CRYSTALLINE FORM OF TRIAZOLOPYRIMIDINONE DERIVATIVE

Abstract

The present invention relates to a polymorphism of a triazolopyrimidinone derivative exhibiting tankyrase inhibitory activity, and a preparation method therefor. The novel polymorphism of the present invention exhibits excellent non-hygroscopicity and stability, and exhibits excellent solubility and bioavailability, and thus is suitable as a raw material for pharmaceutical preparations.

Description

Crystalline forms of triazolopyrimidinone derivatives

[0001] The present invention relates to a crystalline form of a triazolopyrimidinone derivative exhibiting tankyrase inhibitory activity. The invention also relates to a method for preparing a crystalline form of the triazolopyrimidinone derivative.

[0002] Tankyrase belongs to the poly(ADP-ribose) polymerase (PARP) protein family, which consists of 17 members that share the catalytic PARP domain. Recently, it was reported that intracellular axin levels are influenced by the PARP enzyme family members tankyrase-1 and tankyrase-2 (also known as PARP5a and PARP5b, respectively) (Huang et al., 2009, Nature, 461(7264): 614-620).

[0003] Inhibitors of tankyrase-1 and tankyrase-2 are known to have therapeutic potential in various solid tumors, such as colorectal carcinoma, colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreatic adenocarcinoma, and prostate cancer. In addition, inhibitors of tankyrase-1 and tankyrase-2 have therapeutic potential for diseases other than cancer, including osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, vascular disease, cardiac disease, non-oncogenic proliferative disease, and neurodegenerative diseases such as Alzheimer's disease.

[0004] As described above, there is a persistent need for novel therapeutics for cancer and hyperproliferative conditions, and efforts are being made to develop novel pharmaceutical compounds that can selectively inhibit the tankyrase enzyme. In particular, triazolopyrimidinone derivatives of the following chemical formula (I) are known as selective tankyrase inhibitors (International Publication No. WO 2016 / 006974) and are being developed as a treatment for colorectal cancer in patients with a KRAS mutation or in patients who are non-responsive to Erbitux (European Journal of Cancer, 173, (2022), 41-51).

[0005]

[0006] When designing an appropriate dosage form during the pharmaceutical manufacturing process, the physical state of the pharmaceutical ingredient—namely, whether it's crystalline or amorphous—is crucial. However, crystalline ingredients have low solubility, which can lead to reduced bioavailability per unit weight. Amorphous ingredients are unstable, making it difficult to control drug release and blood concentration.

[0007] Therefore, it is necessary to develop a new crystal form that simultaneously solves these problems and exhibits excellent physicochemical properties for the triazolopyrimidinone derivative of the above chemical formula I.

[0008] The purpose of the present invention is to provide a crystalline form of a triazolopyrimidinone derivative having excellent non-hygroscopicity and stability and a method for producing the same.

[0009] Another object of the present invention is to provide a crystalline form of a triazolopyrimidinone derivative capable of improving solubility and bioavailability and a method for preparing the same.

[0010] In order to achieve the above purpose, the inventors of the present invention completed the present invention by producing crystal forms A and B as mentioned below as a result of their research efforts and confirming that both exhibited excellent effects.

[0011] Crystalline Form A and its preparation method

[0012] The present invention provides a crystalline form A of a compound represented by the following chemical formula I having peaks at diffraction angles (2θ±0.2°) of 6.31°, 8.72°, 10.92°, 12.12°, 13.16°, and 15.98° in a powder X-ray diffraction pattern:

[0013]

[0014] According to a specific example of the present invention, the crystalline form A may further include one or more peaks at diffraction angles of 5.43°, 7.93°, 17.56°, or 18.22° (2θ±0.2°) in a powder X-ray diffraction pattern.

[0015] According to a specific example of the present invention, the crystalline form A may further include one or more peaks at diffraction angles (2θ±0.2°) of 20.63°, 21.14°, 22.23°, 23.13°, 23.98°, 25.31°, 26.08°, 26.99°, or 32.04° in a powder X-ray diffraction pattern.

[0016] According to a specific example of the present invention, the crystalline form A may have a melting point of about 235 to about 245°C when the heating rate is 2°C / min, and specifically may have a melting point of about 238 to about 242°C. More specifically, the crystalline form A may have a melting point of about 239.7°C when the heating rate is 2°C / min.

[0017] In addition, the present invention provides a method for producing the above crystalline form A. Specifically, the method may include the following steps:

[0018] (A-1) A step of adding a mixed solvent of acetone and water to the compound represented by the above chemical formula I and stirring; and

[0019] (A-2) Step of filtering and drying the generated solid.

[0020] According to a specific example of the present invention, the volume ratio of acetone and water in the mixed solvent may be 4:6 to 6:4, and preferably 5:5.

[0021] Crystalline Form B and its preparation method

[0022] The present invention provides a crystalline form B of a compound represented by the above chemical formula I having peaks at diffraction angles (2θ±0.2°) of 7.83°, 9.47°, 10.24°, 12.32°, 15.16°, and 16.29° in a powder X-ray diffraction pattern.

[0023] According to a specific example of the present invention, the crystalline form B may further include one or more peaks at diffraction angles of 6.12°, 18.46°, or 19.05° (2θ±0.2°) in a powder X-ray diffraction pattern.

[0024] According to a specific example of the present invention, the crystalline form B may further include one or more peaks at diffraction angles (2θ±0.2°) of 20.63°, 21.33°, 24.39°, 25.19°, 26.66°, or 27.54° in a powder X-ray diffraction pattern.

[0025] According to a specific example of the present invention, the crystalline form B may have a melting point of about 245 to about 255°C when the heating rate is 2°C / min, and specifically may have a melting point of about 247 to about 250°C. More specifically, the crystalline form B may have a melting point of about 248.7°C when the heating rate is 2°C / min.

[0026] In addition, the present invention provides a method for preparing the above-described crystalline form B. Specifically, the method may include the following steps:

[0027] (B-1) A step of adding acetone, acetonitrile, 2-butanone, toluene or isopropanol to the compound represented by the above chemical formula I and stirring; and

[0028] (B-2) Step of filtering and drying the generated solid.

[0029] The crystal form of the present invention is advantageous for pharmaceutical preparations because it has low hygroscopicity, excellent stability under accelerated and long-term storage conditions, and can be stably maintained without change in content over a long period of time.

[0030] In addition, the crystal form of the present invention has high solubility and bioavailability and can be usefully used as a raw pharmaceutical material.

[0031] Figure 1 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form A according to Example 1 of the present invention.

[0032] Figure 2 shows the results of powder X-ray diffraction analysis (PXRD) of crystalline form B according to Example 2 of the present invention.

[0033] Hereinafter, to facilitate understanding of the present invention, examples and experimental examples will be provided in detail. However, the following examples and experimental examples are intended only to illustrate the content of the present invention and are not intended to limit the scope of the present invention. The examples and experimental examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0034] Reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, TCI, and Daejung Chemicals, unless otherwise specified, and HLPC was measured using the 1000 series from Agilent Technologies.

[0035] In addition, the various solid forms of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one prepared by the following examples were confirmed by X-ray diffraction patterns and melting points using X-ray diffraction methods.

[0036] Specifically, powder X-ray diffraction analysis was performed using a BRUKER D8 Focus equipped with a rotational meter and a solid-state detector, and was measured under the conditions of an analysis range of 5° to 50°, a step of 0.020°, and a step time of 171.6 s using Cu-Kα rays. In addition, the melting point was measured using Buchi's M-565 Melting Point at a temperature of 2°C / min and the value was measured at 200 to 260°C.

[0037] Manufacturing example. Preparation of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one.

[0038]

[0039] 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-7-isopropoxy-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15 g, 32.4 mmol) was added 92 mL of acetic acid and 16.1 mL of sulfuric acid, and the internal temperature was raised to 45 to 50 ℃ and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 230 mL of purified water was added dropwise for 30 minutes while stirring. After the dropping was completed, the internal temperature was cooled to 5 to 10 ℃ and stirred for 1 hour. The precipitated crystals were filtered and diluted in 150 mL of acetone, and the internal temperature was raised to 40 to 45 ℃ and stirred for 1 hour. The reaction solution was slowly cooled to 5 to 10°C and 150 mL of purified water was added. The precipitated crystals were stirred for 30 minutes, filtered, and dried under reduced pressure to obtain the title compound (11.5 g, 84%) as an off-white solid.

[0040] Example 1. Preparation of crystalline form A

[0041] 1 g of 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one prepared in the manufacturing example of the present invention was added to acetone:water = 50:50 and stirred at 40 to 50°C overnight. The resulting solid was filtered and dried in a hot air dryer at 50°C to obtain crystalline form A.

[0042] The powder X-ray diffraction (PXRD) peak and melting point of the above solid were analyzed, and the PXRD results are shown in Fig. 1.

[0043] As confirmed in Fig. 1, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 6.31°, 8.72°, 10.92°, 12.12°, 13.16°, and 15.98°.

[0044] Additionally, the solid compound was confirmed to have a melting point of 239.7°C when the heating rate was 2°C / min.

[0045] Example 2. Preparation of crystalline form B

[0046] 1 g of (5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one prepared in the manufacturing example of the present invention was added to various solvents according to Table 1 below and stirred at 40 to 50°C overnight. The resulting solid was filtered and dried in a hot air dryer at 50°C to obtain crystalline form B.

[0047]

[0048] The powder X-ray diffraction (PXRD) peak and melting point of the above solid were analyzed, and the PXRD results are shown in Fig. 2.

[0049] As confirmed in Fig. 2, the solid compound exhibited main peaks at 2θ (±0.2°) values ​​of 7.83°, 9.47°, 10.24°, 12.32°, 15.16°, and 16.29°.

[0050] Additionally, the solid compound was confirmed to have a melting point of 248.7°C when the heating rate was 2°C / min.

[0051] Experimental Example 1. Hygroscopicity (DVS) Measurement Experiment

[0052] Hygroscopicity was tested using the crystal forms manufactured in the examples of the present invention.

[0053] a. Equipment used in the experiment

[0054] - Model name: DVS Intrinsic (Surface Measurement Systems)

[0055] - Specifications

[0056] Temperature Range: 20 ~ 40℃

[0057] Temperature stability: ±0.2℃

[0058] Humidity range: 0 ~ 98% RH

[0059] RH Accuracy: ±1% RH

[0060] Typical gas (Nitrogen + water vapor) flow rate: 200 sccm

[0061] Sample chamber: 40 mm wide x 50 mm deep x 50 mm high

[0062] Heating system: Peltier + Cartridge

[0063] b. Sample information

[0064] Experiments were performed on the crystal forms of the above examples.

[0065] c. Experimental conditions

[0066] - Temperature: 25 ℃

[0067] - Humidity: Initial 0%, Maximum 95%

[0068] - Solvent: Water

[0069] d. Experimental method

[0070] A certain amount (10-20 mg) of the crystalline form manufactured in the example was placed on a sample pan in the sample chamber, and then nitrogen was flowed through a tube connected to the sample chamber for the first hour to remove moisture inside the chamber and the sample. The humidity inside the chamber was controlled by controlling the water vapor, and the target relative humidity was gradually increased from the initial 0% to about 10% to measure the moisture content of the crystalline form. The mass of the sample was measured (from 0% RH to 95% RH) and the change in sample weight according to the increase or decrease in humidity was graphed.

[0071] The changes in moisture content of the crystal forms according to the examples are as shown in Table 2 below.

[0072]

[0073] As a result of the analysis, as shown in Table 2 above, the crystalline form of the present invention was observed to have excellent non-hygroscopicity with little change in moisture content. This indicates that the crystalline form of the present invention is pharmaceutically superior in all processes, including manufacturing, storage, and formulation of the active ingredient.

[0074] Experimental Example 2. Acceleration Stability Test

[0075] The crystalline powder according to the embodiment of the present invention was double-packaged in a PE bag and then tertiary-packaged in an aluminum bag, and then stored at 40±2°C and RH 75±5% for 0 and 6 months, after which impurities were measured using HPLC. The results are shown in Table 3 below.

[0076]

[0077] From the results in Table 3 above, it was confirmed that the crystalline form of the present invention did not show any significant changes in the flexible substances and contents, and that the crystalline form was maintained. Therefore, it was confirmed that the crystalline form of the present invention can stably maintain a high purity for 6 months under accelerated conditions, exhibiting excellent stability, showing almost no change in moisture content, and exhibiting significantly low hygroscopicity.

[0078] Experimental Example 3. Long-term Stability Test

[0079] The crystalline powder according to the embodiment of the present invention was double-packaged in a PE bag and then tertiary-packaged in an aluminum bag, and stored at 25±2°C and RH 60±5% for 0 and 12 months, after which impurities were measured using HPLC. The results are shown in Table 4 below.

[0080]

[0081] From the results in Table 4 above, it was confirmed that the crystalline form of the present invention did not show any significant changes in the flexible substances and contents, and that the crystalline form was maintained. Therefore, it was confirmed that the crystalline form of the present invention can stably maintain a high purity for 12 months, exhibiting excellent stability, showing almost no change in moisture content, and exhibiting significantly low hygroscopicity.

Claims

1. Crystalline form A of the compound represented by chemical formula I below, having an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ±0.2°) of 6.31°, 8.72°, 10.92°, 12.12°, 13.16°, and 15.98°: Formula I .

2. Crystalline form A according to claim 1, characterized in that said powder X-ray diffraction pattern additionally comprises at least one peak at a diffraction angle (2θ ± 0.2°) equal to 5.43°, 7.93°, 17.56° or 18.22°.

3. Crystalline form A according to claim 2, characterized in that said powder X-ray diffraction pattern further comprises at least one peak at a diffraction angle (2θ ± 0.2°) equal to 20.63°, 21.14°, 22.23°, 23.13°, 23.98°, 25.31°, 26.08°, 26.99° or 32.04°.

4. Crystalline form A according to claim 1, characterized in that said crystalline form A has a melting point from 235 to 245°C at a heating rate of 2°C / min.

5. A method for obtaining crystalline form A of a compound represented by chemical formula I, according to paragraphs 1-4, including (A-1) adding a mixed solvent of acetone and water to a compound represented by the following chemical formula I, followed by stirring; (A-2) filtering and drying the resulting solid: Formula I .

6. The method according to paragraph 5, characterized in that the volume ratio of acetone and water in the mixed solvent is from 4:6 to 6:

4.

7. Crystalline form B of the compound represented by the following chemical formula I, having an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ±0.2°) of 7.83°, 9.47°, 10.24°, 12.32°, 15.16° and 16.29°: Formula I .

8. Crystalline form B according to claim 7, characterized in that said powder X-ray diffraction pattern additionally comprises at least one peak at a diffraction angle (2θ±0.2°) equal to 6.12°, 18.46° or 19.05°.

9. Crystalline form B according to claim 8, characterized in that said powder X-ray diffraction pattern further comprises at least one peak at a diffraction angle (2θ±0.2°) equal to 20.63°, 21.33°, 24.39°, 25.19°, 26.66° or 27.54°.

10. Crystalline Form B according to claim 7, characterized in that said Crystalline Form B has a melting point from 245 to 255°C at a heating rate of 2°C / min.

11. A method for obtaining crystalline form B of a compound represented by chemical formula I, according to paragraphs 7-10, comprising (B-1) adding acetone, acetonitrile, 2-butanone, toluene or isopropanol to a compound represented by the following Chemical Formula I, followed by stirring; (B-2) filtering and drying the resulting solid: Formula I .

12. A pharmaceutical composition for preventing or treating cancer, comprising crystalline form A according to claims 1-4 and crystalline form B according to claims 7-10.

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