Evobrutinib Compound Salt Forms and Their Preparation Methods

Abstract

The present invention relates to a crystal form of Compound I mesylate and a preparation method thereof. The crystal form of Compound I mesylate provided by the present invention has stable physicochemical properties, can be stored stably for a long time, and has a simple preparation method with good repeatability, which has important practical application value for the future development of this drug.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, it relates to the salt crystal forms of Evobrutinib compound and methanesulfonic acid and their preparation methods. Background Art

[0002] Evobrutinib is an investigational, oral, highly selective Bruton's tyrosine kinase (BTK) inhibitor with potential anti-tumor activity. After administration, Evobrutinib can inhibit the activity of BTK and the activation of the B cell antigen receptor (BCR) signaling pathway. This prevents the activation of B cells and the activation of the downstream survival pathway mediated by BTK, thereby inhibiting the growth of malignant B cells overexpressing BTK. BTK is a member of the BTK / Tec family of cytoplasmic tyrosine kinases and is overexpressed in B cell malignancies; it plays an important role in the development, activation, signal transduction, proliferation, and survival of B lymphocytes.

[0003] The chemical name of the Evobrutinib compound is 1-[4-[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one (hereinafter referred to as "Compound I"), and its structural formula is as follows:

[0004]

[0005] Nearly half of drug molecules exist and are administered in the form of salts. Salt formation can improve some undesirable physicochemical or biopharmaceutical properties of drugs, such as changing the solubility or dissolution rate of drugs, reducing hygroscopicity, enhancing stability, altering the melting point, improving grinding performance, facilitating preparation and purification, improving permeability, etc. It is very necessary to select a suitable salt form for drug development. At the same time, a salt form may have multiple crystal forms. Different crystal forms have different melting points, solubilities, dissolution properties, chemical stabilities, mechanical stabilities, etc. These physicochemical properties sometimes directly affect the effectiveness and processing performance of drugs. Therefore, comprehensive and systematic salt form screening and crystal form screening in drug research and development, and selecting the most suitable salt form and its crystal form for development, is one of the important research contents that cannot be ignored.

[0006] Some crystalline forms of the compound of formula (I) have been reported. The original research company reported the malonate NF1, succinate NF1, oxalate NF1, fumarate NF1, maleate NF1, and citrate NF1 of compound I in US10464923B2. It is described in this patent text that the solubility of the above salt forms in FaSSIF and FeSSIF is improved to a certain extent compared with the free crystalline form A1. However, in order to further improve the solubility of compound I in different media, thereby improving bioavailability and drug efficacy, it is very necessary to screen and select more salt forms and crystalline forms of compound I with excellent properties, so as to provide new choices for the industrial production of this drug, which has important practical significance.

[0007] During the experiment, the inventors of the present application surprisingly found that compound I and methanesulfonic acid can exist stably in the form of a salt, which has advantages in terms of physicochemical properties, formulation processing performance, and bioavailability, etc. For example, it has advantages in at least one aspect among melting point, solubility, hygroscopicity, purification effect, stability, adhesiveness, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc., providing a better choice for the development of drugs containing compound I, and having very important practical application value. Summary of the Invention

[0008] The main object of the present invention is to provide a salt form crystalline form of compound I and methanesulfonic acid and its preparation method.

[0009] According to the object of the present invention, the present invention provides a salt form crystalline form of compound I and methanesulfonic acid.

[0010] Furthermore, the present invention provides that the salt form of compound I and methanesulfonic acid is crystalline form DCI (hereinafter referred to as salt form DCI).

[0011] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the salt form DCI has characteristic peaks at 1, or 2, or 3 of the diffraction angle 2θ values of

[0012] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction of the salt form DCI has characteristic peaks at 1, or 2, or 3 of the diffraction angle 2θ values of ; preferably, the X-ray powder diffraction of the salt form DCI has characteristic peaks at 3 of the diffraction angle 2θ values of

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction of the salt form DCI has diffraction angle 2θ values of There are characteristic peaks at 1, or 2, or 3 positions; preferably, the X-ray powder diffraction of the salt form DCI has characteristic peaks at 3 positions when the diffraction angle 2theta value is There are characteristic peaks at 3 positions.

[0014] Non-limitingly, the X-ray powder diffraction pattern of the salt form DCI is basically as Figure 1 shown.

[0015] Non-limitingly, an endothermic peak starts to appear near 191 °C for the salt form DCI, and the differential scanning calorimetry diagram is basically as Figure 2 shown.

[0016] Non-limitingly, the 1 1H NMR of the salt form DCI is basically as Figure 3 shown.

[0017] For the purpose of the present invention, the present invention also provides a preparation method of the salt form DCI, and the preparation method includes:

[0018] Adding the solid of compound I and methanesulfonic acid into a vial according to a molar ratio of 1:(0.66 - 1.5), then adding a ketone or ester solvent, stirring for 12 - 72 hours, separating and drying to obtain the salt form crystal DCI of compound I and methanesulfonic acid.

[0019] Further, the selected ketone is preferably acetone; the selected ester is preferably ethyl acetate; the stirring temperature is preferably -20 °C to 60 °C, more preferably 30 °C; the drying condition is preferably 20 °C to 50 °C; the separation is centrifugation or filtration.

[0020] The salt form DCI provided by the present invention has the following beneficial effects:

[0021] 1) The salt form DCI provided by the present invention has good stability.

[0022] Under the conditions of 25°C / 60% RH (relative humidity) and 40°C / 75% RH, the salt form of DCI of the present invention was placed in a closed environment for 3 months respectively, and its crystal form remained unchanged. This indicates that the salt form of DCI has good physical stability. Especially under the accelerated condition of 40°C / 75% RH, after being placed for 3 months, the crystal form still remains stable and no crystal transformation occurs. This further demonstrates that the salt form of DCI still has good physical stability even under high temperature and high humidity conditions, which ensures that the drug is not prone to crystal transformation during subsequent processes, production, and transportation. In addition, before and after being placed under the condition of 25°C / 60% RH (relative humidity), the chemical purity of the salt form of DCI did not change, and the purity remained above nearly 99%, indicating that the salt form of DCI has good chemical stability. Moreover, even under the accelerated condition of 40°C / 75% RH, the chemical purity did not show an obvious decrease. This further illustrates that the salt form of DCI has good chemical stability. Good physical and chemical stability ensures that the drug can maintain quality stability during subsequent formulation development, process production, as well as drug production and transportation, ensuring the quality and efficacy of the drug, which is of great significance.

[0023] In addition, the salt form of DCI has better mechanical stability. Before and after grinding, the salt form of DCI did not undergo crystal transformation, and no obvious decrease in the crystallinity of the sample was observed. However, after grinding the free base crystal form A2, the crystallinity decreased significantly. This shows that the salt form of DCI has better mechanical stability. Good mechanical stability can ensure that the sample will not easily undergo crystal transformation due to external forces such as mechanical grinding and crushing during the subsequent formulation process, reducing the risk of crystal transformation during the formulation process and improving the developability of the formulation process.

[0024] Crystal form stability is of great significance for drug development. If crystal transformation occurs, it will directly affect the solubility of the drug and thus affect the bioavailability of the drug, thereby changing the efficacy of the drug. Good chemical stability can ensure that almost no new impurities are generated or the impurity content hardly increases during the storage of the drug, thus ensuring the safety of the drug. Good mechanical stability can also improve the drug's resistance to mechanical damage during the formulation process and reduce the risk of crystal transformation. Therefore, the good physical and chemical stability, as well as good mechanical stability of the salt form of DCI, provide guarantees for the subsequent production and development of drugs and have high industrial development value.

[0025] 2) The salt form of DCI of the present invention has low hygroscopicity.

[0026] According to the method in the Pharmacopoeia (General Principles 9103 Hygroscopicity Test of Drugs in Chinese Pharmacopoeia 2020 Edition, test conditions: 25 ± 1 °C, 80% relative humidity), the hygroscopicity of salt form DCI of the present invention was investigated. The results showed that the weight gain due to hygroscopicity of salt form DCI was 0.7%. In addition, regarding the description of hygroscopicity characteristics and the definition of weight gain due to hygroscopicity (General Principles 9103 Hygroscopicity Test of Drugs in Chinese Pharmacopoeia 2020 Edition, test conditions: 25 ± 1 °C, 80% relative humidity) principle, the weight gain range of salt form DCI was: the weight gain due to hygroscopicity was less than 2.0% but not less than 0.2%, belonging to slightly hygroscopic. This result indicates that salt form DCI has low hygroscopicity. Low hygroscopicity can ensure that the sample can maintain a low weight gain due to hygroscopicity without deliquescence during the subsequent production, processing, storage and transportation processes, thus ensuring the stable quality of the drug.

[0027] In the present invention, the "stirring" is completed by a conventional method in the art, such as magnetic stirring or mechanical stirring. The stirring speed is 50 - 1800 revolutions per minute. Among them, magnetic stirring is preferably 300 - 900 revolutions per minute, and mechanical stirring is preferably 100 - 300 revolutions per minute.

[0028] The "separation" is completed by a conventional method in the art, such as centrifugation or filtration. The operation of "centrifugation" is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10000 revolutions per minute until all the solids sink to the bottom of the centrifuge tube.

[0029] The "drying" can be carried out at room temperature or a higher temperature. The drying temperature is from room temperature to about 50 °C, or to 40 °C. The drying time can be 2 - 48 hours, or overnight. The drying is carried out in a fume hood, a forced-air oven or a vacuum oven.

[0030] In the present invention, "crystal" or "polymorph" refers to a solid characterized by an X-ray powder diffraction pattern. Those skilled in the art can understand that the physicochemical properties discussed here can be characterized, and the experimental errors therein depend on the instrument conditions, sample preparation, and sample purity. In particular, as is well known to those skilled in the art, the X-ray powder diffraction pattern usually varies with different instrument conditions. It should be particularly noted that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also change with the experimental conditions. Therefore, the order of the diffraction peak intensities cannot be used as the sole or decisive factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown in the present invention are illustrative rather than for absolute comparison. In addition, the experimental error of the diffraction peak positions is usually 5% or less, and the errors at these positions should also be taken into account, usually allowing an error of ±0.2. In addition, due to the influence of experimental factors such as sample thickness, an overall shift in the diffraction peak angle will occur, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the examples referred to here. Any crystal form with an X-ray powder diffraction pattern having the same or similar characteristic peaks as those in these spectra falls within the scope of the present invention.

[0031] Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0032] In some embodiments, the salt form DCI of the present invention is pure and substantially free of any other crystal forms. In the present invention, "substantially free of" when referring to a new crystal form means that this crystal form contains less than 20% (by weight) of other crystal forms, especially less than 10% (by weight) of other crystal forms, more especially less than 5% (by weight) of other crystal forms, and even more especially less than 1% (by weight) of other crystal forms.

[0033] In the present invention, the term "about", when used to refer to measurable values such as mass, time, temperature, etc., means a certain floating range around the specific value, and this range can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 XRPD pattern of the salt form DCI obtained according to Example 1.

[0035] Figure 2 DSC pattern of the salt form DCI obtained according to Example 1.

[0036] Figure 3 For the salt form DCI obtained according to Example 1 11H NMR spectrum.

[0037] Figure 4 Overlay XRPD patterns of salt form DCI before and after stability study (from top to bottom: starting crystal form, stored at 25 °C / 60% RH for 3 months, stored at 40 °C / 75% RH for 3 months).

[0038] Figure 5 Overlay XRPD patterns of salt form DCI before and after grinding (the upper curve is the pattern before grinding, and the lower curve is the pattern after grinding).

[0039] Figure 6 Overlay XRPD patterns of two samples in Example 1.

[0040] Figure 7 Overlay XRPD patterns of free base crystal form A2 before and after grinding (the upper curve is the pattern before grinding, and the lower curve is the pattern after grinding). Detailed Description of the Invention

[0041] The present invention will be described in detail with reference to the following examples, which describe in detail the preparation and use methods of the crystal forms of the present invention. It will be apparent to those skilled in the art that many changes to both materials and methods can be made without departing from the scope of the present invention.

[0042] The explanations of the abbreviations used in the present invention are as follows:

[0043] XRPD: X-ray powder diffraction

[0044] DSC: Differential scanning calorimetry

[0045] Instruments and methods for collecting data:

[0046] The X-ray powder diffraction patterns described in the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer.

[0047] The method parameters for the X-ray powder diffraction described in the present invention are as follows:

[0048] X-ray source: Cu Kα

[0049] Kα1(Å): 1.54060; Kα2(Å) 1.54439

[0050] Kα2 / Kα1 intensity ratio: 0.50

[0051] Voltage: 30 kilovolts (kV)

[0052] Current: 10 milliamperes (mA)

[0053] Scanning range: from 3.0 to 40.0 degrees

[0054] The differential scanning calorimetry (DSC) graph of the present invention was collected on a Mettler DSC3, and the method parameters of differential scanning calorimetry (DSC) are as follows:

[0055] Scanning rate: 10 °C / min

[0056] Protective gas: nitrogen

[0057] HPLC purity test method:

[0058] Solution preparation: Take about 1 mg of the sample and dissolve it in 1 ml of acetonitrile. That's it.

[0059]

[0060] Remarks: Integrals are not taken for purity below 0.05%.

[0061] Unless otherwise specified, the following examples are all operated at room temperature. The "room temperature" here does not refer to a specific temperature value, but refers to the temperature range of 10 - 30 °C.

[0062] According to the present invention, the compound I and / or its salt as the raw material include, but are not limited to, solid forms (crystalline or amorphous), oily, liquid forms, and solutions. Preferably, the compound I and / or its salt as the raw material is in solid form.

[0063] The compound I used in the following examples can be prepared according to the method described in Patent CN106831732B.

[0064] Example 1: Preparation method of salt form DCI

[0065] Weigh about 50 mg of compound I and about 9 mg of methanesulfonic acid and add them to a 3 - ml vial. Then add the solvent (see Table 1 for details) to obtain a suspension. The suspension is stirred at room temperature for 72 hours, and the solid is separated by centrifugation and dried. After XRPD detection, the obtained solid is the crystal form DCI shown in the present invention.

[0066] Table 1

[0067] Table 1

[0068]

[0069] In the following (including Examples 2 - 4), taking Sample 1 in Example 1 as an example, the present invention will be described; similar results can also be obtained for Sample 2. To avoid redundancy, it will be omitted.

[0070] Select the XRPD graph of the salt form DCI obtained from Sample 1 in Example 1 as Figure 1As shown, the XRPD data is shown in Table 2. The XRPD pattern of the salt form DCI obtained from Sample 2 is as Figure 6 shown.

[0071] The DSC of Sample 1 is as Figure 2 shown, and an endothermic peak starts to appear when heated to around 191 °C.

[0072] Table 2

[0073]

[0074]

[0075] The NMR spectrum of Sample 1 is as Figure 3 shown, and the specific data is as follows:

[0076] 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, -1H), 8.29 (s, 1H), 7.43–7.39 (m, 2H), 7.24–7.20 (m, 2H), 7.18–7.08 (m, 5H), 7.01 (t, J = 6.0 Hz, 1H), 6.83 (s, 2H), 6.73 (dd, J = 16.7, 10.5 Hz, 1H), 6.02 (dd, J = 16.7, 2.4 Hz, 1H), 5.60 (dd, J = 10.5, 2.4 Hz, 1H), 4.32 (d, J = 12.6 Hz, 1H), 3.97 (d, J = 13.3 Hz, 1H), 3.18 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 12.8 Hz, 1H), 2.53 (t, J = 12.9 Hz, 1H), 2.28 (s, 3H), 1.78 (ddt, J = 10.8, 7.2, 3.5 Hz, 1H), 1.57 (d, J = 12.6 Hz, 2H), 0.93 (p, J = 11.4 Hz, 2H).

[0077] Example 2: Stability of Salt Form DCI

[0078] Weigh approximately 5 mg of each portion of the salt form DCI prepared in the present invention, for a total of 2 portions. After determining the initial purity and crystal form by HPLC and XRPD, they are sealed in aluminum foil bags and placed under the conditions of 25 °C / 60% RH and 40 °C / 75% RH for a period of time, and then the purity and crystal form are determined by HPLC and XRPD again. The experimental results are shown in Table 3 below, and the XRPD overlay pattern is as Figure 4 shown.

[0079] Table 3

[0080] Placement conditions Placement time Crystal form Purity Start —— Salt form DCI 99.34％ 25°C / 60% RH 3 months Salt form DCI 99.26％ 40°C / 75% RH 3 months Salt form DCI 99.08％

[0081] The results show that the salt form of DCI of the present invention can maintain physical and chemical stability for at least 3 months under two conditions of 25°C / 60% RH and 40°C / 75% RH.

[0082] Example 3: Mechanical stability of the salt form of DCI

[0083] Place about 10 mg of the salt form of DCI in a mortar and manually grind it for 5 minutes. Conduct XRPD tests before and after grinding. The comparison of XRPD before and after grinding is as Figure 5 shown. The results show that the crystal form of the salt form of DCI of the present invention remains unchanged after grinding, and no obvious decrease in crystallinity is observed, indicating that the salt form of DCI has good mechanical stability.

[0084] Place about 10 mg of Merck evobrutinib crystalline free base form A2 (US20190010142A1) in a mortar and manually grind it for 5 minutes. Conduct XRPD tests before and after grinding. The comparison of XRPD before and after grinding is as Figure 7 shown. The results show that the crystal form of Merck evobrutinib crystalline free base form A2 remains unchanged after grinding, but there is a relatively obvious decrease in crystallinity.

[0085] The above shows that the salt form of DCI has better mechanical stability.

[0086] Example 4: Hygroscopicity of the salt form of DCI

[0087] Weigh about 30 mg of the salt form of DCI of the present invention and place it under the conditions of 25 ± 5°C and 80% relative humidity for 24 hours. Record the mass of the sample before and after. The specific results are shown in Table 4 below.

[0088] Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (General Principles of Pharmaceutical Hygroscopicity Experiment, 2020 Edition of the Chinese Pharmacopoeia, experimental conditions: 25 ± 1°C, 80% relative humidity, 24 hours):

[0089] Deliquescence: Absorbing sufficient moisture to form a liquid

[0090] Highly hygroscopic: Hygroscopic weight gain not less than 15.0%

[0091] Hygroscopic: Hygroscopic weight gain less than 15.0% but not less than 2.0%

[0092] Slightly hygroscopic: Hygroscopic weight gain less than 2.0% but not less than 0.2%

[0093] Non-hygroscopic or almost non-hygroscopic: Hygroscopic weight gain less than 0.2%.

[0094] Table 4

[0095]

[0096] The results show that the salt form of DCI of the present invention has slightly hygroscopic property and the hygroscopicity is small, indicating that the salt form of DCI is not prone to deliquescence during drug production and storage.

[0097] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. It should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. Compound I The crystal form of its mesylate; Characterized in that, The crystal form of the mesylate of Compound I is crystal form DCI; using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 21.6°±0.2°, 18.3°±0.2°, 7.5°±0.2°, 20.3°±0.2°, 15.6°±0.2°, 26.3°±0.2°, 27.4°±0.2°.

2. The crystal form of the mesylate of Compound I according to claim 1, Characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at 2θ value of 24.0°±0.2°.

3. The crystal form of the mesylate of Compound I according to claim 1, Characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at 2θ value of 17.3°±0.2°.

4. A method for preparing the crystal form of the mesylate of Compound I according to claim 1, Characterized in that: Mix the solid of Compound I, methanesulfonic acid with a solvent; the solvent is a ketone or an ester solvent; stir for 12 to 72 hours, separate and dry to obtain the crystal form DCI of the mesylate of Compound I.

5. The preparation method according to claim 4, Characterized in that, Add the solid of Compound I and methanesulfonic acid into a vial according to a molar ratio of 1:(0.66 to 1.5), then add a ketone or an ester solvent, stir for 12 to 72 hours, separate and dry to obtain the crystal form DCI of the mesylate of Compound I.

6. The preparation method according to claim 4, Characterized in that, The selected ketone is acetone; the selected ester is ethyl acetate; the stirring temperature is -20°C to 60°C; the drying condition is 20°C to 50°C; the separation is centrifugation or filtration.

7. The preparation method according to claim 4, Characterized in that, The stirring temperature is 30°C.

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