Novel Crystal Forms of Peptide Boronic Acid Compounds and Methods for Their Preparation

Abstract

The present invention provides novel crystalline forms of peptide boronic acid compounds and preparation methods thereof, specifically, three crystalline forms, namely, crystalline form A, crystalline form B and crystalline form D, and preparation methods thereof. The above three crystalline forms have stable appearance, are storage stable, suitable for the production of pharmaceutical preparations, and are simple to prepare, do not require concentration operations, have relatively high product clarity, are simple and efficient in process, are suitable for scalable production, and are environmentally friendly.

Description

Technical Field

[0001] The present invention relates to crystal forms of a drug compound, more specifically, three novel crystal forms A, B and D of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide, and a method for preparing the novel crystal forms.

Background Art

[0002] The ubiquitin-proteasome pathway (UPP) is a major pathway for intracellular protein degradation and is involved in many physiologically important cellular processes including signal transduction, immune response, unfolded protein response and cell cycle progression. This pathway is importantly related to the onset of cardiovascular diseases, cancer and neurodegenerative diseases. Proteasome inhibitors have already been used for the treatment of diseases, and in 2003, the sale of the first proteasome inhibitor was approved.

[0003] Currently, proteasome inhibitors used clinically are represented by bortezomib, carfilzomib, and ixazomib. Among them, bortezomib and carfilzomib are administered by intravenous injection and need to be implemented by professional medical staff, so it is inevitable to reduce patients' compliance and quality of life. Moreover, these two drugs show problems of safety and efficacy such as peripheral neurotoxicity, cardiotoxicity and drug resistance in clinical applications. On the other hand, ixazomib is an oral preparation, but its clinical efficacy is relatively low and combination with other drugs is required. Therefore, it is necessary to develop a new oral proteasome inhibitor that is efficient and has low toxicity.

[0004] Chinese Patent No. 112384519 discloses N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborinan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide as a proteasome inhibitor for the treatment of solid tumors and hematological tumors, which has the structure shown in Formula I below.

[0005]

Chemical Structure

[0006] Different crystalline forms of the same compound can change its physicochemical properties, resulting in, for example, different solubilities, thermodynamic stabilities, densities of different forms, or melting points. These properties directly affect the handling or preparation of the compound as a drug substance and formulation, and the physicochemical properties that affect the stability, solubility, and bioavailability of the formulation also have an important impact on the effect or bioavailability of the active ingredient. Therefore, obtaining a stable crystalline form of the compound has important significance.

Summary of the Invention

[0007] The present invention mainly provides a novel crystalline form of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborinan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide and a method for its preparation. Specifically, crystalline form A of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborinan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide is provided, and the X-ray powder diffraction pattern of the above crystalline form A has characteristic peaks at diffraction angles 2θ of 9.09, 11.30, 14.27, 17.00, 17.61, 20.28, 23.75, 24.85, 25.25, and the measurement error of 2θ is ±0.2.

[0008] The method for preparing the above crystalline form A is as follows. Step (1): Dissolve the organic base in organic solvent I, heat the temperature to 70 - 75 °C, Step (2): To the solution obtained in step (1), at a temperature controlled at 70 - 75 °C, dropwise add ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid / organic solvent I solution, Step (3): After completion of the dropping, lower the temperature to 60 °C, stir for 2 hours, then lower the temperature to 20 - 25 °C, stir for 8 hours, filter, and dry to obtain a mixed crystal solid, Step (4): Dissolve the above mixed crystal solid in organic solvent II, stir at 25 - 35 °C for 2 hours, heat the temperature to 55 - 65 °C and stir for 2 hours, maintain a heating rate of 15 °C / hour, stir at 25 - 35 °C for 2 hours, maintain a cooling rate of 15 °C / hour, and crystallize, Step (5): Filter and dry to obtain the above crystal form A.

[0009] In the above method, the organic base is selected from diethanolamine, ethanolamine, or ethylenediamine, Solvent I or II is selected from ethyl acetate, dichloromethane, a ketone solvent, an ether solvent, an alcohol solvent, a nitrile solvent, or a mixture thereof, The volume - mass ratio of solvent I to the organic base is 15 - 45:1 in mL / g unit, The volume - mass ratio of solvent II to the mixed crystal solid is 5 - 15:1 in mL / g unit, In the ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid / organic solvent I solution, the volume - mass ratio of the organic solvent I solution to ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid is 1 - 5:1 in mL / g unit.

[0010] Provided is crystal form B of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide. The X-ray powder diffraction pattern of the above crystal form B has peaks characteristic of diffraction angles 2θ of 8.44, 14.39, 15.08, 16.98, 19.76, 22.17, 22.41, 22.53, 25.62, and the measurement error of 2θ is ±0.2.

[0011] The preparation method of the above crystal form B is as follows. Step (1): Dissolve the crystal form A described in claim 1 in organic solvent III, and stir at 60 °C until it becomes clear. Step (2): Drop an appropriate amount of solvent IV into the solution obtained in step (1), perform crystallization, filtration, and drying to obtain the above crystal form B.

[0012] In the above method, solvent III and solvent IV are independently selected from dimethylformamide, petroleum ether, ketone solvents, ether solvents, alcohol solvents, nitrile solvents, or mixtures thereof. The volume-mass ratio of solvent III to the raw material of crystalline A is 5 - 30:1 in mL / g units. The volume-mass ratio of solvent IV to the raw material of crystalline A is 80 - 120:1 in mL / g units.

[0013] Provided is crystal form D of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide. The X-ray powder diffraction pattern of the above crystal form D has peaks characteristic of diffraction angles 2θ of 6.88, 8.26, 9.15, 11.47, 13.82, 16.61, 18.39, 19.64, 20.80, and is characterized in that the measurement error of 2θ is ±0.2.

[0014] The preparation method of the above crystal form D is as follows. Step (1): Dissolve the crystalline form A according to claim 1 in an organic solvent V, stir at 60 °C for 5 hours, and perform crystallization. Step (2): Filter and dry to obtain crystalline form D thereby.

[0015] The above solvent V is selected from dimethylformamide, petroleum ether, ketone solvents, ether solvents, alcohol solvents, nitrile solvents, or mixtures thereof. Further, the volume-mass ratio of solvent V to the raw material of crystalline form A is 5 to 15:1 in mL / g units.

[0016] The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable vector and a combination of one or more crystals selected from the group consisting of the following. (a) Crystalline form A according to the present invention, (b) Crystalline form B according to the present invention, (c) Crystalline form D according to the present invention.

[0017] Crystalline form A or crystalline form B or crystalline form D of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide, which is a compound of formula I disclosed in the present invention, is used in the preparation of drugs for the prevention or treatment of solid tumors and hematological tumors. The above solid tumors include non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, or hypopharyngeal cancer. The above hematological tumor diseases include leukemia, multiple myeloma, mantle cell lymphoma, or histiocytic lymphoma.

[0018] Crystalline form A or crystalline form B or crystalline form D of the compound of formula I disclosed in the present invention can be administered alone or in combination with other drugs effective for the treatment of such diseases for the prevention and treatment of solid tumors and hematological tumor diseases.

[0019] The present invention further provides a pharmaceutical composition for preventing or treating the above-mentioned solid tumor and hematological tumor diseases, which comprises a therapeutically effective amount of crystalline form A or crystalline form B or crystalline form D of the compound of formula I disclosed in the present invention and a pharmaceutically acceptable carrier. The above-mentioned pharmaceutical composition can usually be tablets, sustained-release tablets, controlled-release tablets, capsules, granules, powders, oral liquids or injections.

[0020] The three crystalline forms provided by the present invention have relatively high solubility, good stability, are advantageous for long-term storage and preservation of drugs, are suitable for the preparation of pharmaceutical preparations, and have a simple preparation method, good reproducibility, high yield, avoid the use of concentration operations, have relatively high clarity of the product, the process is simple and efficient, can be mass-produced, and is environmentally friendly.

Brief Description of the Drawings

[0021]

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Best Mode for Carrying Out the Invention

[0022] Hereinafter, with reference to specific examples, based on general technical knowledge and ordinary means in the art, the present invention will be further described. The following examples are only a part of the preferred embodiments of the present invention and should not be construed as limiting the present invention. Those skilled in the art can make some modifications without departing from the scope of the present invention, and these should also be construed as being within the protection scope of the present invention.

[0023] Example 1: Preparation of Crystal Form A 40 g of diethanolamine and 1.20 L of ethyl acetate were added to a reaction kettle, heated to 70 °C and dissolved. While controlling the temperature of the system at 70 °C, a solution of ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid / ethyl acetate (prepared by dissolving 150 g of ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid in 0.3 L of ethyl acetate solution) was added dropwise. After the addition was completed, the temperature was lowered to 60 °C, stirred at 60 °C for 2 hours, then lowered to 25 °C, and stirred at 25 °C for 8 hours while controlling the temperature at 25 °C. Filtration was carried out, and the filter cake was dried to obtain 147 g of a white mixed crystal solid. The X-ray powder diffraction pattern thereof is shown in Figure 1.

[0024] 5 g of the mixed crystal solid sample obtained above and 50 mL of acetonitrile were added to a reaction kettle, stirred at 30 °C for 2 hours, then heated to 60 °C, and slurried for 2 hours while maintaining a heating rate of 15 °C / hour. Further, the temperature was lowered to 30 °C and slurried, and slurried for 2 hours while maintaining a cooling rate of 15 °C / hour. Filtration was carried out, and drying was carried out at 35 °C to obtain 4.8 g of a white solid, namely crystal form A. The X-ray powder diffraction pattern thereof is shown in Figure 2, the DSC pattern is shown in Figure 3, and the infrared pattern is shown in Figure 4.

[0025] Example 2: Preparation of Crystal Form B 1 g of a sample of Crystal A and 20 mL of N,N-dimethylformamide were added to a reaction kettle and heated to 65 °C for dissolution. 100 mL of petroleum ether was added dropwise for crystallization and dried at 35 °C to obtain 0.72 g of a white solid, namely Crystal B. Its X-ray powder diffraction pattern is shown in Figure 5, the DSC pattern is shown in Figure 6, and the infrared pattern is shown in Figure 7.

[0026] Example 3: Preparation of Crystal Form D 1 g of a sample of Crystal A and 10 mL of tetrahydrofuran were added to a reaction kettle and heated to 60 °C and stirred for 5 hours. It was filtered and dried at 25 °C to obtain 0.85 g of a white solid, namely Crystal D. Its X-ray powder diffraction pattern is shown in Figure 8, the DSC pattern is shown in Figure 9, and the infrared pattern is shown in Figure 10.

[0027] Example 4: Samples of the mixed crystal sample of Example 1, the sample of Crystal Form A, the sample of Crystal Form B of Example 2, and the sample of Crystal Form D of Example 3, which were batch-produced of the four crystal forms, were taken for solubility tests and kinetic solubility tests in ultrapure water, and the solubility test results are shown in Table 1 and Table 2. Thereby, it was found that the mixed crystal, Crystal Forms A, B, and D of Compound I showed excellent solubility.

[0028] [Table 1]

[0029] [Table 2]

[0030] Example 5: Samples of the mixed crystal sample of Example 1, the sample of Crystal Form A, the sample of Crystal Form B of Example 2, and the sample of Crystal Form D of Example 3, which were batch-produced of the four crystal forms, were taken for a hygroscopicity test in the process where the relative humidity changed from 0% to 80% RH at 25 °C. Thereby, it was found that Crystal Forms A and B of Compound I were relatively less hygroscopic than Crystal Form D and were more suitable for the preparation of solid preparations.

[0031]

Table 3

[0032] Example 6: Stability Test of Different Crystal Forms of Compound I Samples of the mixed crystal sample of Example 1, the sample of Crystal Form A, the sample of Crystal Form B of Example 2, and the sample of Crystal Form D of Example 3, which were batch-produced, were taken, and were sampled at each time point of 0 day, 5 days, and 10 days under the conditions of high temperature (60 °C, dark place), high humidity (relative humidity 90% ± 5%, dark place), and light illumination (4500 lx ± 500 lx), and HPLC measurement and stability influencing factor test were carried out. The results are shown in Table 4 below. During the 10-day test period, the change in the content of the mixed crystal sample of Example 1 was relatively large under high humidity conditions and was unstable. The samples of Crystal Forms A, B, and D showed no obvious change in content, no change in crystal form, and stable quality during the 10-day test period.

[0033]

Table 4

Claims

1. Crystals of crystalline form A of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide, wherein the X-ray powder diffraction pattern of the crystals of crystalline form A has peaks characteristic of diffraction angles 2θ of 9.09, 11.30, 14.27, 17.00, 17.61, 20.28, 23.75, 24.85, 25.25, and the measurement error of 2θ is ±0.

2. Crystals of crystalline form A, characterized by the above.

2. Crystals of crystalline form B of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide, wherein the X-ray powder diffraction pattern of the crystals of crystalline form B has peaks characteristic of diffraction angles 2θ of 8.44, 14.39, 15.08, 16.98, 19.76, 22.17, 22.41, 22.53, 25.62, and the measurement error of 2θ is ±0.

2. Crystals of crystalline form B, characterized by the above.

3. Crystals of crystalline form D of N-((R)-1-(((R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl)amino)-3-(methylthio)-1-oxopropyl-2-yl)-2,5-dichlorobenzamide, wherein the X-ray powder diffraction pattern of the crystals of crystalline form D has peaks characteristic of diffraction angles 2θ of 6.88, 8.26, 9.15, 11.47, 13.82, 16.61, 18.39, 19.64, 20.80, and the measurement error of 2θ is ±0.

2. Crystals of crystalline form D, characterized by the above.

4. A pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and (a) the crystals of crystalline form A according to Claim 1, (b) the crystals of crystalline form B according to Claim 2, and (c) the crystals of crystalline form D according to Claim 3 in a combination of one or more crystals selected from the group consisting of and is characterized by the above. A pharmaceutical composition.

5. A method for preparing the crystals of crystalline form A according to Claim 1, comprising Step (1) of dissolving an organic base in organic solvent I and heating the solution to 70 - 75°C. Step (2) of dropping a solution of ((R)-1-((R)-2-(2,5-dichlorobenzoylamino)-3-(methylthio)propionamide)-3-methylbutyl)boronic acid / organic solvent I into the solution obtained in step (1) at a temperature controlled to 70 to 75 °C, Step (3) of cooling to 60 °C after completion of dropping, stirring for 2 hours, cooling to 20 to 25 °C, stirring for 8 hours, filtering, and drying to obtain a mixed crystal solid, Step (4) of dissolving the mixed crystal solid in organic solvent II, stirring at 25 to 35 °C for 2 hours, heating to 55 to 65 °C and stirring for 2 hours, maintaining a heating rate of 15 °C / hour, stirring at 25 to 35 °C for 2 hours, maintaining a cooling rate of 15 °C / hour, and crystallizing, Step (5) of filtering and drying to thereby obtain the crystals of crystal form A, including, Among them, the organic base is selected from diethanolamine, ethanolamine, or ethylenediamine, Solvent I is ethyl acetate, and solvent II is acetonitrile, The volume-mass ratio of solvent I to the organic base is 15 to 45:1 in mL / g units, The volume-mass ratio of solvent II to the mixed crystal solid is 5 to 15:1 in mL / g units, A preparation method characterized by this.

6. A method for preparing crystals of crystal form B according to claim 2, Step (1) of dissolving the crystals of crystal form A according to claim 1 in organic solvent III and stirring at 60 °C until clear, Step (2) of dropping an appropriate amount of solvent IV into the solution obtained in step (1), crystallizing, filtering, and drying to thereby obtain the crystals of crystal form B, including, Among them, solvent III is dimethylformamide, and solvent IV is petroleum ether, The volume-mass ratio of solvent III to the raw material of the crystals of crystal form A is 5 to 30:1 in mL / g units, The volume-mass ratio of solvent IV to the raw material of the crystals of crystal form A is 80 to 120:1 in mL / g units, A preparation method characterized by this.

7. A method for preparing crystals of crystal form D according to claim 3, Step (1) of dissolving the crystals of crystal form A according to claim 1 in organic solvent V and stirring at 60 °C for 5 hours and crystallizing, Step (2) of filtering and drying to thereby obtain the crystals of crystal form D, including, Among them, solvent V is tetrahydrofuran, The volume-mass ratio of solvent V to the raw material of the crystals of crystal form A is 5 to 15:1 in mL / g units, A preparation method characterized by this.

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