Crystalline forms of 6-((5-methyl-3-(6-methylpyridin-3-yl) isoxazol-4-yl) methoxy)-n-(tetrahydropyridin-4-yl) pyridazin-3-carboxamide

Abstract

Described herein are novel crystalline forms of 6-((5-methyl-3-(6-methylpyridin-3-yl) isoxazol-4-yl) methoxy)-N-(tetrahydropyran-4-yl) pyridazine-3-carboxamide, as well as pharmaceutical compositions comprising the crystalline forms, processes for their preparation and their use in drug therapy.

Description

Technical Field

[0001] The present invention relates to novel crystalline forms of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide, pharmaceutical compositions comprising said crystalline forms, processes for their preparation and their use in medical therapy. Background Art

[0002] It is important to identify a drug form that can be conveniently manufactured, formulated, and administered to patients.

[0003] Furthermore, in the manufacture of oral pharmaceutical compositions, it is important that the drug is in a form that provides reliable and reproducible plasma concentrations following administration to a patient.

[0004] The chemical stability, solid-state stability, and "shelf life" of the drug substance are also particularly important factors. Ideally, the drug substance and compositions containing it should be able to be effectively stored for a considerable period of time without exhibiting significant changes in the physicochemical properties of the active ingredient (e.g., its chemical composition, density, hygroscopicity, and solubility).

[0005] Furthermore, it is important to be able to provide the drug in a form that is as chemically pure as possible.

[0006] It is known that amorphous pharmaceutical materials may present some problems in this regard. For example, such materials are often difficult to handle and formulate, provide unreliable solubility, and are often found to be unstable and chemically impure.

[0007] Therefore, the skilled person will appreciate that if a drug in a stable crystalline form can be easily obtained, many of the above problems can be solved. Therefore, in the manufacture of commercially viable and pharmaceutical drug compositions, it is important to provide a drug in a substantially crystalline and stable form whenever possible. However, it should be noted that this goal is not always achievable. In fact, it is generally impossible to predict the crystallization behavior of a compound (either itself or in salt form) based solely on molecular structure. This can only be determined empirically.

[0008] WO2018104419 (the entire contents of which are incorporated herein by reference) discloses a series of compounds which are GABA A Positive allosteric modulators (PAMs) of α5 receptors. WO2018104419 teaches that the compounds disclosed therein are potentially useful agents that can be used to treat many GABA-mediated diseases. AMedical conditions mediated by α5 receptor activity, such as Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS) and fragile X disorder. A specific compound disclosed in WO2018104419 is 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (hereinafter referred to as Compound I), and its structure is shown below.

[0009]

[0010] Compound I is also known under INN alogabat (WHO Drug Information, Vol. 35, No. 2, 2021, 366).

[0011] However, any crystalline form of Compound I is not disclosed in WO2018104419. Summary of the invention

[0012] In a first aspect, the present invention provides certain crystalline forms of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I).

[0013]

[0014] In a further aspect, the present invention provides a pharmaceutical composition comprising any of the crystalline forms described herein.

[0015] In a further aspect, the present invention provides a crystalline form as described herein for use as a medicament. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A characteristic XRPD diffraction pattern of crystalline Form A of Compound 1 is shown.

[0017] Figure 2 A characteristic XRPD diffraction pattern of crystalline Form B of Compound 1 is shown.

[0018] Figure 3 A characteristic XRPD diffraction pattern of crystalline Form 4 of Compound 1 is shown. DETAILED DESCRIPTION

[0019] definition

[0020] The term "acceptable" with respect to a formulation, composition or ingredient as used herein means having no persistent detrimental effect on the general health of the subject being treated.

[0021] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the administered agent that will alleviate one or more symptoms of the disease or condition being treated to a certain extent. The result may be a reduction and / or alleviation of the signs, symptoms or causes of the disease or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a crystalline form disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The effective amount will be selected according to the specific patient and disease level. It should be understood that the "effective amount" or "therapeutically effective amount" varies between subjects due to changes in drug metabolism, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies. In some embodiments, the term "effective amount" or "therapeutically effective amount" used refers to the crystalline form described herein administered, which will alleviate one or more symptoms of the disease or condition being treated to a certain extent.

[0022] As used herein, the term "prevention" refers to prophylactic treatment and includes preventing or delaying the appearance of clinical symptoms of a state, disorder or condition that develops in a mammal, and particularly in a human, that may have or is susceptible to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0023] A "detectable amount" is a quantity that can be detected using standard analytical methods (e.g., ion chromatography, mass spectrometry, NMR, HPLC, gas chromatography, elemental analysis, IR spectroscopy, inductively coupled plasma atomic emission spectroscopy, USP <231> Method II, etc.) (ICH Guidelines, Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996)).

[0024] Crystalline form

[0025] In one aspect, the present invention provides crystalline Form A of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I),

[0026]

[0027] It has an X-ray powder diffraction (XRPD) pattern, the X-ray powder diffraction (XRPD)

[0028] Figures include radiation at 18.47, 19.04 and 20.02 [°2θ ± 0.2°2θ, Cu Kα1 ] at the peak.

[0029] In one embodiment, the crystalline Form A has an X-ray powder diffraction (XRPD) pattern comprising XRPD patterns at 5.08, 16.20, 18.47, 19.04 and 20.02 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0030] In one embodiment, the crystalline Form A has an X-ray powder diffraction (XRPD) pattern comprising XRPD patterns at 5.08, 8.08, 14.87, 16.20, 18.47, 19.04 and 20.02 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0031] In one embodiment, the crystalline Form A has an X-ray powder diffraction (XRPD) pattern comprising 5.08, 8.08, 9.20, 10.17, 10.82, 12.75, 14.87, 15.37, 16.20, 17.42, 18.47, 18.80, 19.04, 19.66, 20.0 2, 21.10, 21.72, 22.39, 23.14, 23.80, 24.36, 24.57, 24.72, 25.03, 25.31, 25.57, 26.13, 26.48, 28.17, 28.37, 28.98, 29.12, 29.52, 30.14, and 31.46 [°2θ ± 0.2°2θ, Cu Kα1 radiation ] at the peak.

[0032] In one embodiment, the crystalline Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1 .

[0033] In another aspect, the present invention provides a crystalline Form B of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I) having an X-ray powder diffraction (XRPD) pattern including chromatic aberrations at 9.33, 18.39 and 22.58 [°2θ±0.2°2θ, Cu Kα1 radiation ] at the peak.

[0034] In one embodiment, the crystalline Form B has an X-ray powder diffraction (XRPD) pattern comprising XRPD patterns at 9.33, 17.42, 18.39, 19.97 and 22.58 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0035] In one embodiment, the crystalline Form B has an X-ray powder diffraction (XRPD) pattern comprising XRPD patterns at 9.33, 13.05, 15.73, 17.42, 18.39, 19.97 and 22.58 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0036] In one embodiment, the crystalline Form B has an X-ray powder diffraction (XRPD) pattern comprising 9.33, 11.87, 13.05, 15.73, 16.77, 16.92, 17.42, 18.39, 18.73, 19.62, 19.97, 21.08, 21.35, 22.46, 22.58, 23.75, 24.03, 24.92, 26.39, 26.79, 27.10, 27.94, 29.19, 29.61, 30.86 and 31.76 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0037] In one embodiment, the crystalline Form B has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 2 .

[0038] In another aspect, the present invention provides crystalline Form 4 of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I) having an X-ray powder diffraction (XRPD) pattern including chromatic aberrations at 6.64, 20.03 and 24.15 [°2θ±0.2°2θ, Cu Kα1 radiation ] at the peak.

[0039] In one embodiment, the crystalline Form 4 has an X-ray powder diffraction (XRPD) pattern comprising XRPD patterns at 6.64, 16.76, 20.03, 24.15 and 27.68 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

[0040] In one embodiment, the crystalline Form 4 has an X-ray powder diffraction (XRPD) pattern including chromatic aberrations at 6.64, 16.76, 20.03, 21.46, 22.20, 24.15 and 27.68 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation. ] at the peak.

[0041] In one embodiment, the crystalline Form 4 has an X-ray powder diffraction (XRPD) pattern comprising 30.82, 31.77, 32.30, 33.61, 34.97, 35.37, 36.70, 37.71, 38.63, 39.77, 40.91, 41.11, 42.97, 43.70, 44.97, 45.71, 46.97, 47.70, 48.63, 49.04, 49.24, 49.81, 40.97, 48.63, 49.70, 48.63, 49.97, 48.63, 49.70, 48.63, 49.97, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70, 48.63, 49.70 ] at the peak.

[0042] In one embodiment, the crystalline Form 4 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3 .

[0043] Preparation of crystalline forms

[0044] In one aspect, the invention provides methods of preparing the crystalline forms described herein, wherein the methods are as outlined in the Examples. It should be noted that the solvents, temperatures and other reaction conditions presented in the Examples may vary.

[0045] In a further aspect, the invention provides a crystalline form as described herein, when obtained by the method described in the Examples.

[0046] Suitable solvent

[0047] The therapeutic agent that can be used in mammals (such as humans) must be prepared according to management guidelines. Such government-mandated guidelines are called good manufacturing practices (GMP). The GMP guidelines outline the acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvents in the final product. Preferred solvents are those solvents that are suitable for GMP equipment and meet industrial safety considerations. The categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C (R3), (November 2005).

[0048] Solvents are divided into three categories. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that have limited use in the manufacturing process of therapeutic agents. Class 3 solvents are solvents that have low toxic potential and pose a low risk to human health. Data for Class 3 solvents have shown low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0049] Class 1 solvents that should be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0050] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene and xylene.

[0051] Three types of solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), isopropylbenzene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran.

[0052] In some embodiments, the composition comprising the crystalline form described herein includes a residual amount of an organic solvent. In some embodiments, the composition comprising the crystalline form described herein includes a detectable amount of an organic solvent. In some embodiments, the composition comprising the crystalline form described herein includes a residual amount of Class 3 solvents. In some embodiments, Class 3 solvents are selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, isopropylbenzene, dimethyl sulfoxide, ethanol, ethyl acetate, ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran. In some embodiments, Class 3 solvents are selected from the group consisting of 1-butanol, 2-butanol, ethanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, 1-propanol and 2-propanol. In some embodiments, the Class 3 solvent is ethanol or 1-propanol.

[0053] The crystalline forms described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, 1-propanol, ethanol, acetic acid, etc. For example, acetic acid solvate can be obtained by evaporative crystallization from a solvent mixture consisting of acetic acid and n-heptane.

[0054] Amorphous form

[0055] Despite the disadvantages generally associated with amorphous drug substances (see above), it may still be desirable to provide a drug substance in an amorphous form, depending on its physical and biochemical properties. Accordingly, the present invention also provides amorphous 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I).

[0056] Pharmaceutical compositions / formulations

[0057] Pharmaceutical compositions are prepared in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate processing of the active compounds into pharmaceutically acceptable preparations. Suitable techniques, carriers and excipients are included in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pennsylvania: Mark Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mark Publishing Company, Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), the entire contents of which are incorporated herein by reference.

[0058] In one aspect, the invention relates to a pharmaceutical composition comprising any of the crystalline forms described herein and at least one pharmaceutically acceptable excipient.

[0059] In one embodiment, the pharmaceutical compositions of the present invention are for oral administration to a mammal.

[0060] In certain embodiments, the pharmaceutical composition of the present invention is a tablet.

[0061] In one embodiment, the pharmaceutical composition of the present invention is a tablet comprising a core and a coating.

[0062] In one embodiment, the inner core comprises at least one pharmaceutically acceptable excipient selected from the group consisting of isomalt, microcrystalline cellulose, croscarmellose sodium, sucralose, colloidal silicon dioxide and sodium stearyl fumarate.

[0063] In one embodiment, the coating is Opadry II white 32F280008.

[0064] Contemplated pharmaceutical compositions provide a therapeutically effective amount of a crystalline form described herein, enabling administration, for example, once a day, twice a day, three times a day, etc. In one embodiment, the pharmaceutical composition provides an effective amount of a crystalline form described herein, enabling once a day administration.

[0065] In one embodiment, the pharmaceutical composition of the present invention provides 1 mg to 50 mg, preferably 2 mg to 30 mg, more preferably 3 mg to 20 mg of the crystalline form described herein. In a preferred embodiment, the pharmaceutical composition of the present invention provides 3 mg, 4 mg, 10 mg or 20 mg of the crystalline form described herein. In a preferred embodiment, the pharmaceutical composition of the present invention provides 3 mg of the crystalline form described herein. In a preferred embodiment, the pharmaceutical composition of the present invention provides 4 mg of the crystalline form described herein. In a preferred embodiment, the pharmaceutical composition of the present invention provides 10 mg of the crystalline form described herein. In a preferred embodiment, the pharmaceutical composition of the present invention provides 20 mg of the crystalline form described herein.

[0066] Use of the crystalline form of the invention

[0067] The compounds described herein are useful for treating or preventing GABA A Valuable pharmacological properties of medical conditions mediated by alpha 5 receptor activity.

[0068] In one aspect, the invention provides a crystalline form as described herein for use as a medicament.

[0069] In one aspect, the invention provides a crystalline form as described herein for use in treating or preventing GABA A Medical conditions mediated by alpha 5 receptor activity.

[0070] In one aspect, the invention provides a method for treating or preventing GABA in a mammal. A A method for treating a medical condition mediated by α5 receptor activity, the method comprising administering to the mammal a therapeutically effective amount of a crystalline form described herein.

[0071] In one aspect, the invention provides a crystalline form as described herein for use in treating or preventing GABA in a mammal. A Use in methods of treating medical conditions mediated by α5 receptor activity.

[0072] In one aspect, the invention provides a crystalline form as described herein for use in the manufacture of a method for treating or preventing GABA in a mammal. A Use in medicine for medical conditions mediated by alpha 5 receptor activity.

[0073] In one embodiment, GABA AThe medical condition mediated by α5 receptor activity is selected from the group consisting of Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS) and fragile X disorder.

[0074] In one embodiment, GABA A The medical condition mediated by α5 receptor activity is selected from the group consisting of Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS) and fragile X disorder.

[0075] In a preferred embodiment, GABA A The medical condition mediated by alpha5 receptor activity is selected from autism spectrum disorder (ASD) and Angelman syndrome.

[0076] In a preferred embodiment, GABA A Such medical condition mediated by alpha5 receptor activity is autism spectrum disorder (ASD).

[0077] In a preferred embodiment, GABA A The medical condition mediated by alpha 5 receptor activity is Angelman syndrome.

[0078] Examples

[0079] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but are merely representative.

[0080] Example 1 - Preparation of Crystalline Form A

[0081] About 2.5 g of crude 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide was dissolved in 50 mL of ethanol under reflux conditions. The resulting brownish solution was allowed to cool to ambient temperature, while seed crystals were added at 35° C. to 40° C. The beige suspension was stirred at ambient temperature for 1 h and at 0° C. to 5° C. for 1 h.

[0082] The crystals were isolated by filtration, rinsed with 10 mL ethanol / n-heptane 1:1 and 10 mL n-heptane. The solid was dried at 55° C. / 5 mbar to give 1.9 g of voluminous white crystals.

[0083] Example 2 - Alternative preparation of crystalline form A

[0084] 306.9 mg of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide was dissolved in 6 mL THF at ambient temperature. The vial was covered with a paper towel to allow the solvent to evaporate slowly at ambient temperature. After 1 day, the solvent was evaporated to give 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide crystalline Form A.

[0085] Example 3 - Preparation of Crystalline Form B

[0086] 330 g of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide were dissolved in 5 L of ethanol at 65 ° C (turbid and light green solution with undissolved white particles). Filter through a carbon filter. Rinse with 1 L of ethanol. Evaporate the solvent at 60 ° C (bath temperature) and 200 mbar. Crystallization begins when 1 L of ethanol is distilled off. The solvent is reduced until a viscous suspension remains (an additional 4.5 L of ethanol is distilled off). Under permanent stirring, the suspension is cooled to ambient temperature. Then stir at 0-5 ° C for 30 min. The crystals are separated by filtration and rinsed in batches with 0.6 L of cold ethanol (0-5 ° C). The solid is dried at 60 ° C / 2 mbar for 4 hours to obtain 321 g of white crystals.

[0087] Form B exhibited excellent stability under all conditions tested (see Example 6).

[0088] Example 4 - Preparation of Crystalline Form 4

[0089] Approximately 300 mg of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide was dissolved in 6 mL of 1,4-dioxane at ambient temperature. The vial was covered with a paper towel to allow the solvent to evaporate slowly at ambient temperature. After 10 days, the solvent was completely evaporated. The crystalline residue was identified as 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide Form 4.

[0090] Form 4 was found to convert to Form B by providing a slurry of Form 4 in various solvents and solvent / water mixtures at a temperature ranging from 20°C to 60°C.

[0091] At temperatures >110°C, Form 4 was found to convert to Form A.

[0092] Example 5 - XRPD

[0093] Experimental methods

[0094] X-ray diffraction patterns were recorded in transmission geometry under ambient conditions using a STOE STADIP diffractometer (Cu Kα1 radiation, primary Ge-monochromator, Mythen 1K silicon strip detector, angular range 3° to 42° 2θ, 0.02° 2θ step size, 20 s measurement time per step). The samples were prepared and analyzed without further processing of the material (e.g. grinding or sieving).

[0095] The measurement and evaluation of X-ray diffraction data were performed using WinXPOW software (STOE&Cie GmbH, Darmstadt, Germany).

[0096] result

[0097] As described above, the crystalline form of Compound I was characterized by XRPD. The unique XRPD peaks of the crystalline form are presented in Table 1. Characteristic XRPD diffractograms of the crystalline form are shown in Figures 1 to 3.

[0098] Table 1 - Typical XRPD peaks of Compound I

[0099]

[0100]

[0101] Example 6 - Competitive slurry experiment

[0102] Competitive long-term slurry equilibrium experiments (including Form A and Form B) were performed in various solvents over a temperature range of 5°C to 65°C.

[0103] All of these experiments yielded Form B, demonstrating its remarkable stability.

[0104] Table 2 – Competitive slurry experiments

[0105]

[0106] Table 2 (continued)

[0107]

[0108]

[0109] Table 2 (continued)

[0110]

[0111]

[0112] Table 2 (continued)

[0113]

Claims

1. Crystalline Form A of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I), It has an X-ray powder diffraction (XRPD) pattern including X-ray diffraction patterns at 18.47, 19.04 and 20.02 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation ] at the peak.

2. The crystalline Form A according to claim 1, having an X-ray powder diffraction (XRPD) pattern comprising 5.08, 8.08, 9.20, 10.17, 10.82, 12.75, 14.87, 15.37, 16.20, 17.42, 18.47, 18.80, 19.04, 19.66, 2 0.02, 21.10, 21.72, 22.39, 23.14, 23.80, 24.36, 24.57, 24.72, 25.03, 25.31, 25.57, 26.13, 26.48, 28.17, 28.37, 28.98, 29.12, 29.52, 30.14, and 31.46 [°2θ ± 0.2°2θ, Cu Kα1 radiation ] at the peak.

3. The crystalline Form A according to claim 1, which has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1.

4. Crystalline Form B of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I), It has an X-ray powder diffraction (XRPD) pattern including X-ray diffraction patterns at 9.33, 18.39 and 22.58 [°2θ±0.2°2θ, Cu Kα1 radiation ] at the peak.

5. The crystalline Form B of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising 200 Å at 9.33, 11.87, 13.05, 15.73, 16.77, 16.92, 17.42, 18.39, 18.73, 19.62, 19.97, 21.08, 21.35, 22.46, 22.58, 23.75, 24.03, 24.92, 26.39, 26.79, 27.10, 27.94, 29.19, 29.61, 30.86 and 31.76 [° 2θ ± 0.2° 2θ, Cu Kα1 radiation] ] at the peak.

6. The crystalline Form B according to claim 4, which has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 2.

7. Crystalline Form 4 of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I), It has an X-ray powder diffraction (XRPD) pattern including X-ray diffraction patterns at 6.64, 20.03 and 24.15 [°2θ±0.2°2θ, Cu Kα1 radiation ] at the peak.

8. The crystalline Form 4 of claim 7 having an X-ray powder diffraction (XRPD) pattern comprising 30.84, 31.73, 32.11, 33.97, 34.70, 35.37, 36.71, 37.90, 38.73, 39.77, 40.91, 41.30, 42.77, 43.61, 44.73, 45.97, 46.57, 47.71, 48.97, 49.10, 50.11, 51.13, 52.73, 53.97, 54.73, 55.98, 56.11, 57.12, 58.13, 59.14, 50.15, 51.16, 52.17, 53.18, 54.19, 55.20, 56.21, ] at the peak.

9. The crystalline Form 4 according to claim 7, which has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 3.

10. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 9, and at least one pharmaceutically acceptable excipient, preferably wherein the pharmaceutical composition is in a form suitable for oral administration to a mammal.

11. The crystalline form according to any one of claims 1 to 9 for use as a medicament.

12. The crystalline form according to any one of claims 1 to 9 for use in the treatment or prevention of Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis and / or fragile X disorder.

13. A method of treating or preventing Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis and / or fragile X disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a crystalline form according to any one of claims 1 to 9.

14. Use of a crystalline form according to any one of claims 1 to 9 in a process according to claim 13.

15. Use of the crystalline form according to any one of claims 1 to 9 in the manufacture of a medicament for treating or preventing Alzheimer's disease, mild cognitive impairment, age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder, Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis and / or fragile X disorder in a mammal.

16. The invention as herein before described.

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