Solid form of a CYP11A1 inhibitor having the structure of 4H-pyran-4one

Abstract

This invention provides a novel solid form of 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one that possesses properties and stability that enable large-scale production. [Solution] A compound is provided which is crystalline form 1 of 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran-4-one(I), having an X-ray powder diffraction pattern characterized by peaks appearing at diffraction angles 2θ (±0.2) of 4.5, 8.8, 9.0, 15.9, 17.6, and 20.5.

Description

Technical Field

[0001] The present invention relates to a novel solid form of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl piperidin-4-yl)methoxy)-4H-pyran-4-one (I) and the preparation thereof. The present invention further relates to pharmaceutical compositions comprising such novel solid form as well.

Background Art

[0002] The compound of formula (I), 2-(isoindolin-2-ylmethyl)-5-((1-( methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one and derivatives thereof are disclosed in WO2018 / 115591. The compound represented by formula (I) is a selective inhibitor of CYP11A1 enzyme, and is useful in the treatment of hormonally regulated cancers such as prostate cancer and breast cancer therapy.

[0003]

Chemical Formula

[0004] In general, in the preparation of pharmaceutical compositions, there is a need for a form of active ingredient that has a balance of desired properties such as dissolution rate, bioavailability, flowability, processability, filtrability hygroscopicity, compressibility and / or storage stability. For example, a form of active ingredient having the required solubility and bioavailability is desired, which does not convert into a different form with different properties during manufacture or storage of the pharmaceutical composition, and also has sufficient stability. It is also desirable to have sufficient stability.

Prior Art Literature

Patent Literature

[0005] [Patent Document 1] WO2018 / 115591 [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, it will enable the large-scale manufacturing of marketable pharmaceuticals suitable for treating diseases such as cancer. One or more forms of compound (I) possessing desirable properties and stability are desired. [Means for solving the problem]

[0007] Compound (I) is used in the large-scale manufacturing of pharmaceuticals such as tablets or capsules. One or more solid forms having the necessary properties to enable this (which include stability and processability) It was found that it is possible to obtain it in this state.

[0008] In one embodiment, the present disclosure relates to 2-(isoindoline-2-ylmethyl) in crystalline form. -5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran -4-on(I) is provided.

[0009] In another embodiment, the present disclosure relates to 2-(isoindoline-2-ylmethyl) in crystalline form 1 -5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran -4-on(I) is provided.

[0010] In another embodiment, the present disclosure relates to 2-(isoindoline-2-ylmethyl) in crystalline form 2. -5-((1-(methylsulfonyl)piperidine-4-yl)methoxy)-4H-pyran -4-on(I) is provided.

[0011] In another aspect, said crystalline form 2 is in the form of a dihydrate.

[0012] In another aspect, the present disclosure provides 2-(isoindolin-2-ylmethyl) -5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran -4-one (I) of crystalline form 3.

[0013] In another aspect, the present disclosure provides 2-(isoindolin-2-ylmethyl) -5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran -4-one (I) of crystalline form 4.

[0014] In another aspect, the present disclosure provides 2-(isoindolin-2-ylmethyl) -5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran -4-one (I) of crystalline form 5. In another aspect, said crystalline form 5 is in the form of a variable hydrate .

[0015] In another aspect, the present disclosure provides 2-(isoindolin-2-ylmethy l)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-py ran-4-one (I) in amorphous form.

[0016] In another aspect, the present disclosure provides substantially pure crystalline form 1 to crystalline form 5 of compound (I) , wherein at least 90%, preferably at least 95%, more preferably at least 98%, by weight of compound (I) is present in said crystalline form.

[0017] In another aspect, the present disclosure relates to treatment of a disease in which inhibition of CYP11A1 is desired Methods to do so, in particular, hormone-regulated cancers such as prostate cancer and breast cancer (hormone-regulated cancers) This provides a method for treating (only regulated cancer), and here, The method involves administering a therapeutically effective amount of compound (I) in the solid form to subjects requiring such treatment. This includes administering one of the following:

[0018] In yet another embodiment, the Disclosure provides one or more of the above solid forms of compound (I). The present invention provides a pharmaceutical composition containing the excipients together. [Brief explanation of the drawing]

[0019] [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of crystalline form 1 of compound (I). [Figure 2] Figure 2 shows the X-ray powder diffraction pattern of crystalline form 2 of compound (I). [Figure 3] Figure 3 shows the X-ray powder diffraction pattern of crystalline form 3 of compound (I). [Figure 4] Figure 4 shows the X-ray powder diffraction pattern of crystalline form 4 of compound (I). [Figure 5] Figure 5 shows the X-ray powder diffraction pattern of compound (I) in crystalline form 5 (water content 0.3-0.6). [Figure 6] Figure 6 shows the X-ray powder diffraction pattern of compound (I) in crystalline form 5 (water content 0.3). [Figure 7] Figure 7 shows the X-ray powder diffraction pattern of compound (I) in crystalline form 5 (water content 0.6). [Figure 8] Figure 8 shows the X-ray powder diffraction pattern of compound (I) in its amorphous form. [Figure 9] Figure 9 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 1 of compound (I). [Figure 10]Figure 10 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 2 of compound (I). [Figure 11] Figure 11 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 3 of compound (I). [Figure 12] Figure 12 shows a differential scanning calorimetry (DSC) thermogram of crystalline form 4 of compound (I). [Figure 13] Figure 13 shows a differential scanning calorimetry (DSC) thermogram of compound (I) in crystalline form 5 (water content 0.3-0.6). [Figure 14] Figure 14 shows a differential scanning calorimetry (DSC) thermogram of compound (I) in crystalline form 5 (water content 0.3). [Figure 15] Figure 15 shows a differential scanning calorimetry (DSC) thermogram of compound (I) in crystalline form 5 (water content 0.6). [Figure 16] Figure 16 shows a scanning electron microscope image (magnification 100x, bar 200 μm) of crystalline form 3 of compound (I). [Figure 17] Figure 17 shows a scanning electron microscope image (magnification 100x, bar 200 μm) of compound (I) in crystalline form 5 (water content 0.3-0.6). [Modes for carrying out the invention]

[0020] This disclosure relates to 2-(isoindoline-2-ylmethyl)-5-((1-( Methylsulfonyl piperidine-4-yl methoxy)-4H-pyran-4-one(I) To provide.

[0021] Crystal morphologies 1-5 of compound (I) were specifically identified by X-ray powder diffraction (XRPD) studies. It is marked.

[0022] Accordingly, in one embodiment, this disclosure is approximately 4.5, 8.8, 9.0, 15.9, 17.6 It also has an X-ray powder diffraction pattern in which a characteristic peak is observed at a diffraction angle of 20.5° 2θ. This provides crystalline form 1 of compound (I).

[0023] In another embodiment, this disclosure relates to approximately 4.6, 7.2, 9.1, 14.8, 16.6 and 1 Compounds exhibiting an X-ray powder diffraction pattern with a characteristic peak at diffraction angle 2θ. (I) provides a crystal form 2.

[0024] In another embodiment, this disclosure relates to approximately 9.2, 12.7, 14.8, 16.3, 17.0 and The X-ray powder diffraction pattern shows a characteristic peak at a diffraction angle of 2θ of 21.3°. The crystal form 3 of compound (I) is provided.

[0025] In another embodiment, this disclosure relates to approximately 6.3, 15.7, 16.5, 19.6, 20.8 and The X-ray powder diffraction pattern shows a characteristic peak at a diffraction angle of 2θ of 21.5°. The crystalline form 4 of compound (I) is provided.

[0026] In another aspect, this disclosure relates to approximately 9.4, 10.0, 10.5, 11.6, 13.5, Characteristic peaks are observed at diffraction angles 2θ of 15.2, 16.5, and 20.0 in the X-ray powder radiography. The present invention provides a crystalline form 5 of compound (I) having a folding pattern.

[0027] In yet another embodiment, this disclosure relates to approximately 4.5, 8.8, 9.0, 15.9, and 17.6. Characteristic peaks were observed at diffraction angles 2θ of 19.6, 19.7, 20.5, and 21.3. The present invention provides a crystalline form 1 of compound (I) having an X-ray powder diffraction pattern. In this case, the crystal morphology 1 is further characterized by the X-ray powder diffraction pattern shown in Figure 1. To be marked.

[0028] In yet another embodiment, this disclosure relates to approximately 4.6, 7.2, 9.1, 10.7, and 11.1. , 12.1, 13.7, 14.8, 16.6, 17.0, 17.3, 17.8, 18.3 X-ray powder diffraction pattern showing characteristic peaks at diffraction angles 2θ of 21.7 and 22.3. The present invention provides a crystalline form 2 of compound (I) having n. In yet another embodiment, the crystalline form 2 Furthermore, it is characterized by the X-ray powder diffraction pattern shown in Figure 2. In another embodiment, the crystalline form 2 is in the form of a dihydrate.

[0029] In yet another aspect, this disclosure relates to approximately 5.0, 8.2, 9.2, 10.1, and 10.8. 12.7, 14.8, 15.6, 16.3, 17.0, 17.2, 18.5, 18.9 Characteristic peaks were observed at diffraction angles 2θ of 19.3, 20.2, 21.3, and 21.7. The present invention provides a crystalline form 3 of compound (I) having an X-ray powder diffraction pattern. In this case, crystal morphology 3 is further characterized by the X-ray powder diffraction pattern shown in Figure 3. To be marked.

[0030] In yet another aspect, this disclosure relates to approximately 6.3, 15.7, 16.5, 17.1, and 17. 0.8, 18.2, 18.7, 19.1, 19.6, 20.8, 21.3, 21.5, 22 X-ray powder diffraction pattern showing characteristic peaks at diffraction angles 2θ of 0.2, 22.9, and 27.7. A crystalline form 4 of compound (I) having turns is provided. In yet another embodiment, the crystalline form State 4 is further characterized by the X-ray powder diffraction pattern shown in Figure 4.

[0031] In yet another embodiment, this disclosure relates to approximately 9.4, 10.0, 10.5, 11.6, and 13. 0.5, 14.6, 15.2, 16.5, 16.9, 18.1, 18.8, 20.0, 22 The X-ray powder diffraction pattern shows characteristic peaks at diffraction angles 2θ of 0.3 and 23.3. The crystalline form 5 of compound (I) is provided. In another embodiment, the crystalline form 5 is variable It exists in the form of a hydrate.

[0032] The term "variable hydrate" is used herein. If this is the case, it is possible to incorporate various numbers of water molecules without destroying the crystal lattice. It exhibits a crystalline form. Therefore, such a crystalline form has stoichiometric quantities within its lattice structure. Alternatively, non-stoichiometric amounts of water molecules can be incorporated. Generally, the crystalline form of compound (I) Compound (I) may contain up to approximately 1 molecule of water per molecule of compound (I). In particular, compound ( Crystal form 5 of (I) contains approximately 0.3 to 0.6 molecules of water per molecule of compound (I). It contains.

[0033] Approximately 0.3 to 0.6 molecules, approximately 0.3 molecules, and approximately 0.6 molecules per molecule of compound (I) The X-ray powder diffraction patterns of crystal form 5 with the water content are shown in Figures 5, 6, and 6, respectively. This is shown in Figure 7. Therefore, in one embodiment, the crystal morphology 5 is as shown in Figures 5, 6 and 7. Further characterization is provided by the X-ray powder diffraction patterns shown in Figure 5. The small fluctuation in peak position between Figure 6 and Figure 7 is related to the crystal structure of variable hydrate crystal form 5. This relates to the variable, non-stoichiometric water content.

[0034] The peak position of the above XRPD was measured using CuKα radiation (λ=1.5418Å). The values ​​shown are those obtained when the X-ray powder diffraction pattern peaks are mentioned herein. Location is affected by various factors (e.g., temperature, sample handling, and equipment used). Those skilled in the art will recognize that the diffraction angle 2θ may vary by ±0.2 degrees accordingly.

[0035] Amorphous compound (I) can be prepared, for example, by grinding compound (I) in a suitable container and then dissolving it. It can be properly prepared by heating until melting occurs. Then, the melting By rapidly cooling a material, for example using liquid nitrogen, a glassy amorphous substance can be obtained. It can be done.

[0036] The crystalline form 1 of compound (I) is obtained, for example, by dissolving compound (I) in dichloromethane, Then, an antisolvent such as diethyl ether is added, and the crystalline product is isolated. It can be properly prepared by this method. In particular, crystalline form 1 is obtained by dichloroforming compound (I). Dissolve in methane, add diethyl ether under stirring, and then the mixture is preferably Alternatively, it can be prepared by aging at a low temperature (for example, 0-10°C, or approximately 5°C). It is possible. The ratio of diethyl ether to dichloromethane is, for example, about 3: The ratio can be 1 to approximately 5:1, for example, about 4:1. Aging typically takes several hours, for example, a short time. It continues for at least 3 hours, for example, about 24 hours. Crystal form 1 is filtered and reduced It can be recovered by drying under pressure.

[0037] The crystalline form of compound (I) is, for example, compound (I) with water as a cosolvent (e.g., 2-Propyl). A mixture of panol, acetone, ethanol, acetonitrile, or tetrahydrofuran Dissolve it, and then cool the solution to, for example, 0-10°C, to properly It can be prepared. The cooled mixture is preferably typically left for several hours, for example. Then, age it at a low temperature (e.g., 0-10°C) for at least 3 hours, for example, about 24 hours. The appropriate ratio of water to cosolvent is generally about 1:2 to about 2:1 by volume, for example, about 1: It is 1. Crystal form 2 can be recovered, for example, by filtration, and It is possible to obtain crystalline form 2 by evaporating the solvent, for example, at room temperature. The crystal form 2 typically crystallizes as needle-shaped crystals.

[0038] Alternatively, crystalline form 2 can be prepared by freeze-drying. Compound (I) First, a mixture of water and a co-solvent (e.g., ethanol, methanol, or 2-propanol) It can be dissolved in suitable solvents such as the following. The appropriate ratio of water to cosolvent is, on a volume basis, 1 Generally, the ratio is approximately 1:2 to 2:1, for example, approximately 1:1. Then, the solution is, for example, approximately - The mixture is frozen at a temperature of 20°C to approximately -40°C, and then the solvent is removed at this freezing temperature under reduced pressure. Next, the obtained crystal form 2 can be recovered.

[0039] Alternatively, crystalline form 2 can be prepared by high-speed evaporation. For example, the compound ( I) A concentrated aqueous solution (e.g., 0.795 mg / mL) is prepared under reduced pressure and high temperature, for example, 1 Evaporate under 00-200 millibars and at 50-70°C. Then, the obtained crystalline form You can recover 2.

[0040] The crystalline form 3 of compound (I) is obtained, for example, by heating (for example, by heating to 60-80°C) (While) compound (I) can be appropriately prepared by dissolving it in ethanol. Next, the solution is cooled to room temperature over a period of 2 to 10 hours, for example, over 3 hours. Crystal form 3 can be recovered, for example, by filtration, and under vacuum. It can be dried at high temperatures, for example, 40-60°C. Crystal morphology 3 is typically, It crystallizes as needle-shaped crystals.

[0041] Alternatively, crystalline form 3 involves mixing compound (I) with ethyl acetate, and then, for example, 60 It can be prepared by heating to ~80°C. A clear solution is then obtained. Add acetonitrile until it is thickened. Stir the resulting solution over 2 to 10 hours, for example. Then, cool it to room temperature over 3 hours. Crystal form 3 can be recovered, for example, by filtration. It is possible to dry under vacuum at high temperatures, for example, 40-60°C. ru.

[0042] The crystalline form 4 of compound (I) is obtained, for example, by dissolving compound (I) in a mixture of ethanol and water. It can then be properly prepared by allowing it to do so and then evaporating the solvent. The appropriate ratio of Knoll to water is approximately 90:10 to 98:2, for example, approximately 96:4. The concentration of compound (I) in the solvent should be appropriately about 5-10 mg / mL, for example, about 7.5 mg. The concentration is g / mL. Evaporation of the solvent is carried out, for example, by boiling under atmospheric pressure. This can be done. Then, the obtained crystal form 4 can be recovered.

[0043] The crystalline form of compound (I) 5 is obtained, for example, by heating (for example, by heating to about 50-7°C) (While) Compound (I) is converted to acetone, acetonitrile, ethyl acetate, dichloromethane (D By completely dissolving it in CM, methyl ethyl ketone (MEK), or nitromethane... Then, it can be properly prepared. Next, the solution is cooled for several hours, for example, 2 hours. Next, allow it to mature at a low temperature (e.g., 0-10°C) for at least 3 hours, for example, about 24 hours. To achieve this. After maturation, the solvent is evaporated, for example at room temperature, and then, under vacuum and at high temperature, for example. Then, remove the solvent completely at approximately 40°C. Next, add compound (I) at a rate of approximately 0.6 min per molecule. Crystal form 5 containing water can be recovered. Crystal form 5 is typically processed It crystallizes as bulky, prismatic crystals with excellent properties and filtration capabilities.

[0044] Alternatively, crystalline form 5 is a mixture of compound (I) with methanol, acetonitrile, ethyl acetate, or It is dissolved in tetrahydrofuran, followed by diethyl ether and methyl tert-butyl ether. Preparation by adding an antisolvent such as ether, hexane, or heptane. It is possible. The solvent:antisolvent ratio, on a volume basis, is appropriately about 1:3. The ratio is approximately 1:5, for example, approximately 1:4. Then, the mixture is heated at a low temperature, for example, 0-10°C. At ℃, for example, at about 5℃, for several hours, for example, at least 3 hours, for example, about 24 hours, suitable Allow to mature thoroughly. The solid substance can be recovered, for example, by filtration, and Then, it is dried to obtain a crystalline form 5 containing approximately 0.6 molecules of water per molecule of compound (I). It can be obtained.

[0045] Alternatively, in crystalline form 5, first compound (I) is dissolved in a suitable solvent (e.g., methanol, diphosphate). Chloromethane (DCM), acetone, acetonitrile, or nitromethane) at high temperatures (for example) The anti-solvent vapor diffusion method (ant) involves completely dissolving the substance at approximately 40-60°C. The i-solvent vapor diffusion method is used to adjust the temperature. It can then be prepared. Next, the solution is placed in an open container and mixed with pentane or diethyl acetate. Transfer to a container containing an appropriate antisulfent such as ester. The container without a lid should be stored in the room. At a temperature of 0-10°C or warm or cold (for example, 0-10°C), for a sufficient period of time for crystallization to occur (for example, 2 weeks). ), and keep it in a container with the lid closed. The obtained solid material is recovered, for example by filtration, and dried. By drying, a crystalline form 5 is obtained in which each molecule of compound (I) contains approximately 0.3 molecules of water. It is possible.

[0046] Alternatively, in crystalline form 5, amorphous compound (I) in an open container is mixed with methanol and acetic acid. Vapor diffusion by distributing into a container containing a suitable solvent such as ethyl or acetone. It can be prepared by a dispersion method. The container without a lid should be kept at a low temperature (e.g., 0-10°C). ) Keep it in a sealed container for a sufficient period of time for crystallization to occur (for example, one week). The obtained solid material is recovered, for example by filtration, and dried to obtain one molecule of compound (I). A crystalline form 5 containing approximately 0.6 molecules of water per unit can be obtained.

[0047] Finally, in crystalline form 5, the reaction is completed in molten sulfolane in the presence of cesium carbonate. While heating until (for example, heating to 75°C), 5-hydroxy-2-(isoindole (-2-ylmethyl)-4H-pyran-4-one to (1-(methylsulfonyl)piperidine It can be prepared by reacting with -4-yl)methyl methanesulfonate. Next, the mixture is cooled to, for example, about 55°C, and then acetone is added. Next, water is added. Then, the resulting mixture is left to stand for several hours (for example, 3 hours), for example Then, cool it to approximately 0-10°C, and then stir it. The solid substance can be removed, for example, by filtration. The compound (I) was collected, washed, and dried under vacuum at approximately 40°C, resulting in a concentration of 0.3-0 per molecule. A crystalline form 5 containing 0.6 molecules of water can be obtained.

[0048] The above solid form of compound (I) can be used in tablets, capsules, and capsules, together with excipients known in the art. It can be formulated into pharmaceutical administration forms such as capsules, powders, or suspensions.

[0049] The present invention will be further described by the following non-limiting embodiments. [Examples]

[0050] Analysis method

[0051] XRPD measurements use a copper-filled X-ray tube (40kV x 40mA) as the X-ray source, and CuKα(λ (=1.5418 Å), fixed 0.6 mm divergence slit, 0.0125 mm Ni filter - and L equipped with a 2.5° primary solar slit and a 2.5° secondary solar slit Using the ynxEye 1D detector, the X-ray powder diffractometer "Bruker D8 Adva The procedure was performed using "nce" at room temperature. Data collection was performed within the range of 3 to 33°²θ. The scan was performed at a scanning speed of 0.3° / second in 0.02° steps.

[0052] Differential scanning calorimetry (DSC) is performed using the Mettler Toledo DSC 823e. Using a calorific value scale, a perforated aluminum pan was heated at a constant heating rate of 10°C / min under a nitrogen flow (80 mL / min). It was carried out internally.

[0053] Single crystal diffraction data are obtained using a monochromatic CuKα (λ=1.5418Å) or MoKα emission via a manipulated mirror. Using the radiative mode (λ=0.7107Å), Rigaku Oxford Diffr Data was collected using the action SuperNova dual-wavelength diffractometer. X-ray data acquisition was monitored. And, all data is processed using the CrysAlisPro program by Lauren Corrections were made for the Tuss effect, polarization effect, and absorption effect. For the analysis and refinement of the crystal structure, Ole was used. We used the x2 program, and for structural analysis, we used SHELXS97 and F 2 all matrix least-squares refinement (full-matrix least-squares refi SHELXL was used for the nement.

[0054] Moisture content is measured using a coulometric titrator (SI) according to Karl Fischer (KF) standards. Analytics' TitroLine (registered trademark) 7500 KF traces The tests were conducted using a typical operating range of 1 ppm to 5% water.

[0055] Example 1. Preparation of amorphous compound (I)

[0056] Approximately 200 mg of compound (I) in form 5 is placed in a ceramic crucible (with a glass stirring rod). Gently grind it in the mixture, then stir with a glass stirring rod until melting is observed. It was heated at 135-137°C for 5 minutes. Then, the vessel containing the molten material was placed in liquid N2. It was then rapidly cooled for 2 minutes (crash-cooled) to obtain a glassy substance. The lath-like material was pulverized and analyzed by XRPD. This procedure allowed for the analysis of the amorphous form of compound (I). This was generated.

[0057] Example 2. Preparation of crystalline form 1 of compound (I) by addition of antisolvent.

[0058] 10 mg of amorphous compound (I) is dissolved in 380 μL of dichloromethane (DCM) at room temperature. The mixture was then distributed into the container. The mixture was stirred at room temperature for 10-20 seconds until completely dissolved (6 (00-1000 rpm). Then, at room temperature under constant magnetic stirring (600-1000 rpm). Then, 1.5 mL of diethyl ether was added in four stages. The stirring time between additions was 15 minutes. Yes, it was. After aging the vial at 5°C for 24 hours, the precipitated solid was decanted. The separation was performed by [method]. The resulting solid was air-dried at room temperature and analyzed by XRPD. This procedure [method] Compound (I) in powder form was obtained as crystalline form 1. The XRPD pattern of crystalline form 1 is shown in Figure As shown in 1, and the main peaks are listed in Table 1. DSC analysis was performed on approximately 134 The melting temperature (start) in °C is shown (Figure 9).

[0059] Table 1. X-ray powder reflection (up to 33°2θ) and intensity (normalized) of crystal morphology 1. The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the specified distance between lattice planes. Represents distance (Å).

[0060] [Table 1]

[0061] Example 3a. Preparation of crystalline form 2 of compound (I) by cooling and evaporation crystallization.

[0062] Weigh approximately 30 mg of compound (I) crystalline form 3 into a 4 mL glass vial. It was placed in a container. Various solvents defined in Table 2 were added stepwise at room temperature, and the result was obtained. The solution / suspension was heated at 60°C for 10 minutes until a clear solution was obtained. All solutions were then... Hold at 60°C for another 20 minutes, then cool to 7°C within 2 hours, and then further cool to 5°C for 2 minutes. The mixture was aged for 4 hours. After the cooling program, the solvent was evaporated at room temperature in an open vial. The mixture was induced. The resulting solid was analyzed by XRPD. Each solvent tested produced crystals of compound (I). Formation 2 was produced as a colorless needle-like structure. The XRPD pattern of crystalline form 2 is shown in Figure 2. The main peaks are shown in Table 3. DSC analysis was performed at approximately 68°C and 81°C. The melting temperatures (start) are shown as 134°C and 145°C (Figure 10).

[0063] Table 2.

[0064] [Table 2]

[0065] Table 3. X-ray powder reflectance (up to 33°2θ) and intensity (normalized) of crystal morphology 2. The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the specified distance between lattice planes. Represents distance (Å).

[0066] [Table 3]

[0067] Example 3b. Preparation of crystalline form 2 of compound (I) by freeze-drying.

[0068] A 14-17 mg sample of compound (I) crystalline form 3 was placed in 10-15 mL of Table 4. It was dissolved in various solvents as defined by [the relevant definition]. The solution was frozen, and then the solvent was removed. The material was removed at -33°C and 0.2 mbar for 24 hours. The obtained solid was analyzed by XRPD. Each solvent tested produced crystalline form 2 of compound (I) as a colorless needle-shaped substance.

[0069] Table 4.

[0070] [Table 4]

[0071] Example 3c. Preparation of crystalline form 2 of compound (I) by rapid evaporation.

[0072] Dissolve 15 mg of compound (I) in crystalline form 3 in water to obtain a concentration of 0.8 mg / mL. A concentrated solution was prepared by the following method. The solvent was then vaporized at 150 mbar and 58°C for 24 hours. The reaction was induced. The resulting solid was analyzed by XRPD. This procedure determined the crystal form of compound (I). State 2 was generated.

[0073] Example 3d. Single-crystal X-ray diffraction data of crystal morphology 2.

[0074] The unit cell parameters of crystalline form 2 of compound (I) were determined from single-crystal X-ray diffraction data. The following is a summary: T=293(2)K, radiation wavelength CuKα(λ=1.541 8 Å), crystal size 0.06 × 0.06 × 0.3 mm 3 , structural formula C 21 H 26 N2O 5S,2(H2O):

[0075] [Table 5]

[0076] Example 4a. Preparation of crystalline form 3 of compound (I)

[0077] Add 5g of compound (I) to the container under nitrogen, followed by 100mL of ethanol. The mixture was heated to 75°C. The resulting clear solution was allowed to cool to room temperature over approximately 3 hours. Cooled. The product was collected by filtration, washed with cooled ethanol, and then cooled under vacuum at 50°C. After drying, a colorless, needle-shaped substance (4.3 g) was obtained. The product was analyzed by XRPD. This procedure produced crystalline form 3 of compound (I). XRPD pattern of crystalline form 3 The peaks are shown in Figure 3, and the main peaks are listed in Table 5. DSC analysis is The melting temperature (start) is approximately 148°C (Figure 11). Scanning electron microscope of crystal morphology 3. The mirror image (magnification 100x, bar 200 μm) is shown in Figure 16.

[0078] Table 5. X-ray powder reflection (up to 33°2θ) and intensity (normalized) of crystal morphology 3. The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the specified distance between lattice planes. Represents distance (Å).

[0079] [Table 6]

[0080] Example 4b. Alternative method for preparing crystalline form 3 of compound (I)

[0081] Add 5g of compound (I) to the container under nitrogen, followed by the addition of ethyl acetate (50mL). The mixture was heated to 75°C. Acetonitrile was added until a clear solution was obtained. (10 mL) was added. The resulting clear solution was cooled to room temperature over approximately 3 hours. The product was then... The product is collected by filtration, washed with cooled ethanol, and dried under vacuum at 50°C. It was obtained as a colorless, needle-shaped substance (3.9 g). The product was analyzed by XRPD. This resulted in the formation of crystalline form 3 of compound (I).

[0082] Example 4c. Single-crystal X-ray diffraction data of crystal morphology 3.

[0083] The unit cell parameters of crystalline form 3 of compound (I) were determined from single-crystal X-ray diffraction data. The following is a summary: T=293(2)K, radiation wavelength CuKα(λ=1.541 8Å), structural formula C 21 H 26 N2O5S:

[0084] [Table 7]

[0085] Example 5. Preparation of crystalline form 4 of compound (I) by rapid evaporation.

[0086] Dissolve 20 mg of compound (I) in crystalline form 3 in EtOH / water (96:4) by volume and prepare 7 A concentrated solution was prepared by adjusting the concentration to 0.5 mg / mL. The solvent was then subjected to atmospheric pressure. It was evaporated by boiling at 80°C. The resulting solid was analyzed by XRPD. The procedure yielded crystalline form 4 of compound (I) in powder form. XRP of crystalline form 4. The D pattern is shown in Figure 4, and the main peaks are listed in Table 6. DS The 14C analysis shows a melting temperature (start) of approximately 144°C (Figure 12).

[0087] Table 6. X-ray powder reflectance (up to 33°2θ) and intensity (normalized) for crystal morphology 4. The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the specified distance between lattice planes. Represents distance (Å).

[0088] [Table 8]

[0089] Example 6a. Preparation of crystalline form 5 (water content 0.3-0.6) of compound (I)

[0090] Add 250 mL of molten sulfolane to the container under nitrogen, followed by 5-hydroxy-2 -(isoindole-2-ylmethyl)-4H-pyran-4-one (50g), (1-( Methylsulfonyl piperidine-4-yl methylmethanesulfonate (64.1g) And cesium carbonate (80g) was added. The mixture was heated to approximately 75°C and held for 4 hours. The mixture was cooled to 55°C, and then acetone (1) was added while maintaining the temperature > 50°C. 25 mL was added, followed by 250 mL of water. The mixture was stirred for 15 minutes. The resulting mixture was cooled to 5°C over 3 hours, stirred for 2 hours, and then filtered. The product was washed with water (50 mL) and isopropanol (50 mL), and then vacuum After drying at -40°C, 66.9 g of the product was obtained as a prismatic shape with good processability and filterability. A bulky crystal was obtained. The obtained solid was analyzed by XRPD. This procedure revealed that Crystal morphology 5 of compound (I) was formed. Karl Fischer analysis using a coulometric titrator was performed. Therefore, the water content of compound (I) in the crystal lattice is approximately 0.3 to 0.6 molecules per molecule. The XRPD patterns for crystalline form 5 (water content 0.3-0.6) are shown in Figure 5. The main peaks are shown in Table 7. DSC analysis was performed at a melting temperature of approximately 136°C. The temperature (start) is shown (Figure 13). Scanning type of crystal morphology 5 (water content 0.3~0.6). The electron microscope image (magnification 100x, bar 200 μm) is shown in Figure 16.

[0091] Table 7. X-ray powder reflection of crystal morphology 5 (water content 0.3-0.6) (maximum 33°) (Up to 2θ) and intensity (normalized). The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the diffraction angle (degrees). ] represents the specified distance (Å) between lattice planes.

[0092] [Table 9]

[0093] Example 6b. Crystalline form of compound (I) by antisolvent vapor diffusion 5 (water content) Preparation of 0.3)

[0094] 20 mg of compound (I) is used in 400-3000 μL as defined in Table 8. The mixture was then partitioned into various solvents. The mixture was stirred at room temperature (RT) for 10-15 seconds (600). Heat at 50°C (~1000 rpm) for up to 10 minutes if necessary, until completely melted. The 4 mL vials containing the clear, concentrated solution were divided into 2-10 mL portions according to Table 3. Insert into a 20 mL container containing the defined antisulfate with the lid open. Then, the lid of the 20 mL container was closed and it was stored at 5°C or room temperature for two weeks. Open the lid of the 20 mL container, retrieve the 4 mL vial, and put the obtained solid into it. The samples were smeared, air-dried at room temperature, and analyzed by XRPD. Each solvent / antisold combination tested was analyzed. Through this process, crystal form 5 is produced as a bulky, prismatic crystal with good processability and filterability. This was achieved. Karl Fischer analysis determined the amount of compound (I) per molecule in the crystal lattice. The water content was approximately 0.3 molecules. XRPD pattern in crystal form 5 (water content 0.3). The peaks are shown in Figure 6, and the main peaks are listed in Table 9. DSC analysis is It shows a melting temperature (start) of approximately 139°C (Figure 14).

[0095] Table 8.

[0096] [Table 10]

[0097] Table 9. X-ray powder reflection of crystal morphology 5 (water content 0.3) (up to a maximum of 33°2θ) ) and intensity (normalized). The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents the angle. This represents the specified distance (Å) between child faces.

[0098] [Table 11]

[0099] Example 6c. Single-crystal X-ray diffraction data of crystal morphology 5 (water content 0.3).

[0100] The unit cell parameters of the crystal form 5 of compound (I) were determined from single-crystal X-ray diffraction data. The following is a summary: T=293(2)K, radiation wavelength MoKα(λ=0.710 7Å), structural formula C 21 H 26 N2O5S, 0.29(O):

[0101] [Table 12]

[0102] Example 6d. Crystalline form of compound (I) after addition of antisolvent 5 (water content 0 Preparation of .6)

[0103] A 10 mg sample of amorphous compound (I) is used in various ways as defined in Table 10. The mixture was partitioned into the solvent at room temperature. The mixture was left to dissolve completely at room temperature for 10-20 seconds. Stirring (600-1000 rpm). Then, various methods defined in Table 4 The antisolvent was added in four stages at room temperature under constant magnetic stirring (600-1000 rpm). The mixture was added. The stirring time between additions was 15 minutes. The vial was then aged at 5°C for 24 hours. Next, the precipitated solid was separated by decantation. In experiments without precipitation, The solvent is either evaporated at room temperature in an open vial, or vacuum-dried. (200 mbar, 40°C). The obtained solid was air-dried at room temperature and analyzed by XRPD. Depending on the solvent / antisolvent combination, the crystalline form 5 exhibits good processability and filterability. It was formed as a bulky, prismatic crystal with the following characteristics: Karl Fischer analysis revealed the crystal structure. The water content of compound (I) in the sample was approximately 0.6 molecules per molecule. Crystal morphology 5 The XRPD pattern for (water content 0.6) is shown in Figure 7, and the main peak is, This is described in Table 11. DSC analysis shows a melting temperature (start) of approximately 133°C. Figure 15).

[0104] Table 10.

[0105] [Table 13]

[0106] Table 11. X-ray powder reflection of crystal morphology 5 (water content 0.6) (maximum 33°2θ) (at) and intensity (normalized). The value 2θ[°] represents the diffraction angle (degrees), and the value d[Å] represents, This represents the specified distance (Å) between lattice planes.

[0107] [Table 14]

[0108] Example 6e. Crystallized form of compound (I) by cooling and evaporation crystallization 5 (water content 0.6 Preparation of )

[0109] A 10 mg sample of amorphous compound (I) was subjected to various solutions as defined in Table 12. The mixture was distributed into the medium at room temperature (RT). The mixture was then stirred at room temperature (600-1000 rpm). Next, it was heated at 60°C for 30 minutes to completely dissolve it. Then, the solution was left at room temperature for 2 minutes. It was cooled for a while, then aged at 5°C for 24 hours. After the aging period, the solvent was removed when the lid was opened. Evaporate the mixture in the vial at room temperature for 6-7 hours, then remove the solvent under vacuum (40°C, 2°C). (00 mbar), completely removed for 24 hours. Each solvent tested was used to determine the crystalline form of compound (I). A sample size of 5 (water content 0.6) was produced.

[0110] Table 12.

[0111] [Table 15]

[0112] Example 6f. Preparation of crystalline form 5 (water content 0.6) of compound (I) by vapor diffusion.

[0113] Dispense a 10 mg sample of amorphous compound (I) into a 4 mL vial, and then, This was placed into a 20 mL container with the lid open, containing 2 mL of solvent. The solvents tested were methanol, ethyl acetate, and acetone. Then, 20 mL of each was used. The container lid was closed and kept at 5°C for one week. Then, the lid of the 20 mL container was opened and 4 mL was added. The vial was recovered, the resulting solid was decanted, air-dried at room temperature, and analyzed by XRPD. Each solvent tested produced crystalline form 5 (water content 0.6) of compound (I).

[0114] Example 7. Slurry using crystalline form 5 (water content 0.3-0.6) of compound (I). experiment

[0115] A 20 mg sample of compound (I) in crystalline form 5 (water content 0.3-0.6) was subjected to magnetic fields. Under stirring (600-1000 rpm), at room temperature (RT) or 40°C, add 300 μL to Table 13. The suspensions were then dispersed into various solvents defined in the following locations. The resulting suspensions were then heated to their respective temperatures. The samples were aged for one week at [temperature]. After the aging period, the samples were collected, air-dried at room temperature, and analyzed using XRPD. Analysis was performed. After maturation, the sample consisted of crystalline form 5 (water content 0.3) of compound (I). Therefore, form 5 was stable even under conditions of low water activity.

[0116] Table 13.

[0117] [Table 16]

[0118] Example 8. Conversion of crystal form 4 to crystal form 3

[0119] The crystalline form 4 of compound (I) was stored at room temperature in a sealed container. After two weeks, Re-analysis of the solid material using XRPD revealed that it contains a mixture of crystal morphology 4 and crystal morphology 3. This was discovered. This indicates a transformation from form 4 to form 3.

[0120] Example 9. Conversion from crystal form 3 to crystal form 2

[0121] 25-30 mg of compound (I) crystalline form 3 was milled using a Retsch ball mill for 8 It was ground with 0 μL of water. Water was added in two stages, and the total grinding time was 1.5 hours. The values ​​were , and ν = 30 Hz. After the grinding time, solid samples were collected and XRPD Analysis revealed that it contains crystal morphology 2. This indicates that morphology 3 is being converted to morphology 2. This indicates a conversion to [the specified format].

Claims

1. Diffraction angles 2θ (±0.2) at 4.5, 8.8, 9.0, 15.9, 17.6 and 20.5 ) has an X-ray powder diffraction pattern characterized by a peak appearing in ), 2-(isoi (Idolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4-yl A compound that is crystalline form 1 of methoxy)-4H-pyran-4-one(I).

2. The aforementioned crystal form 1 is 4.5, 8.8, 9.0, 15.9, 17.6, 19.6, 19. Characterized by peaks appearing at diffraction angles 2θ (±0.2) at 7, 20.5, and 21.

3. The compound according to claim 1, having an X-ray powder diffraction pattern.

3. Diffraction angles 2θ (±0.2) at 4.6, 7.2, 9.1, 14.8, 16.6, and 17.3 ) has an X-ray powder diffraction pattern characterized by a peak appearing in ), 2-(isoi (Idolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4-yl A compound that is crystalline form 2 of methoxy)-4H-pyran-4-one (I).

4. The aforementioned crystal form 2 is 4.6, 7.2, 9.1, 10.7, 11.1, 12.1, 13. 7, 14.8, 16.6, 17.0, 17.3, 17.8, 18.3, 21.7 and 22 X-ray powder diffraction peaks are characterized by a peak appearing at diffraction angle 2θ (±0.2) of 3. The compound according to claim 3, having turns.

5. The aforementioned crystal form 2, at T = 293 (2) K, is as follows: Table 1 The compound according to claim 3 or 4, having unit cell parameters according to the following conditions.

6. Diffraction angles 2θ (±0) at 9.2, 12.7, 14.8, 16.3, 17.0 and 21.3 2) Having an X-ray powder diffraction pattern characterized by the peak appearing in 2), 2-( Soindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4- A compound that is crystalline form 3 of yl(methoxy)-4H-pyran-4-one(I).

7. The crystal morphology 3 is 5.0, 8.2, 9.2, 10.1, 10.8, 12.7, 14. ８、１５．６、１６．３、１７．０、１７．２、１８．５、１８．９、１９．３、２０． Characterized by peaks appearing at diffraction angles 2θ (±0.2) at 2, 21.3, and 21.

7. The compound according to claim 6, having an X-ray powder diffraction pattern.

8. The aforementioned crystal form 3, at T = 293 (2) K, is as follows: Table 2 The compound according to claim 6 or 7, having unit cell parameters according to the following.

9. Diffraction angles 2θ (±0) at 6.3, 15.7, 16.5, 19.6, 20.8 and 21.5 2) Having an X-ray powder diffraction pattern characterized by the peak appearing in 2), 2-( Soindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidine-4- A compound that is crystalline form 4 of yl(methoxy)-4H-pyran-4-one(I).

10. The crystal form 4 is 6.3, 15.7, 16.5, 17.1, 17.8, 18.2, 1 8.7, 19.1, 19.6, 20.8, 21.3, 21.5, 22.2, 22.9 and X-ray powder radiation is characterized by a peak appearing at a diffraction angle of 2θ (±0.2) at 27.7°. The compound according to claim 9, having a folding pattern.

11. 9.4, 10.0, 10.5, 11.6, 13.5, 15.2, 16.5, and 20.0 X-ray powder diffraction pattern characterized by a peak appearing at diffraction angle 2θ (±0.2) 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl) In the crystalline form of (I) piperidine-4-yl) methoxy)-4H-pyran-4-one (I) A certain compound.

12. The crystal form 5 is 9.4, 10.0, 10.5, 11.6, 13.5, 14.6, 1 5.2, 16.5, 16.9, 18.1, 18.8, 20.0, 22.3 and 23.3 X-ray powder diffraction pattern characterized by a peak appearing at diffraction angle 2θ (±0.2) The compound according to claim 11, having the properties of

13. The aforementioned crystal form 5, at T = 293 (2) K, is as follows: Table 3 The compound according to claim 11 or 12, having unit cell parameters according to the following.

14. A method for preparing the compound according to claim 1 or 2, wherein compound (I) is dichlorometh The mixture is dissolved in ethanol, contacted with diethyl ether, and the crystalline product is isolated. A method that includes doing so.

15. A method for preparing the compound according to claim 3, 4, or 5, wherein compound (I) is mixed with water and 2- A mixture of propanol, acetone, ethanol, acetonitrile, or tetrahydrofuran A method comprising dissolving in a solution, cooling the mixture, and isolating the crystalline product.

16. A method for preparing the compound according to claim 6, 7, or 8, wherein compound (I) is ethanol Dissolve it in ethanol, or in a mixture of ethyl acetate and acetonitrile, and then cool the mixture. A method comprising isolating the crystalline product.

17. A method for preparing the compound according to claim 9 or 10, wherein compound (I) is ethanol This includes dissolving the product in a mixture of water, evaporating the solvent, and isolating the crystalline product. Hmm, a method.

18. A method for preparing the compound according to claim 11, 12, or 13, wherein molten sulfolane In the presence of cesium carbonate, while heating, 5-hydroxy-2-(isoindole- 2-ylmethyl)-4H-pyran-4-one to (1-(methylsulfonyl)piperidine- It is reacted with 4-yl)methyl methanesulfonate, acetone is added, and then water is added. A method comprising adding, cooling the mixture, and isolating the crystalline product.

19. A method for preparing the compound according to claim 11, 12, or 13, wherein compound (I) is a Cetone, acetonitrile, ethyl acetate, dichloromethane (DCM), methyl ethyl ketone (MEK) or nitromethane is dissolved, the mixture is cooled, the solvent is evaporated, and A method comprising isolating the crystalline product.

20. A method for preparing the compound according to claim 11, 12, or 13, wherein compound (I) is prepared Dissolve in tanol, acetonitrile, ethyl acetate, or tetrahydrofuran, and mix the two. Contact with diethyl ether, methyl tert-butyl ether, hexane, or heptane. A method comprising the following steps: and isolation of the crystalline product.

21. A pharmaceutical dosage form comprising the compound described in any one of claims 1 to 13.

22. For use in the treatment of hormone-regulated cancers such as prostate cancer and breast cancer. or the compound according to any one of claims 1 to 13.

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