Crystalline forms of fgfr4 selective inhibitor compounds and methods of making and using the same

Abstract

The present invention relates to crystalline Form A of a compound of Formula (I) and processes for its preparation and uses thereof. The crystalline Form A has superior properties in terms of physico-chemical stability, aqueous solubility, bioavailability and processing suitability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical pharmacy, more particularly to a new crystal form of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide diethylsulfate, a preparation method thereof and a pharmaceutical use thereof. BACKGROUND

[0002] PCT / CN2017 / 085135 reported a class of new pyrimidine derivatives, which are FGFR4 pathway inhibitors. A large amount of evidence shows that there are gene amplification mutations of FGFR4 in lung cancer, ovarian cancer, prostate cancer, liver cancer and cholangiocarcinoma, etc. FGFR4 selective inhibitors have the advantage of small toxicity compared with other FGFR inhibitors (Brow, AP et al (2005), Toxocol. Pathol., 449-455). Considering the defects of safety and effectiveness of the currently available drugs, especially considering the application potential of FGFR4 selective inhibitors, the current research on FGFR4 selective inhibitors in anticancer, especially in liver cancer, is far from enough, and it is necessary to research and develop new FGFR4 inhibitors.

[0003] PCT / CN2017 / 085135 discloses a compound of formula (II) free base of N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octan-7-yl)phenyl)acrylamide, the structure of which is shown below:

[0004]

[0005] In vitro cell activity detection found that the compound of formula (II) has good inhibitory activity on liver cancer cells Hep3B with an IC50 value of 0.019 μM, and has good development prospects. However, in the process of drug development of the compound of formula (II), the inventors of the present application found that the common pharmaceutically acceptable salt of the compound of formula (II) cannot be satisfactory in terms of physicochemical properties and drug development, including bioavailability, water solubility, hygroscopicity, etc. Therefore, it is necessary to further study to find a new form suitable for drug use to meet the needs of drug development. SUMMARY

[0006] In view of the shortcomings of the prior art, one of the purposes of the present application is to overcome at least one of the above-mentioned shortcomings in the prior art, and to provide a new compound form. To this end, the present application provides a crystal form A of a compound of formula (I) which is good in chemical and physical stability,

[0007]

[0008] The crystal form has excellent properties in physical and chemical stability, water solubility, bioavailability and hygroscopicity; and the preparation method of the crystal form is simple in operation and easy to industrialize.

[0009] The X-ray powder diffraction (XRD) pattern of the compound of formula (I) in the form A according to the present application has characteristic peaks at the following diffraction angles 2 theta: 6.6 ± 0.2°, 14.6 ± 0.2°, 16.4 ± 0.2°, 17.6 ± 0.2°, 19.6 ± 0.2°, 20.3 ± 0.2°, 20.8 ± 0.2°, 23.0 ± 0.2°, and 26.9 ± 0.2°. Preferably, the compound of formula (I) in the form A according to the present application has further characteristic peaks at the following diffraction angles 2 theta: 22.1 ± 0.2°, 23.3 ± 0.2°, 25.8 ± 0.2°, 28.2 ± 0.2° and 29.8 ± 0.2°.

[0010] More preferably, the X-ray powder diffraction pattern of the compound of formula (I) in the form A according to the present application has further characteristic peaks at the following 2 theta: 7.2 ± 0.2°, 10.2 ± 0.2°, 13.4 ± 0.2°, 19.1 ± 0.2°, 24.6 ± 0.2°, 25.0 ± 0.2° and 30.9 ± 0.2°.

[0011] Preferably, the compound of formula (I) in the form A according to the present application has substantially the same X-ray powder diffraction pattern as shown in Figure 1 Preferably, the compound of formula (I) in the form A according to the present application has substantially the same DSC pattern as shown in

[0012] In one embodiment, the X-ray powder diffraction pattern has the 2 theta and relative intensity data as shown in Table 1 below:

[0013] Table 1

[0014] Peak No. 2Θ (°) Relative intensity (%) 1 6.6±0.2° 46.4 2 7.2±0.2° 7.6 3 10.2±0.2° 3.5 4 13.4±0.2° 4.2 5 14.6±0.2° 30.2 6 16.4±0.2° 75 7 17.6±0.2° 28 8 19.1±0.2° 8.3 9 19.6±0.2° 48 10 20.3±0.2° 100 11 20.8±0.2° 35.5 12 22.1±0.2° 14.1 13 23.0±0.2° 70.5 14 23.3±0.2° 12.4 15 24.6±0.2° 5.5 16 25.0±0.2° 12 17 25.8±0.2° 18.3 18 26.9±0.2° 72.3 19 28.2±0.2° 10.8 20 29.8±0.2° 20.5 21 30.9±0.2° 4.7

[0015] Preferably, the compound of formula (I) in the form A according to the present application has substantially the same DSC pattern as shown in Figure 2 with a melting point of 188 °C.

[0016] Preferably, the compound of formula (I) in the form A according to the present application has substantially the same TGA pattern as shown in Figure 3 with a melting point of 188 °C.

[0017] It is another object of the present application to provide a process for preparing the compound of formula (I) in the form A, comprising the following steps:

[0018] The suspension of the compound of formula (I) is stirred at 10-40℃ for 4-12h, filtered to obtain the crystal form A of the compound of formula (I).

[0019] As preferred, the suspension of the compound of formula (I) refers to the suspension of the compound of formula (I) in the following solvent: alcohol, ketone, ester, ether, alkane, water or mixture thereof.

[0020] As preferred, the solid-liquid ratio (g / mL) of the suspension is 1:3-40.

[0021] As preferred, in the above preparation method, there is a drying step after the filtration.

[0022] The present application also relates to a pharmaceutical composition containing the crystal form A of the compound of formula (I), which comprises a therapeutically effective amount of the crystal form A of the compound of formula (I) and one or more pharmaceutically acceptable carriers.

[0023] The present application also relates to the use of the crystal form A of the compound of formula (I) or the pharmaceutical composition containing the crystal form A of the compound of formula (I) in the preparation of a drug for treating tumors. The tumors are preferably selected from non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer and cholangiocarcinoma, and more preferably selected from liver cancer and cholangiocarcinoma.

[0024] The inventors of the present application have found, through a large number of researches, that the crystal form A of the compound of formula (I) has the advantages of simple crystallization process, easy operation, small pollution, high yield, and industrial production; the crystal form drug of the present application has the advantages of high product purity, excellent physical and chemical properties, good chemical stability, good water solubility, high bioavailability and small hygroscopicity. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The X-ray powder diffraction spectrum of the crystal form A of the compound of formula (I) obtained in Example 1.

[0026] Figure 2 The DSC spectrum of the crystal form A of the compound of formula (I) obtained in Example 1.

[0027] Figure 3 The TGA spectrum of the crystal form A of the compound of formula (I) obtained in Example 1. DETAILED DESCRIPTION

[0028] The following examples are used to further explain the present application, but they do not constitute the limitation or restriction of the scope of the present application.

[0029] The crude compound of formula (I) in the examples of the present application is obtained by self-preparation.

[0030] The solvent used in the present application is not particularly limited, and a commercially available conventional solvent can be used, for example, the ethanol can be commercially available ethanol, including industrial ethanol, anhydrous ethanol, etc.

[0031] Unless otherwise specified, the "stirring" in the method of the present application can be carried out by conventional methods in the art, for example, the stirring mode includes magnetic stirring, mechanical stirring, and the stirring speed is 50-300 rpm / min, preferably 100-200 rpm / min.

[0032] The X-ray powder diffraction instrument and test conditions involved in the present application are as follows: X-ray diffraction instrument model Rigaku D / max-2200 Cu target; operation method: scanning speed 4° / min, scanning step width 0.01°.

[0033] The DSC model involved in the present application is: NETZSCH DSC200 F3 Jaia; the test condition is a temperature rising rate of 10℃ / min, and the temperature range is 25-250℃.

[0034] The thermal gravimetric analyzer (TGA) and test conditions involved in the present application are as follows: TGA model is PerkinElmer TGA400; the test condition is a temperature rising rate of 10℃ / min, and the temperature range is 30-250℃.

[0035] The purity detection condition of the HPLC of the compound of formula (I) involved in the present application is as follows: chromatographic column: Waters, XBridge C18 4.6*150mm, 3.5μm; mobile phase A: buffer solution: acetonitrile = 70:30, mobile phase B: buffer solution: acetonitrile = 35:35, buffer solution: weigh 9.13g of di-potassium hydrogen phosphate trihydrate in 2000mL of pure water, and adjust the pH to 8.0 with phosphoric acid; detection wavelength: 234nm; flow rate: 1.0mL / min; column temperature: 25℃; injection volume: 10μL.

[0036] Gradient elution condition

[0037] Time (min) A(％) B(％) 0 100 0 15 70 30 40 40 60 50 0 100 60 0 100 62 100 0 70 100 0

[0038] It should be emphasized that the values or numerical endpoints involved in the technical solutions of the present application are not limited to the numbers themselves, and the intended protection scope is not limited to the numbers themselves, and those skilled in the art can understand that they include the allowable error range widely accepted in the art, such as experimental error, measurement error, statistical error and random error, etc., and these error ranges are included in the scope of the present application.

[0039] Raw material preparation example:

[0040] The crude compound of formula (I) can be used as the raw material for preparing the crystal form A in the method of the present application, and the raw material can be prepared by reacting the compound of formula (II) with ethanesulfonic acid, and the preparation is as follows: the compound of formula (II) free base (1000 mg, 1.5 mmol) is put into a reaction bottle, 25 ml of acetone and 1.25 ml of water are added, and stirred uniformly, 0.39 g of ethanesulfonic acid (3.3 mmol) is added, and stirred to dissolve at room temperature, the reaction solution is concentrated to remove acetone, filtered, and dried to obtain 1.2 g of amorphous solid of the compound of formula (I) with a yield of 90%.

[0041] Preparation of the crystal form A of the compound of formula (I) in Example 1

[0042] The crude compound of formula (I) 1.0 g is added to 10 ml of methanol to form a suspension, and stirred at 30°C for 12 h, filtered, and dried at 40°C under vacuum to obtain 0.95 g of crystals with a purity of 99.64% detected by HPLC.

[0043] The X-ray powder diffraction pattern of the crystals is shown in detail in Figure 1 , the DSC pattern is shown in Figure 2 , and the TGA pattern is shown in Figure 3, which is named as the crystal form A of the compound of formula (I) in the present application.

[0044] Preparation of the crystal form A of the compound of formula (I) in Example 2

[0045] The crude compound of formula (I) 1.0 g is added to 3 ml of water to form a suspension, and stirred at 10°C for 4 h, filtered, and dried at 40°C under vacuum to obtain 0.65 g of crystals with a purity of 99.60% detected by HPLC. The X-ray powder diffraction pattern (XRD) is measured to confirm that the crystals are the crystal form A of the compound of formula (I).

[0046] Preparation of the crystal form A of the compound of formula (I) in Example 3

[0047] The crude compound of formula (I) 1.0 g is added to 10 ml of acetone to form a suspension, and stirred at 20°C for 8 h, filtered, and dried at 40°C under vacuum to obtain 0.94 g of crystals with a purity of 99.53% detected by HPLC. The X-ray powder diffraction pattern (XRD) is measured to confirm that the crystals are the crystal form A of the compound of formula (I).

[0048] Preparation of the crystal form A of the compound of formula (I) in Example 4

[0049] The crude compound of formula (I) 1.0 g is added to 30 ml of ethyl acetate to form a suspension, and stirred at 25°C for 6 h, filtered, and dried at 40°C under vacuum to obtain 0.93 g of crystals with a purity of 99.57% detected by HPLC. The X-ray powder diffraction pattern (XRD) is measured to confirm that the crystals are the crystal form A of the compound of formula (I).

[0050] Preparation of the crystalline form A of the compound of formula (I)

[0051] The crude 1.0 g of the compound of formula (I) was added to 20 mL of isopropyl ether to form a suspension, stirred at 15 °C for 8 h, filtered, and dried at 40 °C under vacuum to obtain 0.96 g of crystals with a purity of 99.47% as determined by HPLC. X-ray powder diffraction (XRD) analysis confirmed that the crystals were the crystalline form A of the compound of formula (I).

[0052] Preparation of the crystalline form A of the compound of formula (I)

[0053] The crude 1.0 g of the compound of formula (I) was added to 40 mL of n-heptane to form a suspension, stirred at 40 °C for 4 h, filtered, and dried at 40 °C under vacuum to obtain 0.95 g of crystals with a purity of 99.48% as determined by HPLC. X-ray powder diffraction (XRD) analysis confirmed that the crystals were the crystalline form A of the compound of formula (I).

[0054] It was found that the crystalline form A obtained in Examples 2-6 had the same XRD, DSC and TGA patterns as the crystalline form A obtained in Example 1.

[0055] Effect Example 1

[0056] Water solubility comparison experiment: The water solubility of the compound of formula I in the amorphous state and the crystalline form A, and the compound of formula II (free base) was tested at 25 °C, and the results are as follows:

[0057] Sample Solubility in water at 25 °C Form I compound amorphous 115 mg / mL Form I compound crystalline form A 100 mg / mL Form II compound (free base) Insoluble

[0058] From the above results, it can be seen that the water solubility of the compound of formula I is much better than that of the compound of formula II (free base), which indicates that the water solubility of the compound of formula I is greatly improved after salt formation, and the water solubility of the amorphous salt and the crystalline salt is relatively close.

[0059] Effect Example 2

[0060] Stability experiment: The amorphous and crystalline form A of the compound of formula I were placed at 25 °C, 40 °C and under light illumination of 4500 LX for 30 days, and the results are as follows:

[0061]

[0062]

[0063]

[0064] From the above stability results, it can be seen that the amorphous form is easily degraded slowly at room temperature, rapidly degraded under high temperature and light conditions, and especially under long-term light conditions, its appearance and purity are basically destroyed, while the crystalline form can be well preserved under room temperature, high temperature and light conditions, and the difference is obvious.

[0065] Effect Example 3

[0066] Grinding experiment: the amorphous and crystalline form A were ground for 5 minutes, respectively, and then measured by XRD after adding ethanol and water to dryness, and the results were as follows:

[0067]

[0068]

[0069] From the grinding results, the amorphous form showed crystallization after grinding, indicating that it was prone to crystallization during the preparation of the powder or the granulation process.

[0070] Effect Example 4

[0071] Pharmacokinetic experiment

[0072] On the day of the experiment, the ICR mice in group A were given a single gavage of 75 mg·kg-1 of ethanesulfonate amorphous drug preparation, and the ICR mice in group B were given a single gavage of 75 mg·kg-1 of ethanesulfonate crystalline form A drug preparation. Blood samples of 0.15 mL were collected from the orbital plexus at 0.25, 0.5, 1, 2, 4, 8, 10, 12 and 24 h before and after administration, and placed in anticoagulant tubes containing EDTA-K2.

[0073] The non-compartment model in Pharsight Phoenix 7.0 was used to calculate the corresponding pharmacokinetic parameters, and the results are shown in the table below.

[0074] Pharmacokinetic parameters Unit Amorphous Crystalline form A [TECHNICAL FIELD] 1 / 2 ]] h 1.37 1.52 [TECHNICAL FIELD] max ]] h 0.500 0.610 [C max ]]> ng.mL -1 ]] 4110 3985 AUC 0-t ]] ng·h·mL -1 ]] 9660 9342

[0075] It is well known in the art that amorphous forms generally have higher energy due to their unstable form, and generally have significantly better bioavailability than crystalline forms. However, from the above results, it can be seen that the crystalline form A has similar pharmacokinetic parameters to the amorphous form, showing basically the same bioequivalence, which is unexpected.

Claims

1. A compound of formula (I) with crystal form A, characterized in that, Its X-ray powder diffraction pattern exhibits characteristic peaks at the following diffraction angles of 2θ: 6.6±0.2°, 14.6±0.2°, 16.4±0.2°, 17.6±0.2°, 19.6±0.2°, 20.3±0.2°, 20.8±0.2°, 23.0±0.2°, and 26.9±0.2°. Formula (I).

2. The crystal form A of the compound of formula (I) according to claim 1, its X-ray powder diffraction pattern also has characteristic peaks at the following diffraction angles 2θ: 22.1±0.2°, 23.3±0.2°, 25.8±0.2°, 28.2±0.2° and 29.8±0.2°.

3. The crystal form A of the compound of formula (I) according to claim 2, wherein its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 7.2±0.2°, 10.2±0.2°, 13.4±0.2°, 19.1±0.2°, 24.6±0.2°, 25.0±0.2° and 30.9±0.2°.

4. The compound of formula (I) according to any one of claims 1-3, wherein the crystal form A has an X-ray powder diffraction pattern as shown in FIG1.

5. The compound of formula (I) crystal form A according to any one of claims 1-3, having a melting point of 188ºC.

6. The DSC spectrum of the compound of formula (I) A according to claim 5 is shown in Figure 2.

7. The TGA spectrum of the compound of formula (I) A according to any one of claims 1-3 is shown in Figure 3.

8. A pharmaceutical composition comprising crystal form A of compound (I) according to any one of claims 1-7.

9. Use of the compound of formula (I) crystal form A according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating cancer.

Images