GABAA receptor modulator salts, particles and uses thereof

Abstract

Described herein are salts (e.g., fumarates) of 3-(2, 5-difluorophenyl)-7-[1, 1-bis (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 salts (e.g., fumarates) of 3-(2, 5-difluorophenyl)-7-[1, 1-bis (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 salts (e.g., fumarates) The present invention relates to particles of [1, 3-b] pyridazine or a salt thereof and uses thereof.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63,333,075, filed on April 20, 2023, the entire contents of which are incorporated herein by reference. Background Art

[0003] GABA receptors respond to the neurotransmitter gamma-aminobutyric acid (GABA), which is the major inhibitory compound in the vertebrate central nervous system. A GABA receptors are present in all organisms with a nervous system. A Modulation of receptors can be used to therapeutically treat 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 A receptor modulators, but their bioavailability in mice is limited and their half-life is short. Therefore, GABA is still needed A Receptor modulator therapeutics, including improved forms of Compound 1. Summary of the invention

[0004] The present invention describes 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 their uses, as well as 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 its salts and their uses.

[0005] Compound 1 is shown below as the free base (where D is deuterium).

[0006]

[0007]

[0008] 3-(2,5-difluorophenyl)-7-[1,1-di(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl

[0009] -1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazolo[4,3-b]pyridazine BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 A particle size distribution graph corresponding to the particle batch produced in Example 1 (Particle Batch 1) is shown.

[0011] Figure 2 A particle size distribution graph corresponding to a comparative particle batch produced in Example 2 (Particle Batch 2a) is shown.

[0012] Figure 3 A particle size distribution graph corresponding to another comparative particle batch produced in Example 2 (Particle Batch 2b) is shown.

[0013] Figure 4 The XRPD (X-ray Powder Diffraction) trace of Compound 1 Form A hemifumarate salt is shown.

[0014] Figure 5 The XRPD trace of Compound 1 Form B hemifumarate salt is shown.

[0015] Figure 6 Shown are the DSC (Differential Scanning Calorimetry) and TGA (Thermogravimetric Analysis) traces of Compound 1, Form A hemifumarate salt.

[0016] Figure 7 The DSC and TGA traces of Compound 1 Form B hemifumarate salt are shown.

[0017] Figure 8 The XRPD trace of Compound 1 Sulfate Salt Form A is shown.

[0018] Fig. 9 The XRPD trace of Compound 1, Form A, HCl salt is shown.

[0019] Fig.10 The XRPD trace of Compound 1 Phosphate Form A is shown.

[0020] Fig.11 The XRPD trace of Compound 1 Phosphate Form B is shown.

[0021] Fig.12 The XRPD trace of Compound 1 Form A tosylate salt is shown.

[0022] Fig.13 The XRPD trace of the malonate salt Form A of Compound 1 is shown.

[0023] Fig.14 The XRPD trace of Compound 1, Maleate Form A is shown. DETAILED DESCRIPTION

[0024] definition

[0025] Certain terms are defined below, whether used alone or as part of a phrase or other terms.

[0026] The articles "a" and "an" refer to one or more than one of the grammatical objects of the article.

[0027] Numerical values ​​associated with measurements are subject to measurement error, thereby limiting their accuracy. Therefore, unless otherwise indicated, all numerical values ​​provided herein should be understood to be modified by the term "about".

[0028] The term "improvement" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing of the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measurements known to those skilled in the art.

[0029] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein and a carrier or a pharmaceutically acceptable carrier, respectively. Pharmaceutical compositions facilitate administration of the compound to a patient or subject. There are a variety of techniques for administering a composition, including, but not limited to, intravenous, oral, nasal, rectal, vaginal, aerosol, parenteral, buccal, sublingual, ocular, pulmonary, transdermal, and topical administration.

[0030] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound (such as a compound described herein) administered to a subject, in a single dose or as part of a series of doses, that is effective to produce the desired therapeutic effect.

[0031] The term "pharmaceutically 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, which participates in carrying or transporting at least one compound described herein in a patient or carrying or transporting at least one compound described herein to a patient so that the compound can perform its intended function. A given carrier must be "acceptable" in the sense that it is compatible with the other ingredients of a particular formulation (including the compounds described herein) and is 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.

[0032] The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. A list of salts is 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.

[0033] A "signal" may exist as a component of a broadened peak, a shoulder, or a split peak resulting from two or more overlapping or adjacent signals.

[0034] The term "solid form" includes, but is not limited to, polymorphs, crystalline forms, amorphous forms, solvates, and hydrates of a compound.

[0035] The term "substituted" or "substitution" refers to the replacement of a hydrogen attached to another group with an atom or group of atoms as a replacement substituent, wherein each substituent is independently selected.

[0036] The term "treatment" or "treating" refers to the application of one or more specific procedures to improve a disease. "Prophylactic" treatment refers to reducing the rate of progression, delaying the onset of the disease or condition being treated, or reducing the severity of its onset.

[0037] The statement of the range of values ​​herein is intended only as a shorthand method for quoting each individual value falling within the range individually. Unless otherwise specified herein, each individual value is incorporated into the specification as if it were recorded individually herein. Unless otherwise specified herein or clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the described subject matter, and does not limit the scope of the subject matter claimed in addition. Any language in the specification should not be interpreted as indicating any non-claimed elements that are essential to the practice of the described subject matter.

[0038] The grouping of alternative elements or embodiments of the present disclosure should not be construed as limiting. Each group member can be cited and claimed individually or in any combination with other members of the group or other elements present herein. In addition, for reasons of convenience or patentability, a recorded member of a group can be included in another recorded group, or excluded from another recorded group.

[0039] Patents and printed publications are cited throughout this specification, the entire contents of each of which are individually incorporated herein by reference.

[0040] It is to be understood that the embodiments of the present disclosure are illustrative. Therefore, the present disclosure is not limited to as precisely shown and described.

[0041] Compounds and solid forms

[0042] 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 A GABA receptor modulators A Benzodiazepine receptors It acts as a selective allosteric modulator of α2, α3 and α5 isoforms at the α2, α3 and α5 sites.

[0043] Compound 1 and its salts as described herein are synthesized starting from compounds available from commercial sources using any suitable procedure, or prepared using the procedures described herein. The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions for the introduction of the various moieties present in the formulas as provided herein.

[0044] 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, each of which is incorporated by reference in its entirety. The preparation of a compound corresponding to a non-deuterated form of Compound 1 is 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"). Therefore, compound 1 can be prepared in a similar manner to Carling et al. by substituting the appropriate corresponding deuterated reagent.

[0045] The preparation of the salt of Compound 1 can be carried out, for example, by contacting Compound 1 with an acid in a solvent solution and isolating the salt of Compound 1 by removing the solvent.

[0046] Thus, in some embodiments, provided herein is a compound that is a 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.

[0047] 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.

[0048] In some embodiments, the compound has the formula:

[0049]

[0050] Where X is 0.5, 1 or 2.

[0051] In some embodiments, provided herein is a compound as a 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. Sulfuric acid (2.5 M aqueous solution, 861 μL, 1.0 equivalent) was added to the resulting solution (with minimal residual solids). The resulting slurry was seeded with Form A (~10 mg). The slurry was heated to 40°C (insoluble), cooled to 20°C at a rate of 0.1°C / min (maintained at 2°C intervals for 1 hour) and stirred at 20°C overnight. The solids were separated by vacuum filtration and air-dried overnight. The yield of compound 1 sulfate type A was 83% (905 mg, 1.79 mmol).

[0052] In some embodiments, the sulfate salt of Compound 1 has substantially Figure 8 In some embodiments, the sulfate salt of Compound 1 has at least one signal selected from Table A expressed in 2θ.

[0053] Table A: XRPD signals of Compound 1 Sulfate Form A

[0054]

[0055]

[0056] 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) was added hydrochloric acid (3.0 M aqueous solution, 883 μL, 1.0 equivalent). The resulting slurry was seeded with Form A (~10 mg). The slurry was heated to 40°C (insoluble), the slurry was stirred at 40°C for 2 hours, cooled to 20°C at a rate of 0.1°C / min, and maintained at 2°C for 1 hour and stirred overnight at 20°C. 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).

[0057] In some embodiments, the hydrochloride salt of Compound 1 has substantially Fig. 9 In some embodiments, the hydrochloride salt of Compound 1 has at least one signal selected from Table B expressed in 2θ.

[0058] Table B: XRPD signals of Compound 1, Type A hydrochloride

[0059]

[0060]

[0061] 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) of Compound 1 with acetone (34.2 mL, 33 vol). Phosphoric acid (3.0 M aqueous solution, 845 μL, 1.0 equivalent) was added to the resulting solution (with minimal residual solids). The resulting slurry was seeded with Form A (~10 mg). The slurry was heated to 40°C (insoluble), the slurry was stirred at 40°C for 2 hours, cooled to 20°C at a rate of 0.1°C / min, and kept at 2°C for 1 hour and stirred overnight at 20°C. The solid was isolated by vacuum filtration and air dried for 4 hours. The yield of Compound 1 Phosphate Form A was 84% ​​(1.07 g, 2.12 mmol).

[0062] In some embodiments, the phosphate salt of Compound 1 has substantially Fig.10 or Fig.11 In some embodiments, the phosphate salt of Compound 1 has at least one signal selected from Table C or Table D expressed in 2θ.

[0063] Table C: XRPD signals of Phosphate Form A of Compound 1

[0064]

[0065]

[0066] Table D: XRPD signals of Phosphate Form B of Compound 1

[0067]

[0068] In some embodiments, provided herein is a compound that is a toluenesulfonate 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 toluenesulfonate salt of compound 1 is prepared by combining 888 mg (2.17 mmol) of compound 1 with IPA (3.5 mL, 39 vol). Toluenesulfonic acid (3.0 M aqueous solution, 725 μL, 1.0 equivalent) was added to the resulting solution (with minimal residual solids). The resulting thin slurry was heated to 40°C for 2 hours with stirring, it gradually thickened, and seeded with Form A (~10 mg). The slurry was cooled to 20°C at a rate of 0.1°C / min, and kept at 2°C for 1 hour and stirred at 20°C for a weekend. The solid was isolated by vacuum filtration and air dried for 2 hours. The yield of Compound 1 Form A tosylate was 87% (1.10 g, 1.89 mmol).

[0069] In some embodiments, the tosylate salt of Compound 1 has substantially Fig.12 In some embodiments, the tosylate salt of Compound 1 has at least one signal selected from Table E expressed in 2θ.

[0070] Table E: XRPD signals of Compound 1 Form A Tosylate

[0071]

[0072] In some embodiments, provided herein are compounds that are malonic acid 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. In some embodiments, the malonic acid salt of Compound 1 is prepared by combining 1.09 g (2.68 mmol) of Compound 1 with toluene (3.5 mL, 32 vol). To the resulting solution (with minimal residual solids) was added malonic acid (3.0 M aqueous solution, 893 μL, 1.0 equivalent). The resulting slurry was heated to 40° C. with stirring for 2 hours and seeded with Form A (~10 mg). The slurry was cooled to 20° C. at a rate of 0.1° C. / min and maintained 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 the malonate Form A of Compound 1 was 73% (0.996 g, 1.94 mmol).

[0073] In some embodiments, the malonate salt of Compound 1 has substantially Fig.13 In some embodiments, the malonate salt of Compound 1 has at least one signal selected from Table F expressed in 2θ.

[0074] Table F: XRPD signals of the malonate salt Form A of Compound 1

[0075]

[0076] In some embodiments, provided herein are compounds that are maleic acid 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. In some embodiments, the maleic acid salt of Compound 1 is prepared by combining 1.09 g (2.67 mmol) of Compound 1 with toluene (3.5 mL, 32 vol). Maleic acid (3.0 M aqueous solution, 891 μL, 1.0 equiv) is added to the resulting solution (with minimal residual solids). The resulting slurry is seeded with Form A (~10 mg). The slurry was heated to 40°C (insoluble), stirred at 40°C for 2 hours, cooled to 20°C at a rate of 0.1°C / min, and kept at 20°C for 1 hour at 2°C intervals and stirred for several days. The solid was separated by vacuum filtration and air-dried for 4 hours. The yield of the maleate salt of compound 1, type A, was 91% (1.28 g, 2.43 mmol).

[0077] In some embodiments, the maleate salt of Compound 1 has substantially Fig.14 In some embodiments, the maleate salt of Compound 1 has at least one signal selected from Table G expressed in 2θ.

[0078] Table G: XRPD signals of maleate salt Form A of Compound 1

[0079]

[0080] 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 solid form.

[0081] In some embodiments, the solid Form B hemifumarate salt has an X-ray powder diffraction pattern comprising a CuKα1 radiation at about 9.05±0.2°. In some embodiments, the solid Form B hemifumarate has an X-ray powder diffraction pattern comprising CuKα1 radiation at about 9.05±0.2°, about 15.46±0.2°, about 22.55±0.2°, and about 24.61±0.2°. In some embodiments, the solid Form B hemifumarate has a 2θ signal substantially as Figure 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, the solid Form B hemifumarate has substantially Figure 7 In some embodiments, the solid Form B hemifumarate has substantially Figure 7 Thermogravimetric analysis shown.

[0082] In some embodiments, the solid Form A hemifumarate salt has an X-ray powder diffraction pattern comprising a CuKα1 radiation-based X-ray diffraction pattern at about 7.70±0.2° or about 21.80±0.2°. In some embodiments, the solid Form A hemifumarate has an X-ray powder diffraction pattern comprising CuKα1 radiation at about 7.70±0.2°, about 21.80±0.2°, about 25.44±0.2°, and about 28.75±0.2°. In some embodiments, the solid Form A hemifumarate has substantially Figure 4 In some embodiments, the 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, the solid Form A hemifumarate has substantially Figure 6 In some embodiments, the solid Form A hemifumarate has substantially Figure 6 Thermogravimetric analysis shown.

[0083] The powder analyzed by the XRPD spectrum may include components other than the crystalline compound to be identified, which may result in the presence of signals other than those attributable to the crystalline compound to be identified in the XRPD diffraction spectrum. A specific compound may also include two or more adjacent or overlapping signals. Therefore, in some embodiments, the XRPD signal may exist as a component of a broadened peak, a shoulder peak, or a split peak (which is generated by two or more overlapping or adjacent signals). In some embodiments, the XRPD signal may be synonymous with the XRPD peak.

[0084] In some embodiments, the compound or solid form is substantially purified. In some embodiments, the compound or solid form is a crystal. In some embodiments, the compound or solid form is prepared by including a method of precipitating the compound from a solution comprising 3-(2,5-difluorophenyl)-7-[1,1-bis(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 containing acetone or acetonitrile. In some embodiments, the method includes drying the precipitated compound. In some embodiments, the precipitated compound that can be a crystal is reduced (e.g., ground, collided or tumbled) to particles with one or more of the following particle features.

[0085] In some embodiments, a composition comprising one or more compounds described herein is provided. In some embodiments, the composition is a pharmaceutical composition. The composition may further comprise a pharmaceutically acceptable carrier.

[0086] In some embodiments, the compound is present in the composition in an amount of at least about 90% by weight.

[0087] In some embodiments, the composition is a pharmaceutical composition consisting essentially of the compound.

[0088] Particles

[0089] In some embodiments, described herein are particles comprising a compound represented by the following formula or a salt thereof:

[0090]

[0091] In some embodiments, the compound comprises about or at least about 75, 80, 85, 90, 95, or 100% by mass of the particle.

[0092] In some embodiments, the particle comprises a particle surface, wherein the particle surface comprises a coating on at least a portion of the particle surface. In some embodiments, the coating comprises a film coating. In some embodiments, the particle comprises a film coated with a polymer or copolymer to form a microcapsule, which can be used to form chewable taste-masking particles. In some embodiments, the coating comprises a polymer or copolymer. In some embodiments, the coating comprises one or more of cellulose acetate phthalate, cellulose acetate trimellitate, ethyl cellulose, glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, high molecular weight polyethylene, polyvinyl alcohol, polyvinyl pyrrolidone, starch or shellac. In some embodiments, the coating comprises a varnish (e.g., a non-nutritional varnish). In some embodiments, the coating comprises sugar. In some embodiments, the coating comprises a sugar coating. In some embodiments, the particles described herein are sugar coated. In some embodiments, the particles described herein are not sugar coated.

[0093] In some embodiments, a dosage form comprising a plurality of particles comprises coated particles, wherein the coating is independently selected from the coatings described herein for each particle. Thus, in some embodiments, the plurality of particles may include a mixture of enteric coated particles and sustained release coated particles.

[0094] In some embodiments, the particles described herein are encapsulated within a coating.

[0095] In some embodiments of the particles described herein, the coating comprises 25% or less by mass of the coated particle.

[0096] In some embodiments, the particle comprises a diameter of about 0.2-20 μm (eg, about 1-10 μm, eg, about 2-6 μm, eg, about 4 μm).

[0097] In some embodiments, the particles described herein are provided as compositions comprising a plurality of particles, which may include one or more carriers. In some embodiments, a plurality of particles are encapsulated in a capsule, a compression coating, a film coating, or a powder coating. In some embodiments, a particle or a plurality of particles, whether powder, compressed powder, or tablet, is spray-coated. In some embodiments, a plurality of particles are loose powders in an ingestible capsule. In some embodiments, a plurality of particles are compressed into a fragile solid.

[0098] In some embodiments, the plurality of particles comprises one or more of the following:

[0099] 1) a surface weighted average (D3,2) of about 1.5-1.9 μm (e.g., about 1.7 μm);

[0100] 2) a volume-weighted mean diameter (D4,3) of about 3.5-4.5 μm (e.g., about 3.9 μm);

[0101] 3) d(0.1) of about 0.5-0.9 μm (e.g., about 0.7 μm);

[0102] 4) d(0.5) of about 2.5-3.5 μm (e.g., about 2.9 μm);

[0103] 5) d(0.9) of about 6-9 μm (e.g., about 7.8 μm);

[0104] 6) a span of about 0.7-3.4 (e.g., about 2.4);

[0105] 7) a uniformity coefficient of about 0.6-1.0 (e.g., about 0.8); or

[0106] 8) A refractive index of about 1.4-1.6 (e.g., about 1.5).

[0107] In some embodiments, provided herein are oral dosage forms comprising a particle, composition, or pharmaceutical composition described herein. In some embodiments, the oral dosage form comprises a plurality of particles in the form of a powder or compressed powder.

[0108] In some embodiments, a particle, composition, or pharmaceutical composition provided herein is contained in at least one container.

[0109] Composition

[0110] In some embodiments, the particles described herein may be in the form of a composition. In some embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0111] In some embodiments, the compositions described herein comprise a first pharmaceutically active substance, which is Compound 1 or a salt thereof, and a second pharmaceutically active substance, which may be a compound useful for treating a central nervous system disease or disorder.

[0112] method

[0113] Compound 1 and its pharmaceutically acceptable salts may be used as described in U.S. Pat. Nos. 8,003,646, 8,399,467, or 8,921,366. Compound 1 or its pharmaceutically acceptable salts are described therein as GABA A receptor modulators and can be used to treat central nervous system disorders including anxiety, convulsions, neuropathic pain, inflammatory pain, and migraine-related pain.

[0114] In addition, compound 1 or other GABA AThe therapeutic uses of the corresponding non-deuterated forms of receptor modulators or pharmaceutically acceptable salts thereof are described in U.S. Pat. Nos. 6,255,305 or 6,500,828 or WO2006061428, each of which is incorporated by reference in its entirety. The uses described in U.S. Pat. No. 6,255,305 include the treatment of a variety of central nervous system disorders, such as: anxiety disorders, such as panic disorder with or without agoraphobia; agoraphobia without a history of panic disorder; animal phobia and other phobias, including social phobia; obsessive-compulsive disorder; stress disorders, including post-traumatic and acute stress disorders and generalized or substance-induced anxiety disorders; neurosis; convulsions; migraine; and depression or bipolar disorder, such as single or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorder and cyclothymic disorder. The uses described in U.S. Pat. No. 6,500,828 include treating a variety of central nervous system disorders other than those described above, such as: psychiatric disorders, including schizophrenia; neurodegeneration caused by cerebral ischemia; attention deficit hyperactivity disorder; and circadian rhythm disorders, for example, in subjects affected by jet lag or shift work. In addition, the uses described in U.S. Pat. No. 6,500,828 include GABA A Conditions in which selective ligands for GABA receptors may be beneficial include: pain and nociception; vomiting, including acute, delayed, and anticipatory vomiting, particularly vomiting caused by chemotherapy or radiation therapy, and postoperative nausea and vomiting; eating disorders, including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasms or spasticity, for example, in paraplegics; and hearing loss. In addition, U.S. Patent No. 6,500,828 states that GABA A The selective ligand of the receptor may also be effective as a pre-drug before anesthesia or minor surgery, such as endoscopy (including gastroendoscopy). The use described in WO2006061428 includes the treatment of pain, for example, neuropathic, inflammatory or migraine-related pain. WO2006061428 points out that neuropathic pain covers a series of pain syndromes with diverse origins, including diabetic neuropathy, post-herpetic neuralgia, postoperative nerve damage, pain after paraplegia, hypersensitivity to non-painful stimuli (abnormal pain), for example, spontaneous pain, hyperalgesia, diffuse muscle tenderness of myofascial syndrome, gastrointestinal paresthesia (for example, irritable bowel syndrome) or chest pain and a large proportion of back pain after surgery or during migraine attacks, and also points out that cancer-related and AIDS-related pain are also identified as neuropathic pain. WO2006061428 also points out that inflammatory pain covers pain associated with conditions such as trauma, osteoarthritis, rheumatoid arthritis, postoperative recovery and some forms of cancer pain.

[0115] Therefore, in some embodiments, the particles described herein, which include Compound 1 or a pharmaceutically acceptable salt thereof, can be used to treat GABA A Receptor-related diseases, central nervous system diseases or disorders, and diseases or disorders as described above. In some embodiments, the particles described herein can be used as an anxiolytic, anticonvulsant, analgesic (amnesic), sedative, hypnotic, euphoric, or muscle relaxant.

[0116] In some embodiments, the particles described herein can be used as GABA A Receptor modulators and are used to treat various conditions or diseases of the central nervous system.

[0117] In some embodiments, the particles described herein can be used as anxiolytics or analgesics. Thus, in some embodiments, described herein are methods of treating anxiety or pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the particles described herein.

[0118] In some embodiments, described herein are methods for treating GABA in a subject in need thereof. A A method for treating a receptor-related disease or a disease or disorder of the central nervous system, comprising administering to a subject a therapeutically effective amount of a particle, composition, pharmaceutical composition or oral dosage form described herein.

[0119] Although the methods are described with reference to the particles described herein, it should be understood that the particles may also be used in conjunction with these methods in the form of a composition or pharmaceutical composition.

[0120] Actual dosage levels of the active ingredients provided herein (e.g., the pharmaceutically 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 causing toxicity to the patient.

[0121] In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the excretion rate of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, and the age, sex, weight, condition, general health or prior medical history of the patient to be treated.

[0122] Administration routes include, but are not limited to, oral, nasal, rectal, vaginal, aerosol, parenteral, buccal, sublingual, ocular, pulmonary, or topical administration. In some embodiments, the oral or nasal administration route is an oral inhalation or nasal inhalation administration route. The compounds used as described herein can be formulated for administration by any suitable route to achieve the particular method used.

[0123] Thus, administration of the compounds, compositions or combinations disclosed herein includes a variety of enteral or parenteral methods selected from, but not limited to: oral administration in any acceptable form, such as, for example, tablets, liquids (e.g., liquid suspensions of particles), capsules, powders, etc.; topical or transdermal administration in any acceptable form, such as, for example, drops, sprays, creams, gel ointments or patches; oral, intranasal, sublingual, ocular, pulmonary and / or inhalation administration in any acceptable form; rectal administration in any acceptable form; vaginal administration in any acceptable form; peri- or intra-tissue administration in any acceptable form, such as, for example, intraperitoneal, intramuscular, subcutaneous, intravenous or intra-articular injections; intravesical administration in any acceptable form, such as, for example, catheter infusion; and by placement of a device, such as, for example, an implant, a stent, a patch, a pellet, a catheter, an osmotic pump, a suppository, a bioerodible delivery system, a non-bioerodible delivery system or another implanted delayed or sustained release system.

[0124] Local administration results in significantly more delivery of a compound, composition, or combination to a specific location compared to the whole body of a mammal, while systemic administration results in substantially more delivery of a compound, composition, or combination to the whole body of an individual. Routes of administration suitable for treating central nervous system-related diseases or conditions as disclosed herein also include central and peripheral administration. Central administration results in substantially delivery of a compound, composition, or combination to the central nervous system of an individual, and includes, for example, nasal administration, intrathecal administration, epidural administration, and intracranial injection or implantation. In some embodiments, central administration is used to administer a compound, composition, or combination as described herein.

[0125] Central administration by the nasal route (whose goal is to absorb the drug through the vascular plexus of the nasal cavity) is different from administration by nasal inhalation (which delivers the drug through the pulmonary system). Although the latter usually uses liquid or dry powder aerosols with an average particle size of less than about 10 microns, central administration can be achieved using an average particle size of about 10 microns or greater. Mists and aerosols can be produced using nebulizers, dry powder inhalers, pressurized aerosols, and atomizing pumps. It is also feasible to use nasal drops (e.g., a suspension of particles in a liquid) for central administration by the nasal route.

[0126] Peripheral administration results in delivery of a compound, composition or combination to essentially any area of ​​an individual outside the central nervous system, and encompasses any route of administration other than direct administration to the spine or brain.

[0127] Reagent test kit

[0128] In some embodiments, provided herein are packaged particles, packaged compositions, or packaged 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 methods provided herein.

[0129] The particles and related materials of the present invention can be completed as commercial products by the usual steps performed in the art, such as by appropriate sterilization and packaging steps. For example, the material can be treated by UV / vis irradiation (200-500nm), for example using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is generally performed for 1-60min irradiation time, but longer irradiation times can be applied depending on the specific method. The materials according to the present disclosure can be finally aseptically packaged to maintain sterility until use, and packaged (e.g., by adding specific product information instructions) into suitable containers (boxes, etc.).

[0130] According to further embodiments, the particles of the present invention may also be provided in kit form in combination with other components necessary for administering the material to a patient. For example, a disclosed kit, such as a kit for treating cancer, may further comprise, for example, an administration material.

[0131] The kit may be designed in a variety of formats depending on the specific defect it is designed to treat.

[0132] Particle or composition provided herein can be prepared and placed in a container to store at ambient temperature or elevated temperature.When particle or composition are stored in a polyolefin plastic container, compared with, for example, a polyvinyl chloride plastic container, the discoloration of particle (for example, the compound in the particle) or composition can be reduced, whether it is suspended in a liquid composition (for example, an aqueous solution or an organic liquid solution) or as a solid.Not wishing to be bound by theory, the container can reduce the content of the container and be exposed to electromagnetic radiation, whether it is visible light (for example, with a wavelength of about 380-780nm), or ultraviolet (UV) light (for example, with a wavelength of about 190-320nm (UV B light) or about 320-380nm (UV A light)). Some containers also include the ability to reduce the content of the container to be exposed to infrared light, or include a second component with such ability. Some containers further include the ability to reduce the content of the container to be exposed to heat or humidity.Operable containers include containers made of polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutylene or its combination, particularly polyethylene, polypropylene or its combination. In some embodiments, the container is a glass container. The container can be further arranged in a second container, for example, a paper container, a cardboard container, a paperboard container, a metal film container or a foil container, or a combination thereof, to further reduce the exposure of the contents of the container to UV, visible light or infrared light. Products that benefit from discoloration, reduced decomposition or both during storage include dosage forms comprising particles or compositions described herein. Particles or compositions provided herein may need to be stored for up to three months or longer; in some cases, up to one year or longer. The container can be in any form suitable for accommodating contents—for example, a bag, a bottle or a box.

[0133] The following examples further illustrate aspects of the present disclosure. However, they are in no way limiting to the teachings or disclosures as described herein.

[0134] Example

[0135] Example 1

[0136] Micronized particles of Compound 1 free base were produced and subsequently analyzed using a Mastersizer 2000 instrument and a Scirocco 2000 dispersion unit. The data for the particle analysis are shown in Tables 1 and 2 and Figure 1 The data for the non-micronized particles used for comparison (Example 2a and Example 2b below) are shown in Tables 3 and 4 and Figure 2 and Figure 3 middle.

[0137] Table 1: Analysis of micronized particles of Example 1 (see Figure 1 )

[0138]

[0139] Table 2: Micronized particle size distribution data corresponding to Example 1 (see Figure 1 )

[0140]

[0141]

[0142]

[0143] Example 2

[0144] Non-micronized particles of Compound 1 free base were produced 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 Figure 2 and Figure 3 middle.

[0145] Table 3: Analysis of non-micronized particles of Example 2 ( Figure 2 )

[0146]

[0147] Table 4: Analysis of non-micronized particles of Example 2 ( Figure 3 )

[0148]

[0149] Example 3

[0150] The exposure of compound 1 free base after oral (PO) dose administration of 300 mg / kg / dose micronized particles (Example 1) and 300 mg / kg / dose non-micronized particles (Example 2) was evaluated in male cynomolgus monkeys. Table 5 describes the study design, dosing and schedule. Blood samples collected from the femoral vein were collected into K2EDTA-coated polypropylene tubes and plasma was separated. Samples were drawn at the following time points: before administration, 15 minutes, 30 minutes, 1, 2, 4, 8, 10, 12, 14, 24, 30 and 48 hours after administration. The concentration of compound 1 was determined by LC-MS / MS, and pharmacokinetic parameters were determined using Phoenix WinNonlin v8.0 software. The pharmacokinetic parameters are summarized and shown in Table 6.

[0151] Table 5: Study design

[0152]

[0153] Table 6: Summary of pharmacokinetic parameters of Example 3

[0154]

[0155] Example 4

[0156] After oral (PO) administration in 3 male cynomolgus monkeys, a pharmacokinetic analysis comparing the administration of compound 1 with the administration of certain salts of compound 1 was performed. Subjects received a single PO oral gavage of the active pharmaceutical ingredient (API) (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) in a capsule at a dose of 30 mg / kg. After the dose was administered, the animals were rinsed with about 10 ml of tap water to ensure that all APIs were administered. Any abnormal clinical and behavioral signs of the animals were observed twice a day at the sample collection time point. Body weight was measured weekly before and after administration until the study was terminated. Blood samples (0.5 mL) were collected 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration before administration. Each blood sample was collected from the femoral vein, saphenous vein or other available vein of the monkey by direct venipuncture, placed in a polypropylene tube containing K2EDTA as an anticoagulant, and gently inverted several times to mix. The blood samples were kept on wet ice until centrifugation. The blood was centrifuged within 10 minutes of collection. The samples were centrifuged at 3,000g for 5 minutes at 4°C. After centrifugation, the resulting plasma (~0.25mL) was divided into two equal portions (125μL each) into polypropylene tubes, designated as Group A and Group B, respectively. Plasma samples designated for certain metabolites (Group A) were treated with 12.5μL of 2M ascorbic acid (plasma: ascorbic acid = 9:1, v:v), which was prepared in advance by mixing 0.352g of ascorbic acid into 1mL of sterile water in a glass vial and mixing thoroughly. Plasma samples designated for compound 1 (Group B) did not need to be treated with ascorbic acid. After plasma preparation, the samples were quickly frozen on dry ice. All plasma samples were stored frozen at -70°C until analysis. The results are shown in Table 7.

[0157] Surprisingly, the C max The C of compound 1 (free base; 1550 ng / mL) was about 3080 ng / mL, which was higher than that of compound 1 (free base; 1550 ng / mL). max The AUC of the fumarate salt of compound 1 was more than 98%. last The AUC of compound 1 was 38904 ng·h / mL, which was higher than that of compound 1. last (25463ng-h / mL) is more than 50% higher.

[0158] Table 7: Pharmacokinetic data

[0159] form Free base Fumarate Sulfate Hydrochloride <![CDATA[C max (ng / mL)]]> 1550 3080 1151 1583 <![CDATA[T max (h)]]> 4.0 4.7 4.0 4.0 <![CDATA[AUC last (ng*h / mL)]]> 25463 38904 18231 25402 form Phosphate Tosylate Malonate Maleate <![CDATA[C max (ng / mL)]]> 1096 1629 2010 1388 <![CDATA[T max (h)]]> 5.3 10.7 4.7 12.0 <![CDATA[AUC last (ng*h / mL)]]> 18378 23248 24694 20575

[0160] Example 5

[0161] Preparation of hemifumarate salt Form A (acetonitrile solvate) and hemifumarate salt Form B (non-solvated) 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. Seed crystals of Form B were prepared by first combining 20.3 mg (0.050 mM) 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 / ethanol (248mg, 1.0 equivalent) was added and the sample was stirred continuously while temperature cycling (heating and cooling at 2°C / min, keeping 1 hour at 40°C and 5°C) was continued for 48 hours. The sample was separated at 5°C and the suspension was balanced with stirring at 20°C for 2 hours. The birefringent solid was harvested by filtration at room temperature and air-dried overnight. 3-(2,5-difluorophenyl)-7-[1,1-bis(methyl-d3)ethyl-2,2,2-d3]-6-[(1-methyl-1H-1,2,4-triazol-5-yl)methoxy]-1,2,4-triazol [4,3-b]pyridazine (5.51mmol) was combined with acetone (3.5mL, 16vol). To the resulting solution (with very little residual solid) is added fumaric acid (575 mg, 1.0 eq.) and then seeded, for example, with Form B (~10 mg). The slurry is heated to 40°C with stirring for 2 hours, cooled very slowly to 20°C at a rate of 0.1°C / min, and maintained for 1 hour at 2°C intervals, and stirred at 20°C overnight. The solids are separated by vacuum filtration and air-dried for 4 h. The yield of the hemifumarate Form B is 79% (2.02 g, 4.33 mmol). Form A (prepared as above, but with acetonitrile instead of acetone) is converted to Form B within one week under ambient conditions.

[0162] Selected physicochemical data for Form B were collected. Hemifumarate 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), 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 half salt with a 0.5:1 CI:API ratio. Gravimetric vapor sorption (GVS) analysis showed moisture uptake of <0.1%wt between 5-95% RH. No changes in the XRPD spectrum were observed after GVS.

[0163] The intrinsic dissolution rate was determined by forming compacted granules of approximately 75 mg of API using a compression force of 1200 lbf and each granule (die surface area: 0.5 cm 2 ) was immersed in a flat-bottomed container containing 500 mL of medium (0.1 N HCl aqueous solution containing 1% Tween 80 (polyoxyethylene (20) sorbitan monooleate)). At 15, 30, 45, 60, 75, 90, 105 and 120 minutes, an aliquot (1 mL) was taken from the dissolution medium, filtered and analyzed by HPLC. The 8.9 μg / (min·cm 2 ) compared to the slope of the dissolution curve corresponding to 6.2 μg / (min·cm 2 )'s intrinsic dissolution rate.

[0164] Selected physicochemical data for Form A were collected. The hemifumarate 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 loss of 7% wt at up to 80°C (see Figure 6 ).

[0165] For PLM, micrographs were collected using an Olympus BX60 polarizing microscope equipped with an Olympus DP70 camera or an Olympus BX51 polarizing microscope equipped with an Olympus DP71 camera.

[0166] The solid state stability of the fumarate salt of Compound 1 was evaluated by HPLC and XRPD after 2 and 4 weeks of storage under the following conditions: 40°C / 75% RH (open) and 50°C / ambient RH (closed). After 4 weeks under these conditions, no significant changes were observed by HPLC or XRPD.

[0167] DSC was performed using a TA Instruments Q200 or Q2000 differential scanning calorimeter equipped with an autosampler and refrigerated cooling system under a 40 mL / min N2 purge. Unless otherwise stated, DSC thermograms of samples were obtained at 15°C / min in a crimped aluminum pan.

[0168] TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer at 40 mL / min N2 purge for equilibration and 60 mL / min for samples in aluminum pans. Unless otherwise stated, TGA thermograms for samples were obtained at 15°C / min.

[0169] GVS experiments were performed on a surface measurement system DVS-Advantage. Experiments were performed at 25°C. The instrument was operated in step mode and the relative humidity was increased from 40% RH to 75% RH in 10% RH increments, then decreased from 75% RH to 5% RH, then increased from 5% RH to 95% RH a second time, then decreased from 95% RH to 5% RH. The mass balance standard was set to 0.003% mass change (dm / dt) over time. The minimum step time was specified to be 20 minutes and the maximum step time to be 240 minutes.

[0170] Example 6

[0171] Powder X-ray diffraction spectra were collected for selected salt forms described herein, including the 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, respectively). Figure 4 and Figure 5 ). XRPD diffractograms were obtained on a Bruker D8 Advance system using Cu Kα The radiation was acquired with an X-ray tube voltage and current of 40 kV and 40 mA and a LynxEye position sensitive detector with a 3° 2θ opening. The configuration on the incident beam side was as follows: Mirror, mirror exit slit (0.2mm), 2.5deg Soller slit and beam knife. The configuration of the diffraction beam side is as follows: anti-scatter slit (8mm) and 2.5deg Soller slit. The sample is placed flat on a zero background silicon wafer. The sample is rotated at 30rpm. Data is collected with a step size of 0.029°2θ and a step time of 0.1 seconds. Data is collected from 2 to 40°2θ, with a total scan time of 2 minutes and 22 seconds for each sample. The XRPD spectrum is entered into Panalytical HighScore Plus v 2.2. The Kα2 contribution is mathematically stripped from the spectrum, and then the background baseline is determined, and then the signal position and relative intensity are determined. Alternatively, the XRPD diffraction pattern is obtained on a PANalyticalX'Pert Pro diffractometer using Ni-filtered Cu Kα (45kV / 40mA) radiation and a step size of 0.03°2θ and an X'celerator RTMS (real-time multi-strip) detector. Configuration on the incident beam side: variable divergence slit (10 mm illumination length), 0.04 rad Soller slit, fixed anti-scatter slit (0.50°) and 10 mm beam mask. Configuration on the diffracted beam side: variable anti-scatter slit (10 mm observation length) and 0.04 rad Soller slit. The sample was placed flat on a zero background silicon wafer. The results are shown in Table 8.

[0172] Table 8: XRPD signals of Hemifumarate Form A and Hemifumarate Form B of Example 5

[0173]

[0174]

[0175] Example 7: Non-human primate oral crossover study

[0176] The objective of this study was to determine the pharmacokinetic (PK) characteristics of the test article after a single oral administration (with a one-week washout period) to four male non-human primate cynomolgus monkeys. The dosing and crossover design are shown in Table 9.

[0177] Table 9

[0178]

[0179] *34.2 mg / kg of Compound 1 fumarate salt is equivalent to 30 mg / kg of Compound 1 free base on a molar basis.

[0180] Four male animals were used in this study, and four research animals were used for each of the three dosing phases, with a one-week washout period. Food was removed overnight at dose administration, and food was returned four hours after dose administration. Drinking water was provided ad libitum through an automatic drinking device. Two of the four animals were previously treated with compound 1, and the other two had not been exposed to compound 1. The test article (M-3, N-3 or K-13) was provided as a powder wrapped in capsules; stored in a polyolefin bottle at room temperature, for example, in the dark. Table 10 summarizes the results of the study, which shows that the fumarate of compound 1 in micronized and non-micronized forms provides superior exposure to compound 1 compared to subjects administered with compound 1 free base.

[0181] Table 10

[0182] parameter unit M-3 N-3 K-13 AUC (ng·h / mL) 17826 21540 1192 <![CDATA[C max ]]> (ng·mL) 930 1370 86.4 <![CDATA[T max ]]> (h) 10 4 14 <![CDATA[C 24(h) ]]> (ng·mL) 603 684 42

[0183] The micronized and non-micronized particles of Compound 1 hemifumarate in this example are described in Table 11 (micronized) and Table 12 (non-micronized).

[0184] Table 11: Micronized Compound 1 Hemifumarate

[0185]

[0186] Table 12: Non-micronized Compound 1 Hemifumarate

[0187]

[0188] Example 8: Intrinsic Dissolution Rate

[0189] According to USP <1087> Intrinsic dissolution rates (IDR) of compound 1 and seven different salts of compound 1 were measured in 0.1N hydrochloric acid containing 1% Tween 80 (polyoxyethylene (80) sorbitan monooleate). Compacted granules containing about 75 mg of API were prepared using a compression force of 1200 lbf and each granule (die surface area: 0.5 cm 2 ) was immersed in a flat bottom container containing 500 mL of medium using a Distek 2100A dissolution bath and a Distek circulator / heater (set to 37° C.) at a paddle speed of 100 rpm. An aliquot (1 mL) was taken from the dissolution medium at 15, 30, 45, 60, 75, 90, 105, and 120 minutes, filtered, and analyzed by HPLC.

[0190] A summary of the intrinsic dissolution rate and solubility of each tested compound is shown in Tables 13 and 14.

[0191] Table 13: Solubility

[0192]

[0193] Table 14: Intrinsic Dissolution Rates

[0194] <![CDATA[IDR[μg / (min·cm 2 )]]]> Compound 1 (parent free base) 8.9 Fumarate 6.2 HCl salt 6.9 Maleate 7.3 Malonate 6.9 Phosphate 7.0 Sulfate 7.1 Tosylate 8.7

[0195] Example 9: Solid State Stability

[0196] The solid state stability of Compound 1 and seven salts of Compound 1 as in Example 8 was evaluated by HPLC and PXRD after 2 and 4 weeks of storage under the following conditions: 40°C / 75% RH (open); and 50°C / ambient RH (closed).

[0197] 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 spectra after 4 weeks under storage conditions, except for the HCl salt, where a small signal was observed at 10° 2θ for Compound 1 (free base) at 40°C / 75% RH.

[0198] HPLC for IDR and solid-state stability analysis was performed using an Agilent 1260 Infinity system equipped with a G1311B quad pump, a G1329B autosampler, a G1330B autosampler thermostat, a G1316A thermostatic column compartment with a column switching valve, and a G4212B diode array detector.

[0199] Example 10: Melting Point

[0200] The melting points of Compound 1 and its seven salts (as shown in Example 8) were collected and the results are summarized in Table 15.

[0201] Table 15: Melting Points

[0202] Temperature(℃) Compound 1 (parent free base) 202 Fumarate (Type B) 199 HCl salt (Type A) 190 Maleate (Type A) 171 Malonate (Type A) 173 Phosphate (Type A) 217 Phosphate (Type B) 228 Sulfate (Type A) 228 Tosylate (Type A) 227

Claims

1. A compound which is a 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.

2. The compound according to claim 1, which is a 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.

3. The compound according to claim 1, which has the following formula: where X is 0.5, 1, or 2.

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

5. The compound according to any one of claims 1 to 3, which is a solvate.

6. The compound according to any one of claims 1 to 5, which is in solid form.

7. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern comprising a CuKα1 radiation at about 9.05±0.2°. The 2θ signal, or about The 2θ signal based on the d-spacing at .

8. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern comprising X-ray diffraction patterns based on CuKα1 radiation at about 9.05±0.2°, about 15.46±0.2°, about 22.55±0.2°, and about 24.61±0.2°. The 2θ signal, or about about about peace treaty The 2θ signal based on the d-spacing at .

9. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern substantially as shown in Figure 5.

10. The compound of claim 6, wherein the solid form has a differential scanning calorimetry thermogram comprising an endothermic signal at about 199.6 ± 3.0 (eg, ± 0.5) °C.

11. The compound of claim 6, wherein the solid form has a differential scanning calorimetry thermogram substantially as shown in Figure 7.

12. The compound of claim 6, wherein the solid form has a thermogravimetric analysis substantially as shown in Figure 7.

13. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern comprising a CuKα1 radiation at about 7.70±0.2° or about 21.80±0.2°. The 2θ signal, or about or about The 2θ signal based on the d-spacing at .

14. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern comprising X-ray diffraction patterns based on CuKα1 radiation at about 7.70±0.2°, about 21.80±0.2°, about 25.44±0.2°, and about 28.75±0.2°. The 2θ signal, or about about about peace treaty The 2θ signal based on the d-spacing at .

15. The compound of claim 6, wherein the solid form has an X-ray powder diffraction pattern substantially as shown in Figure 4.

16. The compound of claim 6, wherein the solid form 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.

17. The compound of claim 6, wherein the solid form has a differential scanning calorimetry thermogram substantially as shown in Figure 6.

18. The compound of claim 6, wherein the solid form has a thermogravimetric analysis substantially as shown in Figure 6.

19. The compound of any one of claims 1-18, which is substantially purified.

20. The compound according to any one of claims 1 to 19, which is crystalline.

21. A compound according to any one of claims 1 to 20, prepared by a process 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 containing acetone or acetonitrile, the process optionally comprising drying the precipitated compound.

22. A composition comprising a compound according to any one of claims 1 to 21.

23. The composition according to claim 22, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

24. The composition of claim 23, wherein the compound is present in the composition in an amount of at least about 90% by weight.

25. The composition of claim 22, which is a pharmaceutical composition consisting essentially of said compound.

26. A particle 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, or a composition according to any one of claims 22 to 25, wherein the particle comprises one or more of the following: 1) About 3.0-4.0m 2 / g (e.g., about 3.6); or 2) Diameter of about 0.15-50 μm.

27. The particle of claim 26, wherein the compound comprises about or at least about 75, 80, 85, 90, 95, or 100% by mass of the particle.

28. The particle of claim 26 or 27, comprising a particle surface, wherein the particle surface comprises a coating on at least a portion of the particle surface.

29. The particle of claim 26 or 27, wherein the particle is encapsulated within a coating.

30. The particle of claim 28 or 29, wherein the coating comprises 25% or less by mass of the coated particle.

31. The particle of any one of claims 26-30, wherein the particle comprises a diameter of about 0.2-20 μm (eg, about 1-10 μm, eg, about 2-6 μm, eg, about 4 μm).

32. The particle of any one of claims 26-31, wherein the particle is a solid particle.

33. A composition comprising the particles according to any one of claims 26 to 32.

34. A composition comprising a plurality of particles according to any one of claims 26-32.

35. The composition of claim 34, wherein the plurality of particles comprises one or more of: 1) a 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 3.5-4.5 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 2.5-3.5 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 0.7-3.4 (e.g., about 2.4); 7) a uniformity coefficient of about 0.6-1.0 (e.g., about 0.8); or 8) A refractive index of about 1.4-1.6 (e.g., about 1.5).

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the particles according to any one of claims 26 to 32 or the composition according to any one of claims 33 to 35.

37. An oral dosage form comprising the particles of any one of claims 26-32, the composition of any one of claims 33-35, or the pharmaceutical composition of claim 36.

38. The oral dosage form of claim 37, wherein the oral dosage form comprises a plurality of said granules as a powder or as a compressed powder.

39. The compound of any one of claims 1-21, the composition of any one of claims 22-25, the particles of any one of claims 26-32, the composition of any one of claims 33-35, the pharmaceutical composition of claim 36, or the oral dosage form of claim 37 or 38, contained in at least one container.

40. A method for treating GABA in a subject in need thereof A A method for treating a receptor-related disease or a disease or disorder of the central nervous system, comprising administering to the subject a therapeutically effective amount of the compound, particle, composition, pharmaceutical composition or oral dosage form according to any one of claims 1 to 39.

41. A compound which is a sulfate, hydrochloride, phosphate, tosylate, malonate or 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.

42. A method comprising administering to a subject a compound, particle, composition, pharmaceutical composition, or oral dosage form according to any one of claims 1-39 or a compound according to claim 41.

Images