, excipient, lubricant, disintegrant and / or surfactant.

59. The pharmaceutical composition of claim 58, further comprising at least one of hypromellose, sodium lauryl sulfate and lactose monohydrate.

60. The pharmaceutical composition of claim 59, further comprising at least one of croscarmellose and magnesium stearate.

61. A pharmaceutical composition according to any one of claims 54-60, wherein the composition is in the form of a capsule.

62. A pharmaceutical composition according to any one of claims 54-61, wherein the capsule is selected from a hard hydroxypropylmethylcellulose capsule, a hard gelatin capsule or a soft gelatin capsule.

63. A pharmaceutical composition according to any one of claims 54-62, comprising the components in the following table: Provided that the amounts of binder, surfactant, carrier, disintegrant and lubricant are not all 0%.

64. The pharmaceutical composition of claim 63, wherein the binder is hypromellose, the surfactant is sodium lauryl sulfate, the carrier and binder is lactose monohydrate, the disintegrant is cross-linked carboxymethyl cellulose, and the lubricant is magnesium stearate.

65. A method of treating Alzheimer's disease, preventing epileptic seizures, reversing synaptic loss, or reducing Tau accumulation in a subject in need thereof, the method comprising treating the subject with a therapeutically effective amount of a crystalline form or solvate form according to any one of claims 1-10, 16-27, 31-42, 46-51 or 53.

Images