GABAA receptor modulator salts, particles and uses thereof

Abstract

Described herein are salts (e.g., fumarates) of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, and particles comprising 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine or salts thereof, and uses thereof.

Description

[Technical field]

[0001] Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63,333,075, filed April 20, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0002] GABA receptors respond to the neurotransmitter gamma-aminobutyric acid (GABA), the major inhibitory compound in the vertebrate central nervous system. A Receptors occur in all organisms that have a nervous system. A Modulation of the receptor may therefore be useful in therapeutically addressing diseases or disorders of the central nervous system. 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine (Compound 1) is a GABA receptor antagonist. A Although it is a GABA receptor modulator, it has limited bioavailability and a short half-life in mice. Therefore, improved forms of Compound 1, including A There remains a need for receptor modulator therapeutics. Summary of the Invention [Means for solving the problem]

[0003]

[0003] Described herein are salts of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine and uses thereof, as well as particles comprising 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine or salts thereof and uses thereof.

[0004] Compound 1 is shown below as the free base, where D is deuterium.

[0005] [ka] [Brief description of the drawings]

[0006] [Figure 1] FIG. 2 shows a particle size distribution plot corresponding to the particle batch generated in Example 1 (Particle Batch 1). [Diagram 2] FIG. 2 shows a particle size distribution plot corresponding to a comparative particle batch (particle batch 2a) generated in Example 2. [Diagram 3]

[0007] FIG. 13 shows a particle size distribution plot corresponding to another comparative particle batch (particle batch 2b) generated in Example 2. [Figure 4]

[0008] FIG. 1 shows an XRPD (X-ray powder diffraction) trace of Form A of the hemifumarate salt of Compound 1. [Diagram 5]

[0009] FIG. 2 shows an XRPD trace of Form B hemifumarate salt of Compound 1. [Figure 6]

[0010] FIG. 2 shows DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis) traces of Form A hemifumarate salt of Compound 1. [Figure 7]

[0011] FIG. 2 shows DSC and TGA traces of Form B hemifumarate salt of Compound 1. [Figure 8]

[0012] FIG. 2 shows an XRPD trace of Form A of the sulfate salt of Compound 1. [Figure 9]

[0013] FIG. 2 shows an XRPD trace of Form A of the hydrochloride salt of Compound 1. [Figure 10]

[0014] FIG. 2 shows an XRPD trace of Form A of the phosphate salt of Compound 1. [Figure 11]

[0015] FIG. 2 shows an XRPD trace of Form B phosphate salt of Compound 1. [Figure 12]

[0016] FIG. 2 shows an XRPD trace of Compound 1, Form A tosylate salt. [Figure 13]

[0017] FIG. 2 shows an XRPD trace of Compound 1, Form A, malonate salt. [Figure 14]

[0018] FIG. 2 shows an XRPD trace of Form A maleate salt of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] definition

[0019] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0008]

[0020] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0021] Numerical values ​​relating to measurements are subject to measurement errors that provide limitations to their precision. For this reason, all numerical values ​​provided herein should be understood to be modified by the term "about" unless otherwise indicated.

[0009]

[0022] The term "amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measures known to those skilled in the art.

[0010]

[0023] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein and a carrier or a pharma-ceutical acceptable carrier, respectively. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques for administering compositions, including, but not limited to, intravenous, oral, nasal, rectal, vaginal, aerosol, parenteral, buccal, sublingual, ophthalmic, pulmonary, transdermal and topical administration.

[0011]

[0024] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, such as those described herein, administered to a subject, either as a single dose or as part of a series of doses, that is effective to produce the desired therapeutic effect.

[0012]

[0025] The term "pharmaceutical acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting at least one compound described herein into or to a patient so that the compound can perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation, including the compound described herein, and not harmful to the patient. Other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (ed.), Mack Publishing Co., 1985), the entire contents of which are incorporated herein by reference.

[0013]

[0026] The term "pharmaceutical acceptable salts" refers to derivatives of the disclosed compounds where the parent compound is modified by converting an acid or base moiety present therein into its salt form. A list of salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (eds.), VHCA & Wiley-VCH, 2002), the entire contents of which are incorporated herein by reference.

[0014]

[0027] A "signal" may be present as a component of a broad peak, a shoulder peak, or a split peak resulting from two or more overlapping or adjacent signals.

[0028] The term "solid form" includes, but is not limited to, polymorphs, crystalline forms, amorphous forms, solvates, and hydrates of a compound.

[0015]

[0029] The term "substituted" or "substitution" refers to the replacement of a hydrogen attached to another group with an atom or group of atoms as the replacement substituent, where each substituent is independently selected.

[0016]

[0030] The term "treatment" or "treating" refers to the application of one or more specific procedures used for the amelioration of a disease. "Prophylactic" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset.

[0017]

[0031] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand way of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. Any and all examples provided herein, or the use of illustrative language (e.g., "etc.") are intended merely to better clarify the subject matter described, and do not place limitations on the scope of the subject matter otherwise claimed. No language in this specification should be construed as indicating any non-claimed element essential to practicing the subject matter described.

[0018]

[0032] Groupings of alternative elements or embodiments of this disclosure should not be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, recited members of a group may be included in or excluded from other recited groups for reasons of convenience or patentability.

[0019]

[0033] Throughout this specification, references are made to patents and publications, each of which is individually incorporated herein by reference in its entirety.

[0034] It is to be understood that the embodiments of the present disclosure are illustrative and, therefore, the present disclosure is not limited to that precisely as shown and described.

[0020] Compounds and solid forms

[0035] 3-(2,5-Difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine (compound 1) acts as a selective allosteric modulator of GABA receptor α2, α3 and α5 subtypes. A GABA, which can act at the benzodiazepine site of the receptor A It is a receptor modulator.

[0021]

[0036] Compound 1 and its salts as described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein. The general method for the preparation of compounds as described herein is modified by the use of suitable reagents and conditions for the introduction of the various moieties found in the formulas as provided herein.

[0022]

[0037] In some embodiments, compound 1 can be prepared using the methods described in U.S. Pat. Nos. 8,003,646, 8,399,467, or 8,921,366, the contents of each of which are incorporated by reference. The preparation of compounds corresponding to the non-deuterated form of compound 1 has been described in Journal of Medicinal Chemistry, 48(23):7089-92 (Carling et al., "7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2 / alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models"). Thus, compound 1 can be prepared in a similar manner to Carling et al. by substitution with the appropriate corresponding deuterated reagent.

[0023]

[0038] Preparation of a salt of Compound 1 can occur, for example, by contacting Compound 1 with an acid in a solvent solution and isolating the salt of Compound 1 by removing the solvent.

[0039] Thus, in some embodiments, provided herein is a compound that is the fumarate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine.

[0024]

[0040] In some embodiments, the compound is the hemifumarate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine.

[0025]

[0041] In some embodiments, the compound has the formula:

[0026] [ka]

[0027] where X is 0.5, 1, or 2.

[0042] In some embodiments, provided herein is a compound that is the sulfate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the sulfate salt of compound 1 is prepared by combining 880 mg (2.15 mmol) of compound 1 with 34.2 ml of acetone. To the resulting solution (with minimal residual solids), sulfuric acid (2.5 M in water, 861 μL, 1.0 eq.) was added. The resulting slurry was seeded with crystalline form A (about 10 mg). The slurry was heated to 40° C. (did not dissolve), cooled to 20° C. at 0.1° C. / min (held for 1 hour at each 2° C. interval), and stirred at 20° C. overnight. The solid was isolated by vacuum filtration and air-dried overnight. The yield of Form A sulfate salt of Compound 1 was 83% (905 mg, 1.79 mmol).

[0028]

[0043] In some embodiments, the sulfate salt of Compound 1 has an XRPD pattern substantially as shown in Figure 8. In some embodiments, the sulfate salt of Compound 1 has at least one signal selected from Table A with respect to 2θ.

[0029] [Table 1]

[0030]

[0044] In some embodiments, provided herein is a compound that is the hydrochloride salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the hydrochloride salt of compound 1 is prepared by combining 1.08 g, (2.65 mmol) of compound 1 with acetonitrile (36.8 mL, 34 vol). To the resulting solution (with minimal residual solids), hydrochloric acid (3.6 M in water, 883 μL, 1.0 eq.) was added. The resulting slurry was seeded with crystalline Form A (about 10 mg). The slurry was heated to 40° C. (did not dissolve). The slurry was stirred at 40° C. for 2 hours, cooled to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 hour, and stirred at 20° C. overnight. The solid was isolated by vacuum filtration and air-dried for 3 hours. The yield of Compound 1 Form A hydrochloride was 77% (0.912 g, 2.05 mmol).

[0031]

[0045] In some embodiments, the hydrochloride salt of Compound 1 has an XRPD pattern substantially as shown in Figure 9. In some embodiments, the hydrochloride salt of Compound 1 has at least one signal selected from Table B with respect to 2θ.

[0032] [Table 2]

[0033]

[0046] In some embodiments, provided herein is a compound that is a phosphate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the phosphate salt of Compound 1 is prepared by combining 1.04 g (2.53 mmol) with acetone (34.02 mL, 33 vol). To the resulting solution (with minimal residual solids), hydrochloric acid (3.0 M in water, 845 μL, 1.0 eq.) was added. The resulting slurry was seeded with crystalline Form A (about 10 mg). The slurry was heated to 40° C. (did not dissolve). The slurry was stirred at 40° C. for 2 hours, cooled to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 hour, and stirred at 20° C. overnight. The solid was isolated by vacuum filtration and air-dried for 4 hours. The yield of Compound 1 Form A phosphate was 84% ​​(1.07 g, 2.12 mmol).

[0034]

[0047] In some embodiments, the phosphate salt of Compound 1 has an XRPD pattern substantially as shown in Figure 10 or Figure 11. In some embodiments, the phosphate salt of Compound 1 has at least one signal selected from Table C or Table D with respect to 2θ.

[0035] [Table 3]

[0036] [Table 4]

[0037]

[0048] In some embodiments, provided herein is a compound that is the tosylate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the tosylate salt of compound 1 is prepared by combining 888 mg (2.17 mmol) with IPA (3.5 mL, 39 vol). To the resulting solution (with minimal residual solids), tosylic acid (3.0 M in water, 725 μL, 1.0 eq.) was added. The resulting thin slurry was heated to 40° C. with stirring for 2 hours, gradually thickening and seeding with crystalline Form A (about 10 mg). The slurry was cooled to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 h, and stirred at 20° C. over the weekend. The solid was isolated by vacuum filtration and air-dried for 2 h. The yield of Compound 1 Form A tosylate salt was 87% (1.10 g, 1.89 mmol).

[0038]

[0049] In some embodiments, the tosylate salt of Compound 1 has an XRPD pattern substantially as shown in Figure 12. In some embodiments, the tosylate salt of Compound 1 has at least one signal selected from Table E with respect to 2θ.

[0039] [Table 5]

[0040]

[0050] In some embodiments, provided herein is a compound that is a malonate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the malonate salt of compound 1 is prepared by combining 1.09 g (2.68 mmol) with toluene (3.5 mL, 32 vol). To the resulting solution (with minimal residual solids), malonic acid (3.0 M in water, 893 μL, 1.0 eq.) was added. The resulting thin slurry was heated to 40° C. with stirring for 2 hours and seeded with crystalline Form A (about 10 mg). The slurry was cooled to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 hour, and stirred at 20° C. for several days. The solid was isolated by vacuum filtration and air-dried for 2 hours. The yield of Compound 1 Form A malonate salt was 73% (0.996 g, 1.94 mmol).

[0041]

[0051] In some embodiments, the malonate salt of Compound 1 has an XRPD pattern substantially as shown in Figure 13. In some embodiments, the malonate salt of Compound 1 has at least one signal selected from Table F with respect to 2θ.

[0042] [Table 6]

[0043]

[0052] In some embodiments, provided herein is a compound that is the maleate salt of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine. In some embodiments, the maleate salt of compound 1 is prepared by combining 1.09 g (2.67 mmol) with toluene (3.5 mL, 32 vol). To the resulting solution (with minimal residual solids), maleic acid (3.0 M in water, 891 μL, 1.0 eq.) was added. The resulting thin slurry was seeded with crystalline Form A (approximately 10 mg). The slurry was heated to 40° C. (did not dissolve). The slurry was stirred at 40° C. for 2 hours, cooled to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 hour, and stirred at 20° C. for several days. The solid was isolated by vacuum filtration and air-dried for 4 hours. The yield of Compound 1 Form A maleate salt was 91% (1.28 g, 2.43 mmol).

[0044]

[0053] In some embodiments, the maleate salt of Compound 1 has an XRPD pattern substantially as shown in Figure 14. In some embodiments, the maleate salt of Compound 1 has at least one signal selected from Table G with respect to 2θ.

[0045] [Table 7]

[0046]

[0054] In some embodiments, the compound is an anhydrate, hemihydrate, monohydrate, or dihydrate. In some embodiments, the compound is a solvate. In some embodiments, the compound is in a solid form.

[0047]

[0055] In some embodiments, the solid form B hemifumarate has an X-ray powder diffraction pattern comprising a 2-theta signal at about 9.05±0.2° based on CuKα1 radiation (1.54060 Å). In some embodiments, the solid form B hemifumarate has an X-ray powder diffraction pattern comprising 2-theta signals at about 9.05±0.2°, about 15.46±0.2°, about 22.55±0.2°, and about 24.61±0.2° based on CuKα1 radiation (1.54060 Å). In some embodiments, the solid form B hemifumarate has an X-ray powder diffraction pattern substantially as shown in FIG. 5. In some embodiments, the solid form B hemifumarate has a differential scanning calorimetry thermogram comprising an endothermic signal at about 199.6±3.0 (e.g., ±0.5)°C. In some embodiments, solid form B hemifumarate has a differential scanning calorimetry thermogram substantially as shown in Figure 7. In some embodiments, solid form B hemifumarate has a thermogravimetry thermogram substantially as shown in Figure 7.

[0048]

[0056] In some embodiments, the solid form A hemifumarate has an X-ray powder diffraction pattern comprising 2-theta signals at about 7.70±0.2° or about 21.80±0.2° based on CuKα1 radiation (1.54060 Å). In some embodiments, the solid form A hemifumarate has an X-ray powder diffraction pattern comprising 2-theta signals at about 7.70±0.2°, about 21.80±0.2°, about 25.44±0.2°, and about 28.75±0.2° based on CuKα1 radiation (1.54060 Å). In some embodiments, the solid form A hemifumarate has an X-ray powder diffraction pattern substantially as shown in FIG. 4. In some embodiments, solid Form A hemifumarate has a differential scanning calorimetry thermogram comprising an endothermic signal at about 62.1±3.0 (e.g., ±0.5)° C., about 195.2±3.0 (e.g., ±0.5)° C., or both. In some embodiments, solid Form A hemifumarate has a differential scanning calorimetry thermogram substantially as shown in Figure 6. In some embodiments, solid Form A hemifumarate has a thermogravimetry analysis substantially as shown in Figure 6.

[0049]

[0057] Powders analyzed by XRPD spectroscopy may contain components other than the crystalline compound intended to be identified, which may result in signals present in the XRPD diffractogram in addition to those due to the crystalline compound to be identified. A particular compound may also contain two or more adjacent or overlapping signals. Thus, in some embodiments, an XRPD signal may be present as a component of a broad peak, a shoulder peak, or a split peak, which are due to two or more overlapping or adjacent signals. In some embodiments, an XRPD signal may be synonymous with an XRPD peak.

[0050]

[0058] In some embodiments, the compound or solid form is substantially purified. In some embodiments, the compound or solid form is crystalline. In some embodiments, the compound or solid form is prepared by a method comprising precipitating the compound from a solution comprising 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, fumaric acid, and a solvent comprising acetone or acetonitrile. In some embodiments, the method comprises drying the precipitated compound. In some embodiments, the precipitated compound, which may be crystalline, is reduced (e.g., crushed, impacted, or disintegrated) to particles having one or more of the particle characteristics described below.

[0051]

[0059] In some embodiments, a composition is provided that comprises one or more compounds as described herein.In some embodiments, the composition is a pharmaceutical composition.The composition can further comprise a pharma-ceutically acceptable carrier.

[0052]

[0060] In some embodiments, the compound is present in the composition in an amount of at least about 90% by weight.

[0061] In some embodiments, the composition is a pharmaceutical composition consisting essentially of the compound.

[0053] particle

[0062] In some embodiments, described herein is a compound of the formula:

[0054] [ka]

[0055] or a salt thereof.

[0063] In some embodiments, the compound is about or at least about 75%, 80%, 85%, 90%, 95%, or 100% by weight of the particle.

[0056]

[0064] In some embodiments, the particles include a particle surface that includes a coating on at least a portion of the particle surface. In some embodiments, the coating includes a film coating. In some embodiments, the particles include a film coating with a polymer or copolymer to form a microcapsule, which can be used to form a chewable taste-masked granule. In some embodiments, the coating includes a polymer or copolymer. In some embodiments, the coating includes one or more of cellulose acetate phthalate, cellulose acetate trimerate, ethyl cellulose, glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, high molecular weight polyethylene, polyvinyl alcohol, polyvinylpyrrolidone, starch, or shellac. In some embodiments, the coating includes a varnish (e.g., a non-nutritive varnish). In some embodiments, the coating includes a sugar. In some embodiments, the coating includes a sugar coating. In some embodiments, the particles described herein are sugar coated. In some embodiments, the particles described herein are not sugar coated.

[0057]

[0065] In some embodiments, a dosage form comprising a plurality of particles comprises coated particles, where the coating is selected, independently for each particle, from the coatings described herein. Thus, in some embodiments, the plurality of particles can comprise a mixture of enteric coated particles and extended release coated particles.

[0058]

[0066] In some embodiments, the particles described herein are encapsulated within a coating.

[0067] In some embodiments of the particles described herein, the coating is no more than 25% by weight of the coated particle.

[0059]

[0068] In some embodiments, the particles comprise a diameter of about 0.2-20 μm (eg, about 1-10 μm, eg, about 2-6 μm, eg, about 4 μm).

[0069] In some embodiments, the particles described herein are provided as a composition comprising a plurality of particles, which may include one or more carriers.In some embodiments, the plurality of particles is encapsulated in a capsule, a compression coating, a film coating, or a powder coating.In some embodiments, the particle or the plurality of particles is spray coated, whether as a powder, a compression powder, or a tablet.In some embodiments, the plurality of particles is a loose powder in an ingestible capsule.In some embodiments, the plurality of particles is compressed into a brittle solid.

[0060]

[0070] In some embodiments, the plurality of particles comprises: 1) Surface-weighted average (D3,2) of about 1.5-1.9 μm (e.g., about 1.7 μm); 2) a volume-weighted mean diameter (D4,3) of about 3.5 to 4.5 μm (e.g., about 3.9 μm); 3) d(0.1) of about 0.5-0.9 μm (e.g., about 0.7 μm); 4) d(0.5) of about 2.5 to 3.5 μm (e.g., about 2.9 μm); 5) d(0.9) of about 6-9 μm (e.g., about 7.8 μm); 6) A span of about 0.7 to 3.4 (e.g., about 2.4); 7) a uniformity factor of about 0.6 to 1.0 (e.g., about 0.8); or 8) A refractive index of about 1.4 to 1.6 (e.g., about 1.5) Contains one or more of the following:

[0061]

[0071] In some embodiments, provided herein is an oral dosage form comprising the particles, compositions, or pharmaceutical compositions described herein. In some embodiments, the oral dosage form comprises a plurality of particles as a powder or as a compressed powder.

[0062]

[0072] In some embodiments, a particle, composition, or pharmaceutical composition provided herein is contained within at least one container. composition

[0073] In some embodiments, the particles described herein can be in the form of a composition. In some embodiments, the composition is a pharmaceutical composition that further comprises a pharma- ceutically acceptable carrier.

[0063]

[0074] In some embodiments, the compositions described herein include a first pharmaceutical active that is Compound 1 or a salt thereof and a second pharmaceutical active that can be a compound useful in treating a disease or disorder of the central nervous system. method

[0075] Compound 1, and its pharma- ceutically acceptable salts, can be used as described in U.S. Patent Nos. 8,003,646, 8,399,467, or 8,921,366. Compound 1, and its pharma- ceutically acceptable salts, can be used as described in U.S. Patent Nos. 8,003,646, 8,399,467, or 8,921,366. A They are described therein as receptor modulators and are useful in treating disorders of the central nervous system, including anxiety, convulsions, neuropathic pain, inflammatory pain, and migraine-related pain.

[0064]

[0076] Additionally, Compound 1 or other GABA AThe therapeutic use of the corresponding non-deuterated form of receptor modulator or its pharmaceutically acceptable salt is described in US Patent No. 6,255,305 or US Patent No. 6,500,828, or WO2006061428, the entire contents of each of which are incorporated by reference.The uses described in US Patent No. 6,255,305 include the treatment of various disorders of the central nervous system, such as anxiety disorders such as panic disorder with or without agoraphobia; agoraphobia without a history of panic disorder; animal and other phobias, including social phobia; obsessive-compulsive disorder; stress disorders, including post-traumatic and acute stress disorders, and generalized or substance-induced anxiety disorder; neurosis; convulsions; migraine; and depressive or bipolar disorders, such as single episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II mania, and circulatory disorders. The uses described in U.S. Patent No. 6,500,828 include, in addition to those described above, the treatment of various disorders of the central nervous system, such as psychotic disorders, including schizophrenia; neurodegeneration resulting from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, for example in subjects suffering from jet lag or the effects of shift work.Furthermore, the uses described in U.S. Patent No. 6,500,828 include the treatment of pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular chemotherapy or radiation induced emesis, and postoperative nausea and vomiting symptoms; eating disorders, including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasms or spasticity, for example in paraplegic patients; and hearing loss, and the like. A Additionally, U.S. Patent No. 6,500,828 discloses GABA receptor selective ligands for the GABA receptor. AIt is stated that selective ligands for receptors can also be effective as pre-medication before anesthesia or secondary procedures, such as endoscopy, including gastroscopy.The uses described in WO2006061428 include the treatment of pain, such as neuropathic, inflammatory or migraine-related pain.WO2006061428 states that neuropathic pain encompasses a range of pain syndromes of diverse origins, including diabetic neuropathy, post-herpetic neuralgia, nerve damage after surgery, pain following paraplegia, hypersensitivity to non-painful stimuli (allodynia), such as after surgery or during migraine attacks, spontaneous pain, hyperalgesia, diffuse muscle tenderness of myofacial syndromes, sensory dysfunction of the gastrointestinal tract, such as in irritable bowel disease, or most of chest pain and back pain, and further states that cancer and AIDS-related pain are also recognized as neuropathic pain. WO2006061428 further states that inflammatory pain encompasses pain associated with conditions such as trauma, osteoarthritis, rheumatoid arthritis, post-surgical recovery, and some forms of cancer pain.

[0065]

[0077] Thus, in some embodiments, the particles described herein comprising Compound 1 or a pharma- ceutically acceptable salt thereof contain GABA. A It is useful in treating receptor-related diseases, diseases or disorders of the central nervous system, and diseases or disorders as described above.In some embodiments, the particles described herein can be useful as anxiolytics, anticonvulsants, amnesic drugs, sedatives, hypnotics, euphoric drugs, or muscle relaxants.

[0066]

[0078] In some embodiments, the particles described herein comprise GABA. A They are useful as receptor modulators and in treating a variety of disorders or diseases of the central nervous system.

[0067]

[0079] In some embodiments, the particles described herein are useful as anxiolytics or analgesics.Accordingly, in some embodiments, described herein is a method for treating anxiety or pain in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of the particles described herein.

[0068]

[0080] In some embodiments, described herein are methods for administering to a subject a therapeutically effective amount of a particle, composition, pharmaceutical composition, or oral dosage form described herein, comprising administering to a subject a therapeutically effective amount of a particle, composition, pharmaceutical composition, or oral dosage form described herein. A GABA receptor-associated disease or central nervous system disease or disorder in a subject in need of treatment A A method of treating a receptor-related disease or a disease or disorder of the central nervous system.

[0069]

[0081] While the methods as described refer to the particles described herein, it should be understood that the particles, in the form of compositions or pharmaceutical compositions, can be used in conjunction with these methods as well.

[0070]

[0082] Actual dosage levels of the active ingredients provided herein (e.g., the pharma- ceutical active compounds of the particles described herein (e.g., Compound 1)), compositions, or pharmaceutical compositions can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0071]

[0083] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, and the age, sex, weight, condition, general health or previous medical history of the patient being treated.

[0072]

[0084] The route of administration includes, but is not limited to, oral, nasal, rectal, vaginal, aerosol, parenteral, buccal, sublingual, ophthalmic, pulmonary or topical administration.In some embodiments, the oral or nasal route of administration is oral inhalation or nasal inhalation route of administration.The compound for use as described herein can be formulated for administration by any suitable route to achieve the particular method applied.

[0073]

[0085] Thus, administration of the compounds, compositions, or combinations disclosed herein includes a variety of enteral or parenteral approaches selected from, but not limited to: oral administration in any acceptable form, such as tablets, liquid (e.g., liquid suspensions of particles), capsules, powders, etc.; topical or transdermal administration in any acceptable form, such as drops, sprays, creams, gel ointments, or patches, etc.; buccal, nasal, sublingual, ocular, pulmonary and / or inhalation administration in any acceptable form; rectal administration in any acceptable form; intravaginal administration in any acceptable form; peritoneal and intratissue administration in any acceptable form, such as intraperitoneal, intramuscular, subcutaneous, intravenous, or intraarticular injection, etc.; intravesicular administration in any acceptable form, such as catheter instillation, etc.; and by indwelling devices, such as implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems, or another implanted sustained or slow release system.

[0074]

[0086] Local administration results in significantly more delivery of the compound, composition or combination to a specific location compared to the entire body of a mammal, whereas systemic administration results in the delivery of the compound, composition or combination to the entire body of an individual.The administration route suitable for treating central nervous system-related diseases or disorders as disclosed herein further includes both central and peripheral administration.Central administration results in the delivery of the compound, composition or combination to the central nervous system of an individual, and includes, for example, intranasal administration, intrathecal administration, epidural administration, and cranial injection or implantation.In some embodiments, central administration is used to administer the compound, composition or combination described herein.

[0075]

[0087] Central administration by the nasal route, which targets drug absorption via the vascular plexus of the nasal cavity, differs from administration by nasal inhalation, which delivers drugs via the pulmonary system. The latter typically uses liquid or dry powder aerosols with an average particle size of less than about 10 microns, while central administration can be achieved using an average particle size of about 10 microns or more. Mists and aerosols can be generated using nebulizers, dry powder inhalers, pressurized aerosols, and spray pumps. It is also feasible to use nasal drops (e.g., suspensions of particles in liquid) for central administration by the nasal route.

[0076]

[0088] Peripheral administration results in the delivery of a compound, composition or combination to essentially any area of ​​an individual outside the central nervous system, and includes any route of administration other than direct administration to the spine or brain.

[0077] kit

[0089] In some embodiments, provided herein are packaged particles, compositions, or pharmaceutical compositions comprising a container holding a therapeutically effective amount of a particle described herein and instructions for using the particle according to one or more of the methods provided herein.

[0078]

[0090] The particles and related materials can be completed as commercial products by steps conventionally performed in the art, for example by appropriate sterilization and packaging steps. For example, the materials can be treated by UV / vis irradiation (200-500 nm), for example using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is usually performed for irradiation times of 1-60 minutes, although longer irradiation times can be applied depending on the specific method. The materials according to the present disclosure can finally be sterilized wrapped and packaged in suitable containers (boxes, etc.) (e.g., by adding a specific product information pamphlet) to maintain sterility until use.

[0079]

[0091] According to further embodiments, the particles can be provided in kit form in which they are combined with other components necessary for administration of the material to a patient. For example, the disclosed kits, such as for use in the treatment of cancer, can further include, for example, administration materials.

[0080]

[0092] The kits can be designed in a variety of forms based on the particular deficiency they are designed to treat.

[0093] The particles or compositions provided herein can be prepared and placed in a container for storage at ambient or elevated temperatures. When the particles or compositions are stored in a polyolefin plastic container, for example, compared to a polyvinyl chloride plastic container, discoloration of the particles (e.g., compounds in the particles) or composition can be reduced, whether suspended in a liquid composition (e.g., aqueous or organic liquid solution) or as a solid. Without wishing to be bound by theory, the container can reduce exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers further include the ability to reduce exposure of the contents of the container to infrared light, or a second component having such ability. Some containers further include the ability to reduce exposure of the contents of the container to heat or humidity. The container that can be used includes those made of polyolefin, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, especially polyethylene, polypropylene, or combinations thereof.In some embodiments, the container is a glass container.The container can be placed in a second container, such as a paper container, a cardboard container, a paperboard container, a metal film container, or a foil container, or combinations thereof, to further reduce the exposure of the contents of the container to UV light, visible light, or infrared light.Production articles that benefit from reduced discoloration, decomposition, or both during storage include dosage forms that include the particles or compositions described herein.The particles or compositions provided herein may require storage that lasts up to 3 months or longer; in some cases, up to 1 year or longer.The container can be any form suitable for containing the contents, such as a bag, a bottle, or a box.

[0081]

[0094] The following examples further illustrate aspects of the present disclosure, but are in no way a limitation of the teachings or disclosure as set forth herein. EXAMPLES

[0082] Example 1

[0095] Micronized particles of Compound 1 free base were generated and subsequently analyzed using a Mastersizer 2000 instrument and a Scirocco 2000 dispersion unit. The particle analysis data are shown in Tables 1 and 2, and in Figure 1. The data for non-micronized particles used as comparisons (Examples 2a and 2b, below) are shown in Tables 3 and 4, and in Figures 2 and 3.

[0083] [Table 8]

[0084] [Table 9-1]

[0085] [Table 9-2]

[0086] Example 2

[0096] Non-micronized particles of Compound 1 free base were generated and subsequently analyzed using a Mastersizer 2000 instrument and a Scirocco 2000 dispersion unit. The particle analysis data are shown in Tables 3 and 4 and Figures 2 and 3.

[0087] [Table 10]

[0088] [Table 11]

[0089] Example 3

[0097] The exposure of Compound 1 free base following oral (PO) dose administration of 300 mg / kg / dose of micronized particles (Example 1) and 300 mg / kg / dose of non-micronized particles (Example 2) was determined in male cynomolgus monkeys. Table 5 describes the study design and dosing schedule. Blood samples were collected from the femoral vein into K2EDTA-coated polypropylene tubes and plasma was separated. Samples were taken at the following time points: pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 12 hours, 14 hours, 24 hours, 30 hours and 48 hours after dosing. Compound 1 concentration was determined by LC-MS / MS and pharmacokinetic parameters were determined using Phoenix WinNonlin v8.0) software. A summary of pharmacokinetic parameters is shown in Table 6.

[0090] [Table 12]

[0091] [Table 13]

[0092] Example 4

[0098] A pharmacokinetic analysis was performed comparing administration of certain salts of Compound 1 with Compound 1 following oral (PO) administration in three male cynomolgus monkeys. Subjects received a single PO oral gavage of the active pharmaceutical ingredient (API) in a capsule (e.g., Compound 1 fumarate, Compound 1 sulfate, Compound 1 hydrochloride, Compound 1 phosphate, Compound 1 tosylate, Compound 1 malonate, Compound 1 maleate, or Compound 1 free base) at a dose of 30 mg / kg. Following dose administration, animals were flushed with approximately 10 milliliters of tap water to ensure that all API was administered. Animals were observed for any abnormal clinical and behavioral signs twice daily and at the time of sample collection. Body weights were taken prior to dosing and weekly thereafter until the end of the study. Blood samples (0.5 mL) were collected pre-dose, 15 minutes, 30 minutes, and 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours post-dose. Each blood sample was collected via direct venipuncture from the monkey's femoral, saphenous or other available vein, placed in a polypropylene tube containing K2EDTA as an anticoagulant, and mixed by gentle inversion several times. Blood samples were kept on wet ice until centrifugation. Blood was centrifuged within 10 minutes of collection. Samples were centrifuged at 3,000 g for 5 minutes at a temperature of 4° C. The resulting plasma (approximately 0.25 mL) was divided into two equal aliquots (125 μL each) in polypropylene tubes designated Set A and Set B after centrifugation. Plasma samples designated for a particular metabolite (Set A) were treated with 12.5 μL of 2 M ascorbic acid (plasma:ascorbic acid=9:1, v:v) previously prepared by combining 0.352 g of ascorbic acid in 1 mL of sterile water in a glass vial and mixing thoroughly. Plasma samples designated for Compound 1 (Set B) did not require treatment with ascorbic acid. Once plasma was prepared, samples were flash frozen on dry ice. All plasma samples were stored frozen below -70°C prior to analysis. Results are shown in Table 7.

[0093]

[0099] Surprisingly, the fumarate salt of compound 1 had a C of approximately 3080 ng / mL. maxThe fumarate salt of compound 1 had an AUC of 38,904 ng·h / mL, which is more than 98% higher than that of compound 1 (free base; 1550 ng / mL). last which is more than 50% higher than that of compound 1 (25463 ng-h / mL).

[0094] [Table 14]

[0095] Example 5

[0100] Hemifumarate Form A (acetonitrile solvate) and hemifumarate Form B (nonsolvate) of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine were prepared. Seed crystals for Form B were prepared by first combining 20.3 mg (0.050 mmol) of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine with 1000 μL of acetone. Fumaric acid / EtOH (248 mg, 1.0 equiv.) was added and the sample was cycled between temperatures of 40° C. and 5° C. with continuous stirring for 48 hours (heat and cool at 2° C. / min, hold at 40° C. and 5° C. for 1 hour). The sample was isolated at 5° C. and the suspension was equilibrated at 20° C. for 2 hours with stirring. The birefringent solid was collected by filtration at room temperature and air-dried overnight. 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine (5.51 mmol) was combined with acetone (3.5 mL, 16 vol). To the resulting solution (with minimal residual solids) was added fumaric acid (575 mg, 1.0 equiv.) followed by seeding with, for example, Form B (approximately 10 mg). The slurry was heated to 40° C. with stirring for 2 hours, cooled very slowly to 20° C. at a rate of 0.1° C. / min, held at 2° C. intervals for 1 hour, and stirred at 20° C. overnight. The solid was isolated by vacuum filtration and air-dried for 4 hours. The yield of hemifumarate Form B was 79% (2.02 g, 4.33 mmol). Form A (prepared as above but with acetonitrile instead of acetone) converted to Form B in 1 week at ambient conditions.

[0096]

[0101] Selected physicochemical data for Form B was collected. Hemi-fumarate Form B was determined to be crystalline by polarized light microscopy (PLM) and XRPD. DSC analysis showed a very small endotherm at 194.3°C (ΔH=1.7 J / g) immediately followed by a sharp endotherm at 199.6°C (ΔH=105 J / g) and TGA analysis showed a 0.7% wt loss up to 190°C (see Figure 7). Proton NMR confirmed the hemi-salt with a CI:API ratio of 0.5:1. Gravimetric vapor sorption (GVS) analysis showed <0.1% wt water uptake between 5 and 95% RH. No changes in the XRPD pattern were observed after GVS.

[0097]

[0102] Intrinsic dissolution rate was determined by forming compressed pellets of approximately 75 mg of API using a compression force of 1200 lbs (544.32 kg) force and dissolving each pellet (die surface area: 0.5 cm) into a flat-bottom vessel containing 500 mL of media (0.1 N HCl aqueous solution with 1% Tween 80 (Polyoxyethylene (20) Sorbitan Monooleate)) using a Distek 2100A dissolution bath with a paddle speed of 100 rpm and a Distek Circulator / Heater set at 37 °C. 2 ) were immersed in the solution. Sample aliquots (1 mL) were withdrawn from the dissolution medium at 15, 30, 45, 60, 75, 90, 105 and 120 min, filtered and analyzed by HPLC. The slope of the dissolution profile was 8.9 μg / (min cm) for compound 1 (free base). 2 ) compared to 6.2 μg / (min cm 2 ) corresponded to the intrinsic dissolution rate of hemifumarate form B.

[0098]

[0103] Selected physicochemical data was collected for Form A. Hemi-fumarate Form A was determined to be crystalline by polarized light microscopy (PLM) and XRPD. DSC analysis showed a sharp endotherm at 62.1° C. (ΔH=76 J / g) followed by a sharp endotherm at 195.2° C. (ΔH=109 J / g) and TGA analysis showed a 7% wt loss up to 80° C. (see FIG. 6).

[0099]

[0104] For PLM, micrographs were collected using an Olympus BX60 polarizing microscopy equipped with an Olympus DP70 camera or an Olympus BX51 polarizing microscopy equipped with an Olympus DP71 camera.

[0100]

[0105] The solid-state stability of the fumarate salt of Compound 1 was determined by HPLC and XRPD after storage for 2 and 4 weeks at the following conditions: 40° C. / 75% RH (open); and 50° C. / ambient RH (closed). No significant changes were observed by either HPLC or XRPD after 4 weeks under these conditions.

[0101]

[0106] DSC was performed using a TA Instruments Q200 or Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under a 40 mL / min N2 purge. Unless otherwise noted, DSC thermograms of samples were obtained in crimped Al pans at 15 °C / min.

[0102]

[0107] TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer in Al pans under a 40 mL / min N purge for the balance and 60 mL / min for the samples. Unless otherwise noted, TGA thermograms of samples were obtained at 15° C. / min.

[0103]

[0108] GVS experiments were performed on a Surface Measurement Systems DVS-Advantage. Experiments were performed at 25° C. The instrument was operated in step mode, increasing the relative humidity from 40% RH to 75% RH in 10% RH increments, then decreasing from 75% RH to 5% RH, then increasing a second time from 5% RH to 95% RH, then decreasing from 95% RH to 5% RH. The mass balance criterion was set at 0.003% change in mass over time (dm / dt). A minimum step time of 20 minutes and a maximum step time of 240 minutes were specified.

[0104] Example 6

[0109] Powder X-ray diffraction patterns were collected for selected salt forms described herein, including hemifumarate form A (acetonitrile solvate) and hemifumarate form B (non-solvate) of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine (see Figures 4 and 5, respectively). XRPD diffractograms were acquired on a Bruker D8 Advance system using a LynxEye position-sensitive detector with CuKα (λ1=1.54060 Å; λ2=1.54439 Å) radiation, X-ray tube voltage and current of 40 kV and 40 mA, and a 3° 2θ aperture. The configuration on the incident beam side was as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5 deg Soller slit, and beam knife. The configuration on the diffracted beam side was as follows: anti-scatter slit (8 mm) and 2.5 deg Soller slit. Samples were mounted flat on a zero background Si wafer. Samples were spun at 30 rpm. Data were collected with a step size of 0.029°2θ and a step time of 0.1 seconds. Data were collected from 2 to 40°2θ for a total scan time of 2 minutes 22 seconds per sample. XRPD patterns were imported into Panalytical HighScore Plus v 2.2. The Kα2 contribution was mathematically removed from the pattern, followed by the determination of the background baseline, followed by the determination of signal positions and relative intensities. Alternatively, XRPD diffractograms were acquired on a PANalytical X'Pert Pro diffractometer using Ni-filtered CuKα (45 kV / 40 mA) radiation and a step size of 0.03° 2θ and an X'celerator RTMS (Real Time Multi-Strip) detector. Incident beam side configuration: variable divergence slit (10 mm exposure length), 0.04 rad Soller slit, fixed anti-scatter slit (0.50°), and 10 mm beam mask. Diffracted beam side configuration: variable anti-scatter slit (10 mm observation length) and 0.04 rad Soller slit.The samples were mounted flat on a zero background Si wafer and the results are shown in Table 8.

[0105] [Table 15-1]

[0106] [Table 15-2]

[0107] Example 7. Oral non-human primate crossover study

[0110] The objective of this study is to determine the pharmacokinetic (PK) profile of the test article following a single oral dose to four male non-human primates, cynomolgus monkeys, with a one (1) week washout period. The dosing and crossover design are as shown in Table 9.

[0108] [Table 16]

[0109]

[0111] Four male animals are used for this study, and four study animals are used for each of the three dosing phases with a one-week washout period. Food is withheld overnight before dose administration, and food is returned 4 hours after dose administration. Water is provided ad libitum by an automatic watering device. Two of the four animals are pretreated with Compound 1, and the other two are untreated with Compound 1. Test articles (M-3, N-3, or K-13) are provided as encapsulated powders; stored, for example, in polyolefin bottles, at room temperature protected from light. Table 10 summarizes the study results, which show that the fumarate salt of Compound 1 in both micronized and non-micronized forms provides superior exposure to Compound 1 when compared to subjects dosed with Compound 1 free base.

[0110] [Table 17]

[0111]

[0112] Micronized and non-micronized particles of Compound 1 hemifumarate salt in this example are set forth in Table 11 (micronized) and Table 12 (non-micronized).

[0112] [Table 18]

[0113] [Table 19]

[0114] Example 8. Intrinsic Dissolution Rate Compound 1 and seven different salts of Compound 1 are listed in USP <1087> Intrinsic dissolution rate (IDR) determinations were made in 0.1 N hydrochloric acid with 1% Tween 80 (Polyoxyethylene (80) Sorbitan Monooleate) according to the method described above. Compressed pellets containing approximately 75 mg of API were prepared using a compression force of 1200 lbs (544.32 kg) force, and each pellet (die surface area: 0.5 cm) was poured into a flat bottom vessel containing 500 mL of media using a Distek 2100A dissolution bath with a paddle speed of 100 rpm and a Distek Circulator / Heater set at 37°C. 2 ) was immersed. Sample aliquots (1 mL) were withdrawn from the dissolution medium at 15, 30, 45, 60, 75, 90, 105 and 120 min, filtered and analyzed by HPLC.

[0115] A summary of the intrinsic dissolution rate and solubility of each compound tested is presented in Tables 13 and 14.

[0116] [Table 20]

[0117] [Table 21]

[0118] Example 9. Solid State Stability

[0115] The solid-state stability of Compound 1 and seven salts of Compound 1 was determined by HPLC and XRPD after storage for 2 and 4 weeks at the following conditions: 40°C / 75% RH (open); and 50°C / ambient RH (closed), as in Example 8.

[0119] No significant changes were observed in the HPLC data of compounds exposed to 40° C. / 75% RH (open) and 50° C. / ambient RH (closed) for up to 4 weeks. XRPD analysis of stability samples showed no significant changes in the SRPD patterns after 4 weeks at storage conditions, except for the HCl salt where a small signal at 10° 2θ of compound 1 (free base) was observed at 40° C. / 75% RH.

[0120]

[0117] HPLC and solid-state stability analyses for IDR were performed on an Agilent 1260 Infinity system equipped with a G1311B quad pump, a G1329B autosampler, a G1330B autosampler thermostat, a G1316A thermostated column compartment with a column switch valve, and a G4212B diode array detector.

[0121] Example 10. Melting Point Seven melting points of Compound 1 and its salts (as in Example 8) were collected and the results are summarized in Table 15.

[0122] [Table 22]

Claims

1. 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d ３ ) ethyl-2,2,2-d ３ A compound that is the fumarate of ]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine.

2. 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d ３ ) ethyl-2,2,2-d ３ The compound according to claim 1, which is the hemifumarate of ]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine.

3. formula: 【Chemistry 1】 (In the formula, X is 0.5, 1, or 2) The compound according to claim 1.

4. The compound according to any one of claims 1 to 3, which is an anhydrous, hemihydrate, monohydrate, dihydrate, or solvate.

5. A compound according to one of claims 1 to 3, which is in solid form.

6. The solid form has an X-ray powder diffraction pattern containing a 2-theta signal, with a value of approximately 9.05 ± 0.2° based on CuKα1 radiation (1.54060 Å) or approximately 9.76 Å based on d-spacing. The solid form has an X-ray powder diffraction pattern containing a 2-theta signal, based on CuKα1 radiation (1.54060 Å), with angles of approximately 9.05±0.2°, approximately 15.46±0.2°, approximately 22.55±0.2°, and approximately 24.61±0.2°, or based on d-spacing, with angles of approximately 9.76 Å, approximately 5.73 Å, approximately 3.96 Å, and approximately 3.61 Å. The solid form has an X-ray powder diffraction pattern substantially as shown in Figure 5, The solid form has a differential scanning calorimetry thermogram containing an endothermic signal at approximately 199.6 ± 3.0 (e.g., ±0.5) °C, The solid form has a differential scanning calorimetry thermogram substantially as shown in Figure 7, Does the solid form have a thermogravimetric analysis substantially as shown in Figure 7? The solid form has an X-ray powder diffraction pattern containing a 2-theta signal, based on CuKα1 radiation (1.54060 Å), of approximately 7.70 ± 0.2° or approximately 21.80 ± 0.2°, or based on d-spacing, of approximately 11.5 Å or approximately 4.07 Å. The solid form has an X-ray powder diffraction pattern containing a 2-theta signal, based on CuKα1 radiation (1.54060 Å), with angles of approximately 7.70±0.2°, approximately 21.80±0.2°, approximately 25.44±0.2°, and approximately 28.75±0.2°, or based on d-spacing, with angles of approximately 11.5 Å, approximately 4.07 Å, approximately 3.50 Å, and approximately 3.10 Å. The solid form has an X-ray powder diffraction pattern substantially as shown in Figure 4, The solid form has a differential scanning calorimetry thermogram that includes endothermic signals at approximately 62.1 ± 3.0 (e.g., ±0.5) °C, approximately 195.2 ± 3.0 (e.g., ±0.5) °C, or both. The solid form has a differential scanning calorimetry thermogram substantially as shown in Figure 6, or The compound according to claim 5, wherein the solid form has a thermogravimetric analysis substantially as shown in Figure 6.

7. A substantially purified compound according to one of claims 1 to 3.

8. A crystalline compound according to one of claims 1 to 3.

9. A solvent containing acetone or acetonitrile, 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d ３ ) ethyl-2,2,2-d ３ ]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4, 3-b) The compound according to any one of claims 1 to 3, which is prepared by a method comprising precipitating the compound from a solution containing pyridazine and fumaric acid, and which may also comprise drying the precipitated compound.

10. A composition comprising the compound described in one of claims 1 to 3.

11. A pharmaceutical composition further comprising a pharmaceutically acceptable carrier, or The composition according to claim 10, which is a pharmaceutical composition essentially consisting of a compound.

12. The composition according to claim 11, wherein the compound is present in the composition in an amount of at least about 90% by weight.

13. 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d ３ ) ethyl-2,2,2-d ３ Particles comprising ]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof, or the composition according to claim 10: 1) A specific surface area of about 3.0 to 4.0 m ２ / g (e.g., about 3.6); or 2) Diameter of approximately 0.15 to 50 μm; or Both 1) and 2) A particle having the following properties.

14. The particles according to claim 13, wherein the compound constitutes about or at least about 75% by mass, 80% by mass, 85% by mass, 90% by mass, 95% by mass, or 100% by mass of the particles.

15. The particle includes a particle surface with a coating on at least a portion of the particle surface, or The particles according to claim 13, which are encapsulated within the coating.

16. The particle according to claim 15, wherein the coating is 25% or less by mass of the coated particles.

17. The particles according to claim 13, comprising a diameter of approximately 0.2 to 20 μm (for example, approximately 1 to 10 μm, for example, approximately 2 to 6 μm, for example, approximately 4 μm).

18. The particle according to claim 13, which is a solid particle.

19. A composition comprising the particles described in claim 13.

20. A composition comprising a plurality of particles as described in claim 13.

21. Multiple particles: 1) Surface-weighted average (D3,2) of approximately 1.5–1.9 μm (e.g., approximately 1.7 μm); 2) Volume-weighted average diameter (D4,3) of approximately 3.5–4.5 μm (e.g., approximately 3.9 μm); 3) d(0.1) of approximately 0.5 to 0.9 μm (for example, approximately 0.7 μm); 4) d(0.5) of approximately 2.5–3.5 μm (for example, approximately 2.9 μm); 5) d(0.9) of approximately 6-9 μm (for example, approximately 7.8 μm); 6) A span of approximately 0.7 to 3.4 (for example, approximately 2.4); 7) A coefficient of equalization of approximately 0.6 to 1.0 (for example, approximately 0.8); or 8) Refractive index of approximately 1.4 to 1.6 (for example, approximately 1.5) The composition according to claim 20, comprising one or more of the above.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the particles described in claim 13 or a composition containing the particles.

23. An oral dosage form comprising the particles described in claim 13, a composition containing the particles, or a pharmaceutically acceptable carrier, and a pharmaceutical composition containing the particles or the composition containing the particles.

24. The oral dosage form according to claim 23, comprising a plurality of particles as a powder or compressed powder.

25. It is contained in at least one container, A compound according to one of claims 1 to 3, A composition containing the aforementioned compound, 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof, or particles comprising the said composition: 1) Specific surface area of ​​approximately 3.0 to 4.0 m² / g (for example, approximately 3.6); or 2) Diameter of approximately 0.15 to 50 μm; or Both 1) and 2) Particles having, A composition containing the aforementioned particles, A pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the particles or the composition containing the particles, or The particles, a composition containing the particles, or an oral dosage form containing the pharmaceutical composition.

26. A compound which is the sulfate, hydrochloride, phosphate, tosylate, malonate, or maleate of 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine.

27. A compound according to one of claims 1 to 3, Particles containing 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof: 1) Specific surface area of ​​approximately 3.0 to 4.0 m² / g (for example, approximately 3.6); or 2) Diameter of approximately 0.15 to 50 μm; or Both 1) and 2) Particles or Oral dosage form containing the aforementioned particles GABA containing a therapeutically effective dose Ａ GABA in patients requiring treatment for receptor-related disorders or central nervous system disorders or disorders. Ａ A composition for use in methods for treating receptor-related disorders or diseases or disorders of the central nervous system.

28. The compound according to one of claims 1 to 3, Particles containing 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof: 1) Specific surface area of ​​approximately 3.0 to 4.0 m² / g (for example, approximately 3.6); or 2) Diameter of approximately 0.15 to 50 μm; or Both 1) and 2) Particles having, or Oral dosage form containing the aforementioned particles A composition containing the above, which is used as a pharmaceutical.

29. The compound according to one of claims 1 to 3, Particles comprising 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof: 1) Specific surface area of ​​approximately 3.0 to 4.0 m² / g (for example, approximately 3.6); or 2) Diameter of approximately 0.15 to 50 μm; or Both 1) and 2) Particles having, A composition containing the aforementioned particles, A pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the particles or the composition containing the particles, or Oral dosage form comprising the aforementioned particles, the aforementioned composition, or the aforementioned pharmaceutical composition Use of in the manufacturing method of pharmaceuticals.

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