Crystal Form of 6-((5-Methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide

Abstract

The present specification describes 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 containing the same, methods for producing them, and their use in medical therapy.

Description

Technical Field

[0001] The present invention relates to a novel crystalline form of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide, a pharmaceutical composition comprising the crystalline form, a method for producing them, and their use in medical therapy.

Background Art

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

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

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

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

[0006] Amorphous drug materials are known to present several problems in this regard. For example, such materials are typically difficult to handle and formulate, provide unreliable solubility, and are often found to be unstable and chemically impure.

[0007] Therefore, those skilled in the art will understand that many of the above problems can be solved if the drug can be easily obtained in a stable crystalline form. Therefore, in the manufacture of a commercially viable and pharmaceutically acceptable drug composition, it is important to provide the drug in a substantially crystalline and stable form as much as possible. However, it should be noted that this goal is not always achievable. In fact, it is usually impossible to predict how the crystallization behavior of a compound itself or a compound in the form of a salt will be based only on its molecular structure. This can only be determined empirically.

[0008] International Publication No. 2018 / 104419, the entire content of which is incorporated herein by reference, discloses a series of compounds that are positive allosteric modulators (PAMs) of the GABA A α5 receptor. International Publication No. 2018 / 104419 teaches that the compounds disclosed therein are potentially useful agents for the treatment of several medical conditions mediated by GABA A α5 receptor activity, such as Alzheimer's disease, mild cognitive impairment (MCI), age-related decline in cognitive function, 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. One specific compound disclosed in International Publication No. 2018 / 104419 is 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (hereinafter, Compound I), the structure of which is shown below. [Chemical formula]

[0009] Compound I is also known as INN alogabat (WHO Drug Information, Vol. 35, No. 2, 2021, 366).

[0010] However, International Publication No. 2018 / 104419 does not disclose any crystalline forms of Compound I.

Summary of the Invention

[0011] In a first aspect, the present invention provides a specific crystalline form of 6 - ((5 - methyl - 3 - (6 - methylpyridin - 3 - yl)isoxazol - 4 - yl)methoxy) - N - (tetrahydropyran - 4 - yl)pyridazine - 3 - carboxamide (Compound I).

Chemical Formula

[0012] In a further aspect, the present invention provides a pharmaceutical composition comprising any of the crystalline forms described herein.

[0013] In a further aspect, the present invention provides the crystalline forms described herein for use as a medicament.

Brief Description of the Drawings

[0014]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0015] Definitions As used herein, the term “acceptable” with respect to a formulation, composition or ingredient means that it does not exert a continuous harmful effect on the general health of the subject being treated.

[0016] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an administered agent to effect some alleviation of one or more symptoms of a disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, and / or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition, including the crystalline forms disclosed herein, required to effect a clinically significant decrease in disease symptoms. The effective amount is selected based on the particular patient and disease level. It is understood that the "effective amount" or "therapeutically effective amount" will vary depending on the subject, due to variations in drug metabolism, the age, weight, general condition of the subject, the symptoms being treated, the severity of the symptoms being treated, and the judgment of the prescribing physician. In one embodiment, the appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study. In some embodiments, the terms "effective amount" or "therapeutically effective amount" are used with respect to the crystalline forms described herein that are administered to effect some alleviation of one or more symptoms of a disease or condition being treated.

[0017] As used herein, the term "prevent" refers to a prophylactic treatment and includes preventing or delaying the onset of clinical symptoms of a condition, disorder, or symptom in a mammal, particularly a human, who is at risk of or predisposed to having, but has not yet experienced or exhibited, the clinical or subclinical symptoms of the condition, disorder, or symptom.

[0018] A "detectable amount" refers to an amount that can be measured 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 guidances, Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996)).

[0019] Crystalline form 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), [Chemical formula] which has an X - ray powder diffraction (XRPD) pattern containing peaks at 18.47, 19.04, and 20.02 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0020] In one embodiment, the crystalline Form A has an X - ray powder diffraction (XRPD) pattern containing peaks at 5.08, 16.20, 18.47, 19.04, and 20.02 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0021] In one embodiment, the crystalline Form A has an X - ray powder diffraction (XRPD) pattern containing peaks at 5.08, 8.08, 14.87, 16.20, 18.47, 19.04, and 20.02 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0022] In one embodiment, the crystalline Form A has an X - ray powder diffraction (XRPD) pattern containing peaks at 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, 20.02, 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 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0023] In one embodiment, the crystalline form A has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1.

[0024] In a further 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 comprising peaks at 9.33, 18.39, and 22.58 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0025] In one embodiment, the crystalline form B has an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.33, 17.42, 18.39, 19.97, and 22.58 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0026] In one embodiment, the crystalline form B has an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.33, 13.05, 15.73, 17.42, 18.39, 19.97, and 22.58 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0027] In one embodiment, the crystalline form B has an X-ray powder diffraction (XRPD) pattern comprising peaks 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 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0028] In one embodiment, the crystalline form B has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 2.

[0029] In a further 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 comprising peaks at 6.64, 20.03, and 24.15 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0030] In one embodiment, the crystalline form 4 has an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.64, 16.76, 20.03, 24.15, and 27.68 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0031] In one embodiment, the crystalline form 4 has an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.64, 16.76, 20.03, 21.46, 22.20, 24.15, and 27.68 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0032] In one embodiment, the crystalline form 4 has an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.64, 7.66, 10.14, 13.30, 13.85, 15.37, 16.76, 17.26, 17.64, 17.95, 18.51, 18.91, 19.24, 20.03, 20.39, 21.46, 21.87, 22.20, 23.16, 23.47, 24.15, 25.37, 25.98, 26.57, 26.82, 27.08, 27.68, 29.04, 29.24, 29.81, 30.82, and 32.30 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

[0033] In one embodiment, the crystalline form 4 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 3.

[0034] Preparation of the Crystalline Form In one aspect, the present invention provides a method for preparing the crystalline forms described herein, which method is as outlined in the Examples. Note that the solvents, temperatures and other reaction conditions shown in the Examples can vary.

[0035] In a further aspect, the present invention provides the crystalline forms described herein when obtained by the methods described in the Examples.

[0036] Suitable solvents Therapeutic agents administrable to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are referred to as Good Manufacturing Practice (GMP) for the manufacture and quality control of pharmaceuticals and quasi-drugs. GMP guidelines outline, for example, the acceptable levels of contamination of the active therapeutic agent, such as the amount of residual solvent in the final product. Preferred solvents are suitable for use in GMP facilities and solvents that are in line with industrial safety concerns. The categories of solvents are defined, for example, in 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).

[0037] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents whose use during the manufacture of therapeutic agents is restricted. Class 3 solvents are solvents with low toxicity and low risk to human health. Data on Class 3 solvents indicate low toxicity in acute or short-term tests and negative results in genotoxicity tests.

[0038] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0039] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, 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-trichloroethene, and xylene.

[0040] Examples of less toxic Class 3 solvents are acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, 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.

[0041] In some embodiments, the compositions comprising the crystalline forms described herein comprise residual amounts of organic solvent(s). In some embodiments, the compositions comprising the crystals described herein comprise detectable amounts of organic solvent(s). In some embodiments, the compositions comprising the crystalline forms described herein comprise residual amounts of Class 3 solvents. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, 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. In some embodiments, the Class 3 solvent is 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.

[0042] The crystalline forms described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, 1-propanol, ethanol, acetic acid, etc. For example, the acetic acid solvate can be obtained by evaporative crystallization from a solvent mixture consisting of acetic acid and n-heptane.

[0043] Amorphous form Despite the drawbacks associated with APIs that are generally amorphous (see above), nevertheless, depending on their physical and biochemical properties, it may be desirable to provide an amorphous form of the API. Accordingly, the present invention also provides an amorphous 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I).

[0044] Pharmaceutical Composition / Formulation The pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically useful preparation. Suitable techniques, carriers, and excipients are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the entire contents of which are incorporated herein by reference.

[0045] In one aspect, the present invention relates to a pharmaceutical composition comprising any of the crystalline forms described herein and at least one pharmaceutically acceptable excipient.

[0046] In one embodiment, the pharmaceutical composition of the present invention is for oral administration to a mammal.

[0047] In one embodiment, the pharmaceutical composition of the present invention is a tablet.

[0048] In one embodiment, the pharmaceutical composition of the present invention is a tablet comprising a kernel and a coating.

[0049] In one embodiment, the kernel comprises at least one pharmaceutically acceptable excipient selected from isomalt, microcrystalline cellulose, croscarmellose sodium, sucralose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0050] In one embodiment, the coating is Opadry II white 32F280008.

[0051] The contemplated pharmaceutical composition provides a therapeutically effective amount of the 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 the crystalline form described herein enabling once-daily administration.

[0052] In one embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 1 mg to 50 mg, preferably 2 mg to 30 mg, more preferably 3 mg to 20 mg. In a preferred embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 3 mg, 4 mg, 10 mg or 20 mg. In a particularly preferred embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 3 mg. In a particularly preferred embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 4 mg. In a particularly preferred embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 10 mg. In a particularly preferred embodiment, the pharmaceutical composition of the present invention provides the crystalline form described herein in an amount of 20 mg.

[0053] Use of the crystalline form of the present invention The compound described herein is GABA A It has valuable pharmacological properties for the treatment or prevention of medical conditions mediated by GABAα5 receptor activity.

[0054] In one aspect, the present invention provides the crystalline form described herein for use as a medicament.

[0055] In one aspect, the present invention is GABA AProvided herein are crystalline forms for use in treating or preventing medical conditions mediated by α5 receptor activity.

[0056] In one aspect, the present invention provides a method of treating or preventing a medical condition mediated by GABA A α5 receptor activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a crystalline form described herein.

[0057] In one aspect, the present invention provides the use of a crystalline form described herein in a method of treating or preventing a medical condition mediated by GABA A α5 receptor activity in a mammal.

[0058] In one aspect, the present invention provides the use of a crystalline form described herein in the manufacture of a medicament for treating or preventing a medical condition mediated by GABA A α5 receptor activity in a mammal.

[0059] In one embodiment, the medical condition mediated by GABA A α5 receptor activity is selected from Alzheimer's disease, mild cognitive impairment (MCI), age-related decline in cognitive function, 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 / or fragile X disorder.

[0060] In one embodiment, the medical condition mediated by GABA A α5 receptor activity is selected from Alzheimer's disease, mild cognitive impairment (MCI), age-related decline in cognitive function, 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 / or fragile X disorder.

[0061] In a preferred embodiment, GABA A The medical conditions mediated by α5 receptor activity are selected from autism spectrum disorder (ASD) and Angelman syndrome.

[0062] In a particularly preferred embodiment, GABA A The medical condition mediated by α5 receptor activity is autism spectrum disorder (ASD).

[0063] In a particularly preferred embodiment, GABA A The medical condition mediated by α5 receptor activity is Angelman syndrome.

Examples

[0064] The following examples are provided for the illustration of the present invention. These should not be considered as limiting the scope of the present invention, but should be understood as merely representative of them.

[0065] Example 1 - Preparation of Crystal Form A Approximately 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 slightly brownish solution was cooled to ambient temperature, while seed crystals were added at 35 - 40 °C. The beige suspension was stirred at ambient temperature for 1 hour and at 0 - 5 °C for 1 hour.

[0066] The crystals were isolated by filtration and washed with 10 mL of ethanol / n - heptane 1:1 and 10 mL of n - heptane. The solid was dried at 55 °C / 5 mbar to obtain 1.9 g of a large amount of white crystals.

[0067] Example 2 - Alternative Preparation of Crystal Form A 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 of THF at ambient temperature. The vial was covered with tissue paper and the solvent was slowly evaporated at ambient temperature. After 1 day, the solvent was evaporated to obtain crystalline Form A of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide.

[0068] Example 3 - Preparation of Crystalline Form B 330 g of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide was dissolved in 5 L of ethanol at 65 °C (a turbid light green solution containing undissolved white particles). Filtration through a carbon filter. Rinsed with 1 L of ethanol. The solvent was evaporated at 60 °C (bath temperature) and 200 mbar. Crystallization started when 1 L of ethanol was distilled off. The solvent was reduced until a thick suspension remained (a further 4.5 L of ethanol was distilled off). The suspension was cooled to ambient temperature with constant stirring. Then, it was stirred at 0 - 5 °C for 30 minutes. The crystals were isolated by filtration and rinsed with 0.6 L of cold ethanol (0 - 5 °C). The solid was dried at 60 °C / 2 mbar for 4 hours to obtain 321 g of white crystals.

[0069] Form B showed excellent stability under all conditions tested (see Example 6).

[0070] Example 4 - Preparation of Crystalline Form 4 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 tissue paper and the solvent was slowly evaporated at ambient temperature. After 10 days, the solvent had completely evaporated. The crystalline residue was identified as Form 4 of 6 - ((5 - methyl - 3 - (6 - methylpyridin - 3 - yl)isoxazol - 4 - yl)methoxy)-N - (tetrahydropyran - 4 - yl)pyridazine - 3 - carboxamide.

[0071] Form 4 was found to convert to Form B by providing a slurry of Form 4 in various solvents and solvent / water mixtures at temperatures in the range of 20 °C to 60 °C.

[0072] It was found that at temperatures above 110 °C, Form 4 converts to Form A.

[0073] Example 5 - XRPD Experimental Method X - ray diffraction patterns were recorded in transmission geometry at ambient conditions using a STOE STADI P diffractometer (Cu Kα1 line, primary Ge monochromator, Mythen 1K silicon strip detector, angular range 3° to 42° 2 - theta, 0.02° 2 - theta step size, 20 - second measurement time per step). Samples were prepared and analyzed without further processing (e.g., grinding or sieving) of the substance.

[0074] Measurement and evaluation of the X - ray diffraction data were performed using WinXPOW software (STOE & Cie GmbH (Darmstadt, Germany)).

[0075] Results The crystalline forms of Compound I were characterized by the above - described XRPD. The unique XRPD peaks of the crystalline forms are shown in Table 1. Characteristic XRPD diffractograms of the crystalline forms are shown in Figures 1 - 3. [Table 1]

[0076] Example 6 - Competitive Slurry Experiment Competitive long - term slurry equilibrium experiments containing Forms A and B were carried out in various solvents in the temperature range of 5 °C to 65 °C.

[0077] All of these experiments resulted in Form B, demonstrating its excellent stability. [Table 2 - 1] [Table 2 - 2] [Table 2 - 3] [Table 2 - 4]

Claims

1. Crystal Form A of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I), 【Chemical 1】 which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 18.47, 19.04, and 20.02 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

2. The Crystal Form A according to Claim 1, which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 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, 20.02, 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 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

3. The Crystal 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. Crystal Form B of 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide (Compound I), [Chemical 2] which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.33, 18.39, and 22.58 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

5. The Crystal Form B according to Claim 4, which has an X-ray powder diffraction (XRPD) pattern comprising peaks 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 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

6. Crystalline Form B according to claim 4, having an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG.

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), [Chemical 3] Crystalline Form 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.64, 20.03, and 24.15 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

8. Crystalline Form 4 according to claim 7, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.64, 7.66, 10.14, 13.30, 13.85, 15.37, 16.76, 17.26, 17.64, 17.95, 18.51, 18.91, 19.24, 20.03, 20.39, 21.46, 21.87, 22.20, 23.16, 23.47, 24.15, 25.37, 25.98, 26.57, 26.82, 27.08, 27.68, 29.04, 29.24, 29.81, 30.82, and 32.30 [°2 theta ± 0.2° 2 theta, CuKα1 radiation (1.5406 Å)].

9. Crystalline Form 4 according to claim 7, having an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG.

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 decline in cognitive function, 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 for treating or preventing Alzheimer's disease, mild cognitive impairment, age-related decline in cognitive function, 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 the crystalline form according to any one of claims 1 to 9.

14. Use of the crystalline form according to any one of claims 1 to 9 in the method 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 the treatment or prevention of Alzheimer's disease, mild cognitive impairment, age-related decline in cognitive function, 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 described previously herein.

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